Beardsley, Justin; Wolbers, Marcel; Kibengo, Freddie M; Ggayi, Abu-Baker M; Kamali, Anatoli; Cuc, Ngo Thi Kim; Binh, Tran Quang; Chau, Nguyen Van Vinh; Farrar, Jeremy; Merson, Laura; Phuong, Lan; Thwaites, Guy; Van Kinh, Nguyen; Thuy, Pham Thanh; Chierakul, Wirongrong; Siriboon, Suwatthiya; Thiansukhon, Ekkachai; Onsanit, Satrirat; Supphamongkholchaikul, Watthanapong; Chan, Adrienne K; Heyderman, Robert; Mwinjiwa, Edson; van Oosterhout, Joep J; Imran, Darma; Basri, Hasan; Mayxay, Mayfong; Dance, David; Phimmasone, Prasith; Rattanavong, Sayaphet; Lalloo, David G; Day, Jeremy N
Cryptococcal meningitis associated with human immunodeficiency virus (HIV) infection causes more than 600,000 deaths each year worldwide. Treatment has changed little in 20 years, and there are no imminent new anticryptococcal agents. The use of adjuvant glucocorticoids reduces mortality among patients with other forms of meningitis in some populations, but their use is untested in patients with cryptococcal meningitis. In this double-blind, randomized, placebo-controlled trial, we recruited adult patients with HIV-associated cryptococcal meningitis in Vietnam, Thailand, Indonesia, Laos, Uganda, and Malawi. All the patients received either dexamethasone or placebo for 6 weeks, along with combination antifungal therapy with amphotericin B and fluconazole. The trial was stopped for safety reasons after the enrollment of 451 patients. Mortality was 47% in the dexamethasone group and 41% in the placebo group by 10 weeks (hazard ratio in the dexamethasone group, 1.11; 95% confidence interval [CI], 0.84 to 1.47; P=0.45) and 57% and 49%, respectively, by 6 months (hazard ratio, 1.18; 95% CI, 0.91 to 1.53; P=0.20). The percentage of patients with disability at 10 weeks was higher in the dexamethasone group than in the placebo group, with 13% versus 25% having a prespecified good outcome (odds ratio, 0.42; 95% CI, 0.25 to 0.69; P<0.001). Clinical adverse events were more common in the dexamethasone group than in the placebo group (667 vs. 494 events, P=0.01), with more patients in the dexamethasone group having grade 3 or 4 infection (48 vs. 25 patients, P=0.003), renal events (22 vs. 7, P=0.004), and cardiac events (8 vs. 0, P=0.004). Fungal clearance in cerebrospinal fluid was slower in the dexamethasone group. Results were consistent across Asian and African sites. Dexamethasone did not reduce mortality among patients with HIV-associated cryptococcal meningitis and was associated with more adverse events and disability than was placebo. (Funded by the United Kingdom
Bollela, V R; Frigieri, G; Vilar, F C; Spavieri, D L; Tallarico, F J; Tallarico, G M; Andrade, R A P; de Haes, T M; Takayanagui, O M; Catai, A M; Mascarenhas, S
Mortality and adverse neurologic sequelae from HIV-associated cryptococcal meningitis (HIV-CM) remains high due to raised intracranial pressure (ICP) complications. Cerebrospinal fluid (CSF) high opening pressure occurs in more than 50% of HIV-CM patients. Repeated lumbar puncture with CSF drainage and external lumbar drainage might be required in the management of these patients. Usually, there is a high grade of uncertainty and the basis for clinical decisions regarding ICP hypertension tends to be from clinical findings (headache, nausea and vomiting), a low Glasgow coma scale score, and/or fundoscopic papilledema. Significant neurological decline can occur if elevated CSF pressures are inadequately managed. Various treatment strategies to address intracranial hypertension in this setting have been described, including: medical management, serial lumbar punctures, external lumbar and ventricular drain placement, and either ventricular or lumbar shunting. This study aims to evaluate the role of a non-invasive intracranial pressure (ICP-NI) monitoring in a critically ill HIV-CM patient.
Nyazika, Tinashe K; Hagen, Ferry; Machiridza, Tendai; Kutepa, Melody; Masanganise, Faith; Hendrickx, Marijke; Boekhout, Teun; Magombei-Majinjiwa, Tricia; Siziba, Nonthokozo; Chin'ombe, Nyasha; Mateveke, Kudzanai; Meis, Jacques F; Robertson, Valerie J
HIV and cryptococcal meningitis co-infection is a major public health problem in most developing countries. Cryptococcus neoformans sensu stricto is responsible for the majority of HIV-associated cryptococcosis cases in sub-Saharan Africa. Despite the available information, little is known about cryptococcal population diversity and its association with clinical outcomes in patients with HIV-associated cryptococcal meningitis in sub-Saharan Africa. In a prospective cohort, we investigated the prevalence and clinical outcome of Cryptococcusneoformans sensu stricto meningitis among HIV-infected patients in Harare, Zimbabwe, and compared the genotypic diversity of the isolates with those collected from other parts of Africa. Molecular typing was done using amplified fragment length polymorphism genotyping and microsatellite typing. The majority of patients with HIV-associated Cryptococcusneoformans sensu stricto meningitis in this cohort were males (n=33/55; 60.0 %). The predominant Cryptococcus neoformans sensu stricto genotype among the Zimbabwean isolates was genotype AFLP1/VNI (n=40; 72.7 %), followed by AFLP1A/VNB/VNII (n=8; 14.6 %), and AFLP1B/VNII was the least isolated (n=7; 12.7 %). Most of the isolates were mating-type α (n=51; 92.7 %), and only four (7.3 %) were mating-type a. Overall in-hospital mortality was 55.6 % (n=30), and no difference between infecting genotype and clinical outcome of patient (P=0.73) or CD4+ counts (P=0.79) was observed. Zimbabwean Cryptococcusneoformans sensu stricto genotypes demonstrated a high level of genetic diversity by microsatellite typing, and 51 genotypes within the main molecular types AFLP1/VNI, AFLP1A/VNB/VNII and AFLP1B/VNII were identified. This study demonstrates that Cryptococcusneoformans sensu stricto in Zimbabwe has a high level of genetic diversity when compared to other regional isolates.
Jhamb, Rajat; Kashyap, Bineeta; Das, Shukla; Berry, Neha; Garg, Arun
Cryptococcosis, a significant opportunistic infection, has become a global concern since the advent of immunosuppressive chemotherapy or in immunodeficient patients. Host responses range from a harmless colonization to disseminated disease. An accurate or definitive diagnosis in patients with cryptococcal meningitis is often delayed because of the similar clinical presentation and biochemical or cerebrospinal fluid findings to those of a variety of infectious and non-infectious aetiologies, most of which are also especially prevalent in developing countries. Rarely, patients with cryptococcal meningitis can develop immune reconstitution inflammatory syndrome (IRIS) when initiated on combination antiretroviral therapy (cART) the diagnosis which is often missed and can be fatal. Due to the similar presentation of infection and IRIS, it is often confused with the relapse of cryptococcal meningitis. We report a case of paradoxical recurrent meningitis in response to the initiation of cART in a patient diagnosed with cryptococcal meningitis and propose that the recurrent symptoms resulted from a therapy-induced reconstitution of the immune response against residual Cryptococcus neoformans.
van Spil, W E Erwin; Nooijen, Suzan; de Jong, Peter Y P; Aliredjo, Riena P; de Sévaux, Ruud G L; Verhave, Jacobien C
Immunocompromised patients are at increased risk of disseminated cryptococcal infection, often presenting as a primary respiratory infection with yeast cells originating from bird excreta. Because Cryptococcus neoformans has a tropism for cerebrospinal fluid, most patients suffer from meningitis or meningoencephalitis. Symptoms of cryptococcal meningitis are non-specific: headache, fever, nausea, or altered mental state and behaviour. Case descriptions of a renal transplant recipient and an HIV patient illustrate the non-specific presentation of cryptococcal meningitis. Lumbar puncture seemed to be critical in establishing the diagnosis. Cerebrospinal fluid, blood and other tissues were tested for C. neoformans by microscopy, culture and antigen tests. The patients were successfully treated with amphotericin B or liposomal amphotericin B intravenously and flucytosine intravenously or orally, followed by long-term fluconazole. The mortality rate for cryptococcal meningitis is 41% among renal transplant recipients and 20% in HIV patients.
Katchanov, Juri; Branding, Gordian; Jefferys, Laura; Arastéh, Keikawus; Stocker, Hartmut; Siebert, Eberhard
To determine the frequency, imaging characteristics, neuroanatomical distribution and dynamics of magnetic resonance imaging findings in HIV-associated cryptococcal meningitis in immunocompromised patients we compared patients without antiretroviral therapy with patients undergoing immune reconstitution. Neuroimaging and clinical data of 21 consecutive patients presenting to a German HIV centre in a 10-year period between 2005 and 2014 were reviewed. We identified eight patients with magnetic resonance imaging findings related to cryptococcal disease: five patients without antiretroviral therapy and three patients receiving effective antiretroviral therapy resulting in immune reconstitution. The pattern of magnetic resonance imaging manifestations was different in the two groups. In patients not on antiretroviral therapy, pseudocysts (n = 3) and lacunar ischaemic lesions (n = 2) were detected. Contrast-enhancing focal leptomeningeal and/or parenchymal lesions were found in all patients under immune reconstitution (n = 3). Magnetic resonance imaging lesions suggestive of leptomeningitis or meningoencephalitis were detected in all patients with a recurrence of cryptococcal meningitis under immune reconstitution, which differs from the classical magnetic resonance imaging findings in patients without antiretroviral therapy. In antiretroviral therapy-treated patients with past medical history of cryptococcal meningitis, detection of contrast-enhancing focal meningeal and/or parenchymal lesions should prompt further investigations for a recurrence of cryptococcal meningitis under immune reconstitution.
Concha-Velasco, Fátima; González-Lagos, Elsa; Seas, Carlos; Bustamante, Beatriz
Introduction The first-line combination therapy for HIV-associated cryptococcal meningitis (CM), a condition of high mortality particularly in the first two weeks of treatment, consists of amphotericin B plus flucytosine (5-FC). Given that 5-FC remains unavailable in many countries, the knowledge of factors influencing mycological clearance in patients treated with second-line therapy could contribute to effective management. Objectives To determine the factors associated with the clearance of Cryptococcus sp. from the cerebrospinal fluid by the second week of effective antifungal therapy (early mycological clearance) in HIV-associated CM. Methods Retrospective cohort study based on secondary data corresponding to HIV-associated CM cases hospitalized at a tertiary health care center in Lima, Peru where 5-FC remains unavailable. Risk factors associated with early mycological clearance were analyzed by generalized linear regression models. Results From January 2000 to December 2013, 234 individuals were discharged with a diagnosis of HIV-associated CM; in 215 we retrieved the required data. The inpatient mortality was 20% (43/215), 15 of them in the first two weeks of treatment. In the final model (157 cases), adjusted for age, previous episode of CM, ART use, type of antifungal treatment, raised intracranial pressure, frequency of therapeutic lumbar punctures, baseline fungal burden and treatment period, the factors associated with early mycological clearance were: Amphotericin B deoxycholate plus fluconazole as combination therapy (RR, 1.56; 95% CI, 1.14–2.14); severe baseline intracranial pressure (≥35 cm H2O) (RR, 0.57; 95% CI, 0.33–0.99); and baseline fungal burden over 4.5 log10 CFU/mL (RR, 0.61 95% CI: 0.39–0.95). Conclusions In a setting without access to first-line therapy for CM, the combination therapy with amphotericin B deoxycholate plus fluconazole was positively associated with early mycological clearance, while high fungal burden and severe
Liu, Li; Zhang, Renfang; Tang, Yang; Lu, Hongzhou
Extremely elevated intracranial pressure (ICP) in patients with HIV and cryptococcal meningitis is a poor prognostic predictor of death during initial therapy. The risks associated with implanting a cerebrospinal fluid (CSF) shunt into immunocompromised patients with ongoing CSF infection have historically discouraged surgeons from implanting CSF shunts in patients with HIV and cryptococcal meningitis. An unanswered question is whether ventriculoperitoneal (VP) shunts can effectively provide long-term treatment for patients with intracranial hypertension and HIV-associated cryptococcal meningitis in China. Outcomes for 9 patients with HIV-associated cryptococcal meningitis who were given VP shunts for increased ICP were retrospectively analyzed. Each patient's age, sex, clinical manifestations, CD4+ lymphocyte count, HIV viral load, neurological status, CSF features, image findings, anad other opportunistic infections were recorded for analysis. All patients had signs and symptoms of increased ICP, including headaches, nausea, and vomiting. Seven patients (77.78%) had visual loss due to persistent papilledema. The median time from diagnosis of cryptococcal meningitis to VP shunting in the 9 patients was 5 months (range 0.5-12.5 months). Seven patients (77.78%) had good outcomes, with recovery from 1 month to 48 months. Two patients had poor outcomes; one died six months after shunting due to severe adverse reactions to antiretroviral drugs, and the other died two weeks after surgery. Patients with intracranial hypertension and HIV-associated cryptococcal meningitis who cannot tolerate cessation of external lumbar CSF drainage or frequent lumbar punctures may be eligible for VP shunt placement, despite severe immunosuppression and persistent CSF cryptococcal infection.
... Other tests that may be done include: Blood culture Chest x-ray Cryptococcal antigen in CSF or ... the head Gram stain, other special stains, and culture of CSF Treatment Antifungal medicines are used to ...
Zimmer, LO; Nolen, TL; Pramanpol, S; Wallace, D; Walker, ME; Pappas, P; Chetchotisakd, P
Background International clinical trials can provide scientific and logistic benefits in spite of the many challenges. Determining whether a country, especially a developing country, is an appropriate location for the research should include in-country consultation and partnering to assess its social value for the population; that treatments are relevant for the population under study; and that the research infrastructure and ethical oversight are adequate. Collaboration increases the likelihood of study success and helps ensure that benefits accrue to recruited populations and their community. Purpose This paper describes our experiences on a bi-national study and may provide guidance for those planning to engage in future collaborations. Methods A Thai and United States team collaborated to develop and implement a Phase II clinical trial for HIV-associated cryptococcal meningitis to assess safety and tolerability of combination therapy versus standard treatment. Clinical and cultural differences, regulatory hurdles and operational issues were addressed before and during the study to ensure a successful collaboration between the 2 groups. Results The international multicenter study allowed for more rapid enrollment, reduced costs to complete the study, sharing of the benefits of research, greater generalizability of results and capacity building in Thailand; quality metrics in Thailand were equivalent to or better than those in the U.S. Conclusions Conducting successful clinical trials internationally requires early and ongoing collaboration to ensure the study meets sites’ requirements and expectations, conforms to varying national regulations, adheres to data quality standards and is responsive to the health needs of studied populations. PMID:19897055
Bicanic, Tihana; Bottomley, Christian; Loyse, Angela; Brouwer, Annemarie E; Muzoora, Conrad; Taseera, Kabanda; Jackson, Arthur; Phulusa, Jacob; Hosseinipour, Mina C; van der Horst, Charles; Limmathurotsakul, Direk; White, Nicholas J; Wilson, Douglas; Wood, Robin; Meintjes, Graeme; Harrison, Thomas S; Jarvis, Joseph N
Amphotericin B deoxycholate (AmBd) is the recommended induction treatment for HIV-associated cryptococcal meningitis (CM). Its use is hampered by toxicities that include electrolyte abnormalities, nephrotoxicity, and anemia. Protocols to minimize toxicity are applied inconsistently. In a clinical trial cohort of AmBd-based CM induction treatment, a standardized protocol of preemptive hydration and electrolyte supplementation was applied. Changes in blood counts, electrolyte levels, and creatinine levels over 14 days were analyzed in relation to the AmBd dose, treatment duration (short course of 5 to 7 days or standard course of 14 days), addition of flucytosine (5FC), and outcome. In the 368 patients studied, the hemoglobin levels dropped by a mean of 1.5 g/dl (95% confidence interval [CI], 1.0 to 1.9 g/dl) following 7 days of AmBd and by a mean of 2.3 g/dl (95% CI, 1.1 to 3.6 g/dl) after 14 days. Serum creatinine levels increased by 37 μmol/liter (95% CI, 30 to 45 μmol/liter) by day 7 and by 49 μmol/liter (95% CI, 35 to 64μmol/liter) by day 14 of AmBd treatment. Overall, 33% of patients developed grade III/IV anemia, 5.6% developed grade III hypokalemia, 9.5% had creatinine levels that exceeded 220 μmol, and 6% discontinued AmBd prematurely. The addition of 5FC was associated with a slight increase in anemia but not neutropenia. Laboratory abnormalities stabilized or reversed during the second week in patients on short-course induction. Grade III/IV anemia (adjusted odds ratio [aOR], 2.2; 95% CI, 1.1 to 4.3; P = 0.028) and nephrotoxicity (aOR, 4.5; 95% CI, 1.8 to 11; P = 0.001) were risk factors for 10-week mortality. In summary, routine intravenous saline hydration and preemptive electrolyte replacement during AmBd-based induction regimens for HIV-associated CM minimized the incidence of hypokalemia and nephrotoxicity. Anemia remained a concerning adverse effect. The addition of flucytosine was not associated with increased neutropenia. Shorter AmBd courses
Leonhard, Sonja E.; Fritz, Daan; van de Beek, Diederik; Brouwer, Matthijs C.
Abstract Background: Cryptococcal meningitis is an uncommon but severe complication of sarcoidosis. Methods: We present 2 patients with cryptococcal meningitis complicating sarcoidosis and compared findings with 38 cases reported in the literature. Results: When analyzing our patients and 38 cases reported in the literature, we found that median age of sarcoidosis patients with cryptococcal meningitis was 39 years (range 30–48); 27 of 33 reported cases (82%) had a history of sarcoidosis. Only 16 of 40 patients (40%) received immunomodulating therapy at the time of diagnosis of cryptococcal meningitis. The diagnosis of cryptococcal meningitis was delayed in 17 of 40 patients (43%), mainly because of the initial suspicion of neurosarcoidosis. Cerebrospinal fluid (CSF) examination showed mildly elevated white blood cell count (range 23–129/mm3). Twenty-nine of 32 cases (91%) had a positive CSF culture for Cryptococcus neoformans and 25 of 27 cases (93%) had a positive CSF C neoformans antigen test. CD4 counts were low in all patients in whom counts were performed (84–228/mL). Twelve patients had an unfavorable outcome (32%), of which 7 died (19%) and 24 patients (65%) had a favorable outcome. The rate of unfavorable outcome in patients with a delayed diagnosis was 7 of 17 (41%) compared to 5 of 28 (21%) in patients in whom diagnosis was not delayed. Conclusion: Cryptococcal meningitis is a rare but life-threatening complication of sarcoidosis. Patients were often initially misdiagnosed as neurosarcoidosis, which resulted in considerable treatment delay and worse outcome. CSF cryptococcal antigen tests are advised in patients with sarcoidosis and meningitis. PMID:27583871
Leonhard, Sonja E; Fritz, Daan; van de Beek, Diederik; Brouwer, Matthijs C
Cryptococcal meningitis is an uncommon but severe complication of sarcoidosis. We present 2 patients with cryptococcal meningitis complicating sarcoidosis and compared findings with 38 cases reported in the literature. When analyzing our patients and 38 cases reported in the literature, we found that median age of sarcoidosis patients with cryptococcal meningitis was 39 years (range 30-48); 27 of 33 reported cases (82%) had a history of sarcoidosis. Only 16 of 40 patients (40%) received immunomodulating therapy at the time of diagnosis of cryptococcal meningitis. The diagnosis of cryptococcal meningitis was delayed in 17 of 40 patients (43%), mainly because of the initial suspicion of neurosarcoidosis. Cerebrospinal fluid (CSF) examination showed mildly elevated white blood cell count (range 23-129/mm). Twenty-nine of 32 cases (91%) had a positive CSF culture for Cryptococcus neoformans and 25 of 27 cases (93%) had a positive CSF C neoformans antigen test. CD4 counts were low in all patients in whom counts were performed (84-228/mL). Twelve patients had an unfavorable outcome (32%), of which 7 died (19%) and 24 patients (65%) had a favorable outcome. The rate of unfavorable outcome in patients with a delayed diagnosis was 7 of 17 (41%) compared to 5 of 28 (21%) in patients in whom diagnosis was not delayed. Cryptococcal meningitis is a rare but life-threatening complication of sarcoidosis. Patients were often initially misdiagnosed as neurosarcoidosis, which resulted in considerable treatment delay and worse outcome. CSF cryptococcal antigen tests are advised in patients with sarcoidosis and meningitis.
Cherian, Jacob; Atmar, Robert L; Gopinath, Shankar P
OBJECT Patients with cryptococcal meningitis often develop symptomatic intracranial hypertension. The need for permanent CSF diversion in these cases remains unclear. METHODS Cases of cryptococcal meningitis over a 5-year period were reviewed from a single, large teaching hospital. Sources of identification included ICD-9 codes, operative logs, and microscopy laboratory records. RESULTS Fifty cases of cryptococcal meningitis were identified. Ninety-eight percent (49/50) of patients were HIV positive. Opening pressure on initial lumbar puncture diagnosing cryptococcal meningitis was elevated (> 25 cm H2O) in 33 cases and normal (≤ 25 cm H2O) in 17 cases. Thirty-eight patients ultimately developed elevated opening pressure over a follow-up period ranging from weeks to years. Serial lumbar punctures for relief of intracranial hypertension were performed in 29 cases. Thirteen of these patients ultimately had shunting procedures performed after failing to improve clinically. Two factors were significantly associated with the need for shunting: patients undergoing shunt placement were more likely to be women (5/13 vs 0/16; p = 0.01) and to have a pattern of increasing CSF cryptococcal antigen (10/13 vs 3/16 cases; p = 0.003). All patients re-presenting with mycological relapse either underwent or were offered shunt placement. CONCLUSIONS Neurosurgeons are often asked to consider CSF diversion in cases of cryptococcal meningitis complicated by intracranial hypertension. Most patients do well with serial lumbar punctures combined with antifungal therapy. When required, shunting generally provided sustained relief from intracranial hypertension symptoms. Ventriculoperitoneal shunts are the favored method of diversion. To the authors' knowledge, the present study is the largest series on diversionary shunts in primarily HIV-positive patients with this problem.
Subramanyam, V R; Mtitimila, E; Hart, C A; Broadhead, R L
Three cases of cryptococcal meningitis in Malawian children aged 6 weeks, 3 years and 9 years are described. Only 23 cases of cryptococcal meningitis in children have been described previously, but in children from Europe and the USA. These are therefore the first cases of cryptococcosis to be described in African children.
Liu, Tong-Bao; Perlin, David S; Xue, Chaoyang
Fungal meningitis is a serious disease caused by a fungal infection of the central nervous system (CNS) mostly in individuals with immune system deficiencies. Fungal meningitis is often fatal without proper treatment, and the mortality rate remains unacceptably high even with antifungal drug interventions. Currently, cryptococcal meningitis is the most common fungal meningitis in HIV-1/AIDS, and its disease mechanism has been extensively studied. The key steps for fungi to infect brain and cause meningitis after establishment of local infection are the dissemination of fungal cells to the bloodstream and invasion through the blood brain barrier to reach the CNS. In this review, we use cryptococcal CNS infection as an example to describe the current molecular understanding of fungal meningitis, including the establishment of the infection, dissemination, and brain invasion. Host and microbial factors that contribute to these infection steps are also discussed.
Vidal, José E.; Gerhardt, Juliana; Peixoto de Miranda, Érique J.; Dauar, Rafi F.; Oliveira Filho, Gilberto S.; Penalva de Oliveira, Augusto C.; Boulware, David R.
Objectives To evaluate clinical, laboratory, and quantitative cerebrospinal fluid (CSF) cryptococcal cell counts for associations with in-hospital outcomes of HIV-infected patients with cryptococcal meningitis. Design Retrospective study. Methods 98 HIV-infected adult patients with CSF culture-proven cryptococcal meningitis admitted between January 2006 and June 2008 at a referral center in Sao Paulo, Brazil. Results Cryptococcal meningitis was the first AIDS-defining illness in 69% of whom 97% (95/98) had known prior HIV-infection. The median CD4+ T cell count was 39 cells/mcL (IQR: 17–87 cells/mcL). Prior antiretroviral therapy (ART) was reported in 50%. Failure to sterilize the CSF by 7–14 days was associated with baseline fungal burden of ≥10 yeasts/mcL by quantitative CSF microscopy (OR=15.3, 95% CI: 4.1–56.7;P<.001) and positive blood cultures (OR=11.5, 95% CI:1.2–109;P=.034). At 7–14 days, ≥10 yeasts/mcL CSF was associated with positive CSF cultures in 98% vs. 36% when <10 yeasts/mcL CSF (P<.001). In-hospital mortality was 30% and associated with symptoms duration for >14 days, altered mental status (P<.001), CSF WBC counts <5 cells/mcL (P=.027), intracranial hypertension (P=.011), viral loads >50,000 copies/mL (P=.036), ≥10 yeasts/mcL CSF at 7–14 days (P=.038), and intracranial pressure >50 cmH20 at 7–14 days (P=.007). Conclusion Most patients were aware of their HIV-status. Fungal burden of ≥10 yeasts/mcL by quantitative CSF microscopy predicted current CSF culture status and may be useful to customize the induction therapy. High uncontrolled intracranial pressure was associated with mortality. PMID:22578940
Yuanjie, Zhu; Jianghan, Chen; Nan, Xu; Xiaojun, Wang; Hai, Wen; Wanqing, Liao; Julin, Gu
To describe clinical characteristics, treatment and outcome of cryptococcal meningitis in immunocompetent children. Immunocompetent children with cryptococcal meningitis who attended Changzheng Hospital between 1998 and 2007 were retrospectively reviewed. During the 10 years reviewed, 11 children with cryptococcal meningitis were admitted to Changzheng hospital and identified as immunocompetent. The 11 children had a median age of 7.25 years. Headache (100%), fever (81.8%), nausea or vomiting (63.6%) and visual or hearing damage or loss (36.4%) were the most common symptoms before treatment. There is no evidence for other site infection of cryptococcus although all the cryptococcal antigen titre is high in blood. All the patients received amphotericin B or AmB liposome with 5-flucytosine for at least 6 weeks followed by fluconazole or itraconazole as consolidation treatment for at least 12 weeks. Nine patients were cured mycologically; however, sequela of visual damage was showed in one patient. Cryptococcal meningitis seems to be uncharacteristic of symptoms, and central nervous system may be the only common site for infection. Amphotericin B with 5-flucytosine should be the choice of induction treatment in this group of patients.
Rhein, Joshua; Morawski, Bozena M; Hullsiek, Kathy Huppler; Nabeta, Henry W; Kiggundu, Reuben; Tugume, Lillian; Musubire, Abdu; Akampurira, Andrew; Smith, Kyle D; Alhadab, Ali; Williams, Darlisha A; Abassi, Mahsa; Bahr, Nathan C; Velamakanni, Sruti S; Fisher, James; Nielsen, Kirsten; Meya, David B; Boulware, David R
Cryptococcus is the most common cause of adult meningitis in Africa. We assessed the safety and microbiological efficacy of adjunctive sertraline, previously shown to have in-vitro and in-vivo activity against cryptococcus. In this open-label dose-finding study, we recruited HIV-infected individuals with cryptococcal meningitis who presented to Mulago Hospital in Kampala, Uganda between Aug 14, 2013, and Aug 30, 2014. To assess safety and tolerability, the first 60 participants were given sertraline at escalating doses of 100 mg/day, 200 mg/day, 300 mg/day, or 400 mg/day as induction therapy for 2 weeks, followed by consolidation therapy with 200 mg/day for an additional 8 weeks. From Nov 29, 2013, participants were randomly assigned (1:1) to receive open-label sertraline at predetermined doses of 200 mg/day, 300 mg/day, or 400 mg/day as induction therapy for 2 weeks, followed by consolidation therapy with 200 mg/day for 8 weeks. Dose assignment was made via computer-generated, permuted block randomisation stratified by antiretroviral therapy (ART) status for people with a first episode of meningitis. The primary outcome was 2-week cerebrospinal fluid (CSF) clearance rate of cryptococcus, termed early fungicidal activity, measured in patients with a first episode of culture-positive meningitis and two or more CSF cultures. This study is registered with ClinicalTrials.gov, number NCT01802385. Of the 330 individuals assessed, 172 HIV-infected adults with cryptococcal meningitis were enrolled. We gave 100 mg/day sertraline to 17 patients, 200 mg/day to 12 patients, 300 mg/day to 14 patients, and 400 mg/day to 17 patients. 112 participants were randomly assigned to receive sertraline at 200 mg (n=48), 300 mg (n=36), or 400 mg (n=28) daily for the first 2 weeks, and 200 mg/day thereafter. The final population consisted of 17 participants in the 100 mg group, 60 in the 200 mg group, 50 in the 300 mg group, and 45 in the 400 mg in group. Participants receiving any
Rhein, Joshua; Morawski, Bozena M; Hullsiek, Kathy Huppler; Nabeta, Henry W; Kiggundu, Reuben; Tugume, Lillian; Musubire, Abdu; Akampurira, Andrew; Smith, Kyle D; Alhadab, Ali; Williams, Darlisha A; Abassi, Mahsa; Bahr, Nathan C; Velamakanni, Sruti S; Fisher, James; Nielsen, Kirsten; Meya, David B; Boulware, David R
Background Cryptococcus is the most common cause of adult meningitis in Africa. We evaluated the activity of adjunctive sertraline, previously demonstrated to have in vitro and in vivo activity against Cryptococcus. Methods We enrolled 172 HIV-infected Ugandans with cryptococcal meningitis from August 2013 through August 2014 into an open-label dose-finding study to assess safety and microbiologic efficacy. Sertraline 100–400mg/day was added to standard therapy of amphotericin + fluconazole 800mg/day. We evaluated early fungicidal activity via Cryptococcus cerebrospinal fluid (CSF) clearance rate, sertraline pharmacokinetics, and in vitro susceptibility. Findings Participants receiving any sertraline dose averaged a CSF clearance rate of −0·37 (95%CI: −0·41, −0·33) colony forming units (CFU)/mL/day. Incidence of paradoxical immune reconstitution inflammatory syndrome (IRIS) was 5% (2/43) and relapse was 0% through 12-weeks. Sertraline reached steady state concentrations in plasma by day 7, with median steady-state concentrations of 201 ng/mL (IQR, 90–300; n=49) with 200mg/day and 399 ng/mL (IQR, 279–560; n=30) with 400mg/day. Plasma concentrations reached 83% of steady state levels by day 3. The median projected steady state brain tissue concentration at 200mg/day was 3·7 (IQR, 2·0–5·7) mcg/mL and 6·8 (IQR, 4·6–9·7) mcg/mL at 400mg/day. Minimum inhibitory concentrations were ≤2 mcg/mL for 27% (35/128), ≤4 mcg/mL for 84% (108/128), ≤6 mcg/mL for 91% (117/128), and ≤8 mcg/mL for 100% of 128 Cryptococcus isolates. Interpretation Sertraline had faster cryptococcal CSF clearance, decreased IRIS, and decreased relapse compared with historical experiences. Sertraline reaches therapeutic levels in a clinical setting. This inexpensive and off-patent oral medication is a promising adjunctive antifungal therapy. Funding National Institutes of Health, Grand Challenges Canada. PMID:26971081
Schlossberg, D; Brooks, J B; Shulman, J
Cerebrospinal fluid (CSF) from eight patients with cryptococcal meningitis, from ten patients with viral meningitis, and from four control patients without meningitis were analyzed by electron-capture gas-liquid chromatography (EC-GLC). All cryptococcal specimens had similar EC-GLC profiles, and these differed from those of the controls. Viral EC-GLC patterns were different from those obtained with specimens from the patients with cryptococcal infection and from the controls. In addition, specimens from patients with various types of viral infections gave profiles that differed from each other. Two normal CSFs were inoculated with Cryptococcus neoformans; aliquots of these cultures showed an EC-GLC pattern very similar to that seen in CSF of patients with cryptococcal meningitis. The EC-GLC procedure is rapid, reproducible, and easy to perform and may hold promise as an additional aid in the diagnosis of cryptococcal infection. PMID:773956
Ashiru, J O; Akang, E E
Cryptococcal meningitis is an uncommon infection globally, including Nigeria. This systemic fungal infection often is associated with immunodeficiency. The most common causes of meningitis in Nigeria in the 2-3 year age group are the malaria parasites and bacteria. The concomitant infections of Cryptococcal neoformans and Plasmodium falciparum are uncommon. We present here the report of a case of fatal cryptococcal meningitis with malaria infection in a 2 year old child from Nigeria (one of the malaria endemic regions of the world). This case emphasizes the importance of doing a combination of fungal and bacterial cultures as well as looking for malarial parasites in the determination of etiological agents of meningitis in any hospital in Africa. We suggest that cerebrospinal fluid from meningitis cases must be cultured using Sabouraud dextrose agar and any growth on the agar must be examined using Indian ink.
Neo, W L; Durisala, N; Ho, E C
Sensorineural hearing loss is a recognised complication of cryptococcal meningitis. The mechanism of hearing loss in patients with cryptococcal meningitis is different from that in bacterial meningitis. An immune-competent man with cryptococcal meningitis presented with sudden onset, bilateral, severe to profound sensorineural hearing loss and vestibular dysfunction. He was initially evaluated for cochlear implantation. However, he had a significant recovery; he no longer required surgery and was able to cope without a hearing aid. Typically, cochlear implantation is performed with some urgency in patients with hearing loss post-bacterial meningitis, because of the risk of labyrinthitis ossificans. However, this process has not been described in patients with cryptococcal meningitis. Furthermore, patients with hearing loss associated with cryptococcal meningitis have shown varying degrees of reversibility. In this case report, hearing loss from cryptococcal meningitis is compared with that from bacterial meningitis, and the need for cochlear implantation in patients with cryptococcal meningitis is discussed.
Hoque, Romy; Gonzalez-Toledo, Eduardo; Jaffe, Stephen L
A 50-year-old man presented with progressive visual loss, headache, and two days of confusion. A computed tomography of his head suggested subarachnoid hemorrhage with accompanying right parietal ischemic infarction. The magnetic resonance image was consistent with right parietal perisulcal pial and superficial cortical inflammation; a subjacent vasogenic edema with a 1 cm diameter abscess was also present. Funduscopy revealed bilateral multifocal choroidal lesions and retinal perivascular sheathing. He was diagnosed with pseudosubarachnoid hemorrhage secondary to cryptococcal meningitis and choroidal microabscesses with retinal inflammation after a cerebrospinal fluid (CSF) examination revealed cryptococcal yeast forms, as well as high titers of CSF cryptococcal antigen, but no CSF red blood cells.
Sloan, Derek J; Parris, Victoria
Cryptococcal meningitis causes morbidity and mortality worldwide. The burden of disease is greatest in middle- and low-income countries with a high incidence of human immunodeficiency virus (HIV) infection. Patients taking immunosuppressive drugs and some immunocompetent hosts are also at risk. Treatment of cryptococcal meningitis consists of three phases: induction, consolidation, and maintenance. Effective induction therapy requires potent fungicidal drugs (amphotericin B and flucytosine), which are often unavailable in low-resource, high-endemicity settings. As a consequence, mortality is unacceptably high. Wider access to effective treatment is urgently required to improve outcomes. For human immunodeficiency virus-infected patients, judicious management of asymptomatic cryptococcal antigenemia and appropriately timed introduction of antiretroviral therapy are important. PMID:24872723
Kirkpatrick, William R; Najvar, Laura K; Bocanegra, Rosie; Patterson, Thomas F; Graybill, John R
We developed a guinea pig model of cryptococcal meningitis to evaluate antifungal agents. Immunosuppressed animals challenged intracranially with Cryptococcus neoformans responded to fluconazole and voriconazole. Disease was monitored by serial cerebrospinal fluid (CSF) cultures and quantitative organ cultures. Our model produces disseminating central nervous system disease and responds to antifungal therapy.
Chaaban, S; Wheat, L J; Assi, M
Disseminated Cryptococcus disease occurs in patients with defective T-cell immunity. Cryptococcal meningitis following autologous stem cell transplant (SCT) has been described previously in only 1 patient, 4 months post SCT and while off antifungal prophylaxis. We present a unique case of Cryptococcus meningitis pre-engraftment after autologous SCT, while the patient was receiving fluconazole prophylaxis. A 41-year-old man with non-Hodgkin's lymphoma underwent autologous SCT. Post-transplant prophylaxis consisted of fluconazole 400 mg daily, levofloxacin 500 mg daily, and acyclovir 800 mg twice daily. On day 9 post transplant, he developed fever and headache. Peripheral white blood cell count (WBC) was 700/μL. Magnetic resonance imaging of the brain showed lesions consistent with meningoencephalitis. Cerebrospinal fluid (CSF) analysis revealed a WBC of 39 with 77% lymphocytes, protein 63, glucose 38, CSF pressure 20.5 cmH2 O, and a positive cryptococcal antigen. CSF culture confirmed Cryptococcus neoformans. The patient was treated with liposomal amphotericin B 5 mg/kg intravenously daily, and flucytosine 37.5 mg/kg orally every 6 h. He was switched to fluconazole 400 mg daily after 3 weeks of amphotericin therapy, with sterilization of the CSF with negative CSFCryptococcus antigen and negative CSF culture. Review of the literature revealed 9 cases of cryptococcal disease in recipients of SCT. Median time of onset was 64 days post transplant. Only 3 meningitis cases were described; 2 of them after allogeneic SCT. Fungal prophylaxis with fluconazole post autologous SCT is recommended at least through engraftment, and for up to 100 days in high-risk patients. A high index of suspicion is needed to diagnose and treat opportunistic infections, especially in the face of immunosuppression and despite adequate prophylaxis. Infection is usually fatal without treatment, thus prompt diagnosis and therapy might be life saving.
Roy, Monika; Chiller, Tom
Cryptococcal meningitis (CM), a fungal disease caused by Cryptococcus spp., is the most common form of meningitis and a leading cause of death among persons with HIV/AIDS in sub-Saharan Africa. Detection of cryptococcal antigen, which is present several weeks before overt signs of meningitis develop, provides an opportunity to detect infection early. Screening persons with HIV for cryptococcal infection when they access healthcare can identify asymptomatic infected patients allowing for prompt treatment and prevention of death. A newly developed point-of-care assay for cryptococcal antigen, as well as growing evidence supporting the utility and cost-effectiveness of screening, are further reasons to consider broad implementation of cryptococcal screening in countries with a high burden of cryptococcal disease.
Selvan, Lakshmi Dhevi N; Sreenivasamurthy, Sreelakshmi K; Kumar, Satwant; Yelamanchi, Soujanya D; Madugundu, Anil K; Anil, Abhijith K; Renuse, Santosh; Nair, Bipin G; Gowda, Harsha; Mathur, Premendu P; Satishchandra, Parthasarathy; Shankar, S K; Mahadevan, Anita; Keshava Prasad, T S
Cryptococcal meningitis is the most common opportunistic fungal infection causing morbidity and mortality (>60%) in HIV-associated immunocompromised individuals caused by Cryptococcus neoformans. Molecular mechanisms of cryptococcal infection in brain have been studied using experimental animal models and cell lines. There are limited studies for the molecular understanding of cryptococcal meningitis in human brain. The proteins involved in the process of invasion and infection in human brain still remains obscure. To this end we carried out mass spectrometry-based quantitative proteomics of frontal lobe brain tissues from cryptococcal meningitis patients and controls to identify host proteins that are associated with the pathogenesis of cryptococcal meningitis. We identified 317 proteins to be differentially expressed (≥2-fold) from a total of 3423 human proteins. We found proteins involved in immune response and signal transduction to be differentially expressed in response to cryptococcal infection in human brain. Immune response proteins including complement factors, major histocompatibility proteins, proteins previously known to be involved in fungal invasion to brain such as caveolin 1 and actin were identified to be differentially expressed in cryptococcal meningitis brain tissues co-infected with HIV. We also validated the expression status of 5 proteins using immunohistochemistry. Overexpression of major histocompatibility complexes, class I, B (HLA-B), actin alpha 2 smooth muscle aorta (ACTA2) and caveolin 1 (CAV1) and downregulation of peripheral myelin protein 2 (PMP2) and alpha crystallin B chain (CRYAB) in cryptococcal meningitis were confirmed by IHC-based validation experiments. This study provides the brain proteome profile of cryptococcal meningitis co-infected with HIV for a better understanding of the host response associated with the disease.
Day, Jeremy N.; Chau, Tran T.H.; Wolbers, Marcel; Mai, Pham P.; Dung, Nguyen T.; Mai, Nguyen H.; Phu, Nguyen H.; Nghia, Ho D.; Phong, Nguyen D.; Thai, Cao Q.; Thai, Le H.; Chuong, Ly V.; Sinh, Dinh X.; Duong, Van A.; Hoang, Thu N.; Diep, Pham T.; Campbell, James I.; Sieu, Tran P.M.; Baker, Stephen G.; Chau, Nguyen V.V.; Hien, Tran T.
BACKGROUND Combination antifungal therapy (amphotericin B deoxycholate and flucytosine) is the recommended treatment for cryptococcal meningitis but has not been shown to reduce mortality, as compared with amphotericin B alone. We performed a randomized, controlled trial to determine whether combining flucytosine or high-dose fluconazole with high-dose amphotericin B improved survival at 14 and 70 days. METHODS We conducted a randomized, three-group, open-label trial of induction therapy for cryptococcal meningitis in patients with human immunodeficiency virus infection. All patients received amphotericin B at a dose of 1 mg per kilogram of body weight per day; patients in group 1 were treated for 4 weeks, and those in groups 2 and 3 for 2 weeks. Patients in group 2 concurrently received flucytosine at a dose of 100 mg per kilogram per day for 2 weeks, and those in group 3 concurrently received fluconazole at a dose of 400 mg twice daily for 2 weeks. RESULTS A total of 299 patients were enrolled. Fewer deaths occurred by days 14 and 70 among patients receiving amphotericin B and flucytosine than among those receiving amphotericin B alone (15 vs. 25 deaths by day 14; hazard ratio, 0.57; 95% confidence interval [CI], 0.30 to 1.08; unadjusted P = 0.08; and 30 vs. 44 deaths by day 70; hazard ratio, 0.61; 95% CI, 0.39 to 0.97; unadjusted P = 0.04). Combination therapy with fluconazole had no significant effect on survival, as compared with monotherapy (hazard ratio for death by 14 days, 0.78; 95% CI, 0.44 to 1.41; P = 0.42; hazard ratio for death by 70 days, 0.71; 95% CI, 0.45 to 1.11; P = 0.13). amphotericin B plus flucytosine was associated with significantly increased rates of yeast clearance from cerebrospinal fluid (−0.42 log10 colony-forming units [CFU] per milliliter per day vs. −0.31 and −0.32 log10 CFU per milliliter per day in groups 1 and 3, respectively; P<0.001 for both comparisons). Rates of adverse events were similar in all groups, although
Iyer, S P; Movva, K; Wiebel, M; Chandrasekar, P; Alangaden, G; Carron, M; Tranchida, P; Revankar, S G
Cryptococcal meningitis is a relatively common invasive fungal infection in immunocompromised patients, especially in solid organ transplant recipients. Clinical presentation typically includes fever, headache, photophobia, neck stiffness, and/or altered mental status. Unusual presentations may delay diagnosis. Therapy is challenging in renal transplant patients because of the nephrotoxicity associated with amphotericin B, the recommended treatment. We present a case of cryptococcal meningitis in a renal transplant recipient presenting as acute sinusitis with successful treatment using fluconazole as primary therapy.
Sanossian, Nerses; Shatzmiller, Ron A.; Djabiras, Christina; Liebeskind, David S.
BACKGROUND AND PURPOSE Ischemic stroke is a common complication of cryptococcal meningitis. Fluid attenuated inversion recovery vascular hyperintensity (FVH) is a neuroimaging marker of sluggish blood flow usually seen in the setting of acute stroke. FVH have never been described in the setting of meningitis. METHODS Case report. RESULTS A 20-year-old man with cryptococcal meningitis and a magnetic resonance imaging demonstrating FVH had subsequent neurological deterioration and was found to have bilateral ischemic stroke. CONCLUSIONS In conditions with high risk of stroke, such as meningitis, the presence of FVH should alert the clinician to the possibility of impending infarction. PMID:21410814
Kouakou, G A; Ello, N F; Kassi, N A; Keita, M; Doumbia, A; Mossou, C; Kassi, F K; Tanon, A; Ehui, E; Eholié, S P
Assessing the use of high-dose fluconazol monotherapy (1200mg or 800mg) in the treatment and prognosis of HIV-associated cryptococcal meningitis in Ivory Coast. A retrospective study carried out from August 2008 to August 2011 based on patients charts suffering from CM in the Abidjan Tropicals and Infectious Disease Unit. Mortality rate and associated factors were analyzed. Forty-six cases of cryptococcal meningitis (2.5% of hospitalizations) were included. The sex-ratio was of 1.2. The median age was 40.5 [35-47] years. The symptomatology was subacute (93.5%). The main clinical symptoms were syndrome of pure meningeal irritation (65%), fever (100%); 35% of patients had encephalomeningits. Twenty-one (45.7%) was ART-naïve patients. Fluconazole 1200mg was prescribed to 29 (63%) patients. Therapeutic lumbar punctures were performed in 42 (91.3) patients. The mortality rate was 50%. Significant predictors of mortality were encephalomeningitis and therapeutic lumbar puncture. Cryptococcal meningitis associated mortality remains high despite the use of high-dose fluconazole monotherapy. Therapeutic lumbar punctures help to improving the prognosis. Copyright © 2016 Elsevier Masson SAS. All rights reserved.
Lu, Hongzhou; Zhou, Yingjie; Yin, Youkuan; Pan, Xiaozhang; Weng, Xinhua
For a total of 29 non-human immunodeficiency virus 1 cryptococcal meningitis cases, titer changes in the latex agglutination test before and after therapy were reviewed along with clinical manifestations, laboratory findings, and therapy regimens. The cryptococcal antigen titer decreased for every case after therapy and was correlated to fungal clearance as defined by fungus smear and/or culture. However, cryptococcal antigen can remain at low titers for long periods of time after therapy, even when fungus smears and/or cultures become negative.
Botha, R J; Wessels, E
A case of Cryptococcus neoformans meningitis is described in an HIV negative patient with undiagnosed systemic sarcoidosis. The patient presented with signs of meningitis together with generalised lymphadenopathy and hepatosplenomegaly. Cryptococcal meningitis was diagnosed on lumbar puncture. She was treated with intravenous amphotericin B but died within two weeks of admission. Necropsy revealed lesions in the lungs, liver, spleen, lymph nodes, small intestine, and bone marrow consistent with sarcoidosis. Microscopically the lesions contained non-caseating epithelioid cell granulomas typical of sarcoidosis. No Schaumann or Hamazaki-Wesenberg bodies were identified. Cryptococcus neoformans meningitis is generally associated with immunosuppressive disorders. As T cell abnormalities have been described in sarcoidosis, this could have been a case of opportunistic infection. Although rare, sarcoidosis merits consideration in patients with cryptococcal disease in the absence of HIV infection. Images PMID:10711260
Rigi, Mohammed; Khan, Khurrum; Smith, Stacy V; Suleiman, Ayman O; Lee, Andrew G
Cryptococcal meningitis is the most common and severe form of cryptococcal infection. In addition to infiltrative and inflammatory mechanisms, intracranial hypertension commonly complicates cryptococcal meningitis and may cause significant visual and neurological morbidity and mortality. The mainstays of treatment for cryptococcal meningitis include standard antifungal therapy, management of intracranial hypertension, and treatment of underlying immunosuppressive conditions. Early and aggressive management of intracranial hypertension in accordance with established guidelines reduces the risk of long-term visual and neurological complications and death. Traditional recommendations for treating elevated intracranial pressure in idiopathic intracranial hypertension including acetazolamide, weight loss, and avoiding serial lumbar punctures-are not helpful in cryptococcal meningitis and may be harmful.
Singh, Urvinderpal; Aditi; Aneja, Pooja; Kapoor, B K; Singh, S P; Purewal, Sukhpreet Singh
Opportunistic infections are common complications of advanced immuno-deficiency in individuals with Human Immunodeficiency Virus (HIV) infection. Following involvement of the lung, the central nervous system (CNS) is the second most commonly affected organ. We report two cases of concurrent cryptococcal meningitis and tuberculosis (TB) in HIV infected persons. A high suspicion of multiple opportunistic infections should be kept in mind in HIV seropositive individuals.
Background Cryptococcus neoformans is saprophytic encapsulated yeast. Infection is acquired by inhalation of the organism and could be asymptomatic or limited to the lungs, specially in the immunocompetent host. Cryptococcal meningitis is a serious opportunistic infection among post transplant recipients. Cranial nerve palsies and ophthalmoplegia are well known complications of this disease, but bilateral complete ophthalmoplegia is a very rare presentation. Case Presentation A Sri Lankan young male, who is a post kidney transplant recipient, presented with bilateral complete ophthalmoplegia and subsequently was diagnosed to have cryptococcal meningitis based on Indian ink stain and culture of cerebrospinal fluid (CSF). His magnetic resonance imaging (MRI) showed bilateral multiple nodular lesions in both basal ganglia and thalami. Brainstem imaging was normal. Conclusions Cryptococcal meningitis is a serious fungal infection in post transplant patients. It should be suspected in any immunocompromised patient with fever, headache and focal neurological signs. Bilateral thalamic lesions, inflammation and invasion of the cranial nerves and raised intracranial pressure were thought to be possible mechanisms resulting in bilateral complete ophthalmoplegia in this patient. PMID:24885277
Ndiaye, M; Diagne, N R; Seck, L B; Sow, A D; Sène, M S; Diop, A G; Sow, H D; Ndiaye, M M
Cryptococcal meningitis is much less common in children than adults. The purpose of this report is to describe 3 cases of cryptococcal meningitis observed in children admitted to the Neurology Department of the Fann University Hospital Center in Dakar, Senegal between July 2003 and November 2008. There were 2 girls whose ages were 8 and 15 years and one 9-year-old boy. All 3 patients presented acute or chronic meningoencephalitis. Diagnosis was based on direct microscopic examination of India ink preparations of cerebrospinal fluid (CSF) showing Cryptococcus neoformans at direct exam. Two patients were immunocompromised including one presenting severe protein-caloric malnutrition and one infected by HIV-1. The third patient was immunocompetent. All 3 patients were treated by intravenous Fluconazole. The immunocompetent boy died after 1 month of hospitalization due to cardiovascular and respiratory insufficiency. Both girls survived with severe neurosensory sequels. Cryptococcal meningitis that is relatively frequent in adulthood may be underestimated in children and should be tested for in any children presenting meningoencephalitis of undetermined cause.
Wei, Baozhu; Qian, Cheng; Liu, Yang; Lin, Xuan; Wan, Jing; Wang, Yanggan
The objective is to study the role of Ommaya reservoir in the treatment of cryptococcal meningitis. The clinical data of 42 patients with cryptococcal meningitis were retrospectively studied. The Ommaya group included 20 patients, who were treated with Amphotericin B (Am B) and Ommaya reservoir implantation. The non-Ommaya group contained 22 patients, who were just treated with Amphotericin B (Am B). In the Ommaya group (surgical group), all 20 patients with Ommaya reservoir were fully recovered, and their average hospital stay period and average treatment period with Amphotericin B were 105.3 ± 18.3 and 75.0 ± 18.1 days, respectively. In the non-Ommaya group (control group), 16 patients were fully recovered and the average hospital stay period and average treatment period with Amphotericin B of these 22 patients were 139.6 ± 29.5 and 150.0 ± 32.2 days, respectively. In the surgical group, average period of cryptococcus disappearance was 20 ± 8 days, while in the control group, that was 35 ± 10 days. The clinical efficacy was better in surgical group than control group (P < 0.05). Ommaya reservoir implantation is a valuable approach in the treatment of cryptococcal meningitis and can improve the cure rate, decrease mortality, and shorten the period of treatment.
Nidhi, Anand; Meena, Alpana; Sreekumar, Arjun; Daga, Mradul Kumar
Cryptococcus neoformans is the most frequent cause of fungal meningitis in humans. Cryptococcus affects people of all ages and has a worldwide distribution. It is the fourth most common infection in AIDS (CD4 counts <100/mm(3)). Cases also occur in patients with other forms of immunosuppression and in apparently immunocompetent individuals. Chronic high-dose steroid may precipitate such an immunocompromised state and thus create susceptibility to fungal infections. In our case, we describe a 14-year-old boy who was on steroids for tubercular meningitis for a period of 8 weeks after which he developed cryptococcal meningitis. Attention is drawn to the increasing number of reported cases of this disease which have been associated with steroid therapy and this possibility should be remembered when investigating patients with tubercular meningitis especially if they are being treated with steroids. 2017 BMJ Publishing Group Ltd.
Kabanda, Taseera; Siedner, Mark J; Klausner, Jeffrey D; Muzoora, Conrad; Boulware, David R
The cryptococcal antigen (CRAG) lateral flow assay (LFA) had 100% sensitivity and specificity on cerebrospinal fluid samples. Pretreatment LFA titers correlated with quantitative cultures (R(2) = 0.7) and predicted 2- and 10-week mortality. The CRAG LFA is an accurate diagnostic assay for CSF and should be considered for point-of-care diagnosis of cryptococcal meningitis.
Loyse, A; Moodley, A; Rich, P; Molloy, S F; Bicanic, T; Bishop, L; Rae, W I D; Bhigjee, A I; Loubser, N D; Michowicz, A J; Wilson, D; Harrison, T S
HIV-associated cryptococcal meningoencephalitis (CM) is a leading cause of adult meningitis in sub-Saharan Africa. Neuroradiological data is however limited to case reports and small case series from developed countries and/or immunocompetent patients. Eighty seven patients aged ≥18 hospitalized with a first episode of CM had magnetic resonance (MRI) imaging during the first two weeks of admission. A subset of eleven patients had follow-up scans approximately one month from their initial MRI scan. All had prospectively-recorded detailed neurological and visual examinations. An abnormal finding on neurological examination was detected in 33 (39%) patients. 38 (48%) patients experienced some visual loss. Neuroradiological lesions presumed to be cryptococcosis-related, as defined by the presence of dilated Virchow Robin spaces, pseudocysts or cryptococcomas, enhancing nodules, hydrocephalus, meningitis, focal perilesional oedema and infarcts, were detected in 55 (63%) patients. MRI findings suggestive of a second diagnosis were found in 18 (21%) patients. Visual loss was associated with the presence of cryptococcal-related lesions (p = 0.02). Blindness was associated with raised intracranial pressure (ICP) (p = 0.02). Of eleven patients with paired scans, brain swelling was identified on the initial scan in only one patient. The majority of patients had MRI brain scan abnormalities presumed secondary to CM. Dilated Virchow Robin spaces were the commonest neuroradiological lesion. Visual loss was associated with the degree of cerebral involvement as reflected by the presence of MRI abnormalities. Blindness was associated with the presence of raised ICP. Initial generalised brain swelling does not appear to be common, but further studies with paired scans are needed. Copyright © 2014 The British Infection Association. Published by Elsevier Ltd. All rights reserved.
Henao-Martínez, Andrés F; Gross, Lilyana; Mcnair, Bryan; McCollister, Bruce; DeSanto, Kristen; Montoya, Jose G; Shapiro, Leland; Beckham, J David
Cryptococcal meningitis carries a high mortality. Further understanding of immune suppression factors associated with neuroinvasive infection will improve risk stratification and enhance early diagnosis and treatment with antifungal therapy. The aim of the study was to corroborate established or find novel clinical predictors for cryptococcal meningitis. We performed a matched case-control study of Cryptococcus infection in immunocompromised patients with or without cryptococcal meningitis. Data of all patients with a diagnosis of cryptococcal disease were collected at University of Colorado Hospital between 2000 and 2015 (n = 51). Thirty patients were diagnosed with cryptococcal meningitis. We built a logistic regression model for risk factors associated with cryptococcal meningitis. The single-predictor univariate model found that a positive blood culture, positive serum cryptococcal antigen, current malignancy, and headaches were significantly associated with cryptococcal meningitis (p = 0.02). In the adjusted multivariate model, central nervous system disease was significantly associated with a diagnosis of HIV infection (OR 24.45, 95 % CI 1.62-350.37; p = 0.022) and a positive serum cryptococcal antigen test (OR 42.92, 95 % CI 3.26-555.55; p = 0.0055). In patients with HIV infection or a positive serum cryptococcal antigen, the pretest probability of neuroinvasive Cryptococcus infection is increased and an aggressive diagnostic evaluation should be conducted to exclude infection and consider empiric therapy.
Opota, O; Desgraz, B; Kenfak, A; Jaton, K; Cavassini, M; Greub, G; Prod'hom, G; Giulieri, S
Detection of cryptococcal antigen in serum or cerebrospinal fluid allows cryptococcal meningitis diagnosis within few hours with >90% sensitivity. In an HIV-positive patient with Cryptococcus neoformans meningitis, initial antigen detection by immunoagglutination was negative. We thus evaluated a new immunochromatographic detection assay that exhibited a higher sensitivity.
Patil, Shripad A; Katyayani, S; Arvind, N
Cryptococcus neoformans is the causative agent of Cryptococcosis, a chronic and life-threatening infection common in AIDS patients. Sonicated proteins of cryptococci were reported to contain antigenic properties. In the present study antigens are prepared from cryptococcal culture filtrate and by sonication. Secretory antigens are prepared by precipitation of culture filtrate using saturated ammonium sulfate followed by dialysis. Prepared antigens are tested for the presence of antibodies in the CSF samples of cryptococcal meningitis cases by ELISA. Comparison is made between India ink staining, latex antigen test, and the antibodies to the sonicated and secretory antigens. The results indicate that although antigen could be detected in the majority of samples, antibody could also be detected to the extent of 80-85%. It is interesting to note that some samples that were negative for India ink staining also showed high antibody responses. Hence, antibody detection could be a valuable marker in association with India ink staining for the early diagnosis of the cryptococcal infection. This test may also counter false positivity encountered in latex antigen test. Antibody detection assay would be a viable alternative, which has 83% sensitivity and 100% specificity. Thus the presently described test aids in immunodiagnosis of cryptococcal infection.
Yang, YaLi; Sang, Junjun; Pan, Weihua; Du, Lin; Liao, Wanqing; Chen, Jianghan; Zhu, Yuanjie
To summarize the epidemiology, clinical features, treatment, and outcome of cryptococcal meningitis (CM) in autoimmune hemolytic anemia (AIHA) patients and to provide a reference for the prevention and control of AIHA complicated with CM, we evaluated five cases of CM in patients with AIHA treated in our hospital from 2003 to 2013 and eight related foreign cases. All of the clinical isolates were Cryptococcus neoformans var. grubii and grouped into the VNI genotype and serotype A. The clinical features exhibit significant features. Headache, nausea, and fever are common symptoms of AIHA complicated with CM. The early clinical manifestations lack specificity, which may lead to delayed diagnosis and treatment. Long-term use of prednisone (≥15 mg day(-1)), poor control of anemia, and splenectomy are risk factors for AIHA complicated with cryptococcal infection. The combination of intravenous amphotericin B and oral 5-fluorocytosine remains the preferred treatment for AIHA complicated with CM.
Rosen, Lindsey B.; Freeman, Alexandra F.; Yang, Lauren M.; Jutivorakool, Kamonwan; Olivier, Kenneth N.; Angkasekwinai, Nasikarn; Suputtamongkol, Yupin; Bennett, John E.; Pyrgos, Vasilios; Williamson, Peter R.; Ding, Li; Holland, Steven M.; Browne, Sarah K.
Background Cryptococcal meningitis has been described in immunocompromised patients as well as in those for whom no immune defect has been identified. GM-CSF regulates the function of phagocytes and pulmonary alveolar macrophages, critical elements in cryptococcal control. Methods We performed clinical histories, immunological evaluation, and anticytokine autoantibody screening in 4 current patients with cryptococcal meningitis, and identified and tested 103 archived plasma/CSF samples from patients with cryptococcal meningitis. We assessed the ability of anti-GM-CSF autoantibody containing plasmas to inhibit GM-CSF signaling. Results We recognized anti-GM-CSF autoantibodies in an otherwise healthy female with cryptococcal meningitis who later developed pulmonary alveolar proteinosis. Her diagnosis prompted screening of patients with cryptococcal meningitis for anticytokine autoantibodies. We identified 7 HIV uninfected patients with cryptococcal meningitis who tested positive for high-titer anti-GM-CSF autoantibodies. Two of the 7 later developed evidence of PAP. Plasma from all patients prevented GM-CSF-induced STAT-5 phosphorylation and MIP-1α production in normal PBMC. This effect was limited to their IgG fraction. Conclusions Anti-GM-CSF autoantibodies are associated with some cases of cryptococcal meningitis in otherwise immunocompetent patients. These cases need not have associated pulmonary alveolar proteinosis. PMID:23509356
Tanaka, Yuji; Satomi, Kazuo
We herein report the case of a 72-year-old-man with pulmonary cryptococcoma along with cryptococcal meningitis who underwent surgery for pulmonary lesions while receiving chemotherapy. We noted two major clinical issues. First, the presence of pulmonary cryptococcoma had a detrimental influence on the cryptococcal meningitis. Second, resolution of the pulmonary cryptococcoma through antifungal therapy had a beneficial influence on the recovery from cryptococcal meningitis. As observed in the current case with pulmonary and meningeal cryptococcosis, surgery for pulmonary cryptococcoma with continuous antifungal treatment should be considered for cases where the symptoms respond poorly to antifungal therapy and radiographic abnormalities persist. PMID:28050006
Petrou, Panayota; Moscovici, Samuel; Leker, Ronen R; Itshayek, Eyal; Gomori, John M; Cohen, José E
The use of a ventriculoperitoneal (VP) shunt to treat uncontrollable intracranial hypertension in patients with cryptococcal meningitis without hydrocephalus is somewhat unusual and still largely unreported. However, uncontrollable intracranial hypertension without hydrocephalus in these patients is a potentially life-threatening condition. Early diagnosis and shunt placement are essential to improve survival and neurological function. We report uncontrollable intracranial hypertension without hydrocephalus in a 23-year-old woman, which was successfully managed by VP shunt placement. Copyright © 2012 Elsevier Ltd. All rights reserved.
Sharma, A; Lal, V; Modi, M; Khurana, D; Bal, S; Prabhakar, S
Idiopathic CD4 T-lymphocytopenia (ICL) is a syndrome characterized by depletion of CD4 T-cells without evidence of human immunodeficiency virus (HIV) infection. There are a few reported cases of ICL associated with different diseases and clinical conditions, most commonly the opportunistic infections like Tuberculosis, fungal and parasitic diseases which are also seen in HIV-positive patients. We report a case without risk factors or laboratory evidence of HIV infection who presented with refractory cryptococcal meningitis and was found to have ICL.
Kovanda, Laura; Najvar, Laura K.; Bocanegra, Rosie; Olivo, Marcos; Kirkpatrick, William R.; Patterson, Thomas F.
We evaluated the efficacy of isavuconazole against cryptococcal meningitis. Treatment with either oral isavuconazole (120 mg/kg and 240 mg/kg twice a day [BID]) or fluconazole as the positive control significantly improved survival in mice infected intracranially with either Cryptococcus neoformans USC1597 or H99 and significantly reduced brain fungal burdens for both isolates. Concentrations of isavuconazole in plasma and brain tissue also demonstrated that the greatest improvements in survival and fungal burden were associated with elevated exposures. PMID:27324761
O'Reilly, Dominic Anthony
Cryptococcal meningitis is uncommon in children, particularly in infants. A 2-day-old boy was admitted with signs suggestive of meningitis. Lumbar puncture confirmed meningitis and cryptococcal infection (cryptococcal antigen and Indian ink stain-positive). His mother was HIV-negative. This is thought to be the youngest case of cryptococcal meningitis to be reported. Cryptococcal infection should be considered in children of all ages with meningitis where there is possible immunodeficiency or failure to respond to initial treatment with antibiotics.
Tabassum, Saadia; Rahman, Atiya; Herekar, Fivzia; Masood, Sadia
Cryptococcosis is a potentially fatal fungal disease caused by variants of Cryptococcus neoformans species. The respiratory tract is the usual portal of entry, with a peculiar predilection to invade the central nervous system. The skin can be secondarily involved in disseminated infection or be exceptionally involved as primary cutaneous infection by inoculation. The disease is mostly seen in immunodeficiency states. The diagnosis is frequently unsuspected in immunocompetent patients. We report a case of disseminated cryptococcal meningitis in an immunocompetent young adult. The cutaneous eruption prompted the accurate diagnosis. The patient, a 20-year-old female, had fever, cough, headache and intractable vomiting for the past two months and was being managed as a case of tuberculous meningitis. Two weeks after starting antituberculous treatment she developed umbilicated papules on the head and neck region. Necessary laboratory workup identified C. neoformans in cerebrospinal fluid (CSF) and skin specimens. The titers of cryptococcal antigen were measured in CSF and serum for diagnostic and prognostic purposes. Anti-fungal treatment resulted in regression of the cutaneous lesions and resolution of systemic complaints. The case highlights the need for high degree of suspicion, especially in healthy young adults, in the diagnosis of cryptococcosis. The cutaneous eruptions can be the first manifestation or a diagnostic clue of enormous significance.
Kishi, Kazuma; Homma, Sakae; Nakatani, Tatsuo; Nakata, Koichiro
We reviewed the clinical manifestations, sequential changes in cryptococcal antigen titers in serum and cerebrospinal fluid (CSF), and the antifungal drug susceptibility of Cryptococcus neoformans in three patients with cryptococcal meningitis between 1996 and 2000. Cryptococcal antigen titers were measured using the latex agglutination method with Pastrex Cryptococcus (Fuji Mebio, Tokyo) and Serodirect Cryptococcus (Eiken Chemical, Tokyo). The underlying systemic diseases in the three patients were liver cirrhosis, non-Hodgkin's lymphoma associated with miliary tuberculosis, and malignant thymoma associated with systemic lupus erythymatosus. The CSF samples showed positive indian ink staining in two of the three patients and C. neoformans was cultured from all three. The cryptococcal antigen titers in serum were higher than those in the CSF. The serum and CSF cryptococcal antigen titers measured by Serodirect Cryptococcus were higher than those measured by Pastrex Cryptococcus. The maximum titers of antigen in serum and CSF measured by Serodirect Cryptococcus were greater than 1,024 in all three patients. The treatment regimens used for the three patients were amphotericin-B (AMPH-B) and flucytosine (5-FC), fluconazole (FLCZ) and intrathecal AMPH-B, FLCZ and 5-FC, and intrathecal AMPH-B, respectively. The antigen titers in serum and CSF decreased after treatment in all three patients. The antigen titers decreased slowly over 7.3 months in the most seriously ill patient who had non-Hodgkin's lymphoma associated with miliary tuberculosis. The time between the beginning of treatment and CSF cryptococal antigen titers falling to less than 8 was 1.7 to 7.3 months in the three patients, but the serum titers did not decrease to less than 8 during this period. The minimum inhibitory concentration was 0.06-0.25 microgram/ml for AMPH-B, 4-8 micrograms/ml for 5-FC, 2-8 micrograms/ml for FLCZ, 0.125-0.5 microgram/ml for miconazole and 0.03-0.125 microgram/ml for itraconazole
Brouwer, Annemarie E; Teparrukkul, Paprit; Pinpraphaporn, Supraphada; Larsen, Robert A; Chierakul, Wirongrong; Peacock, Sharon; Day, Nicholas; White, Nicholas J; Harrison, Thomas S
Cerebrospinal fluid (CSF) cryptococcal colony-forming unit counts and CSF cryptococcal antigen titers serve as alternative measures of organism load in cryptococcal meningitis. For these measures, we correlated baseline values and rates of decline during the first 2 weeks of therapy in 68 human immunodeficiency virus--seropositive patients with cryptococcal meningitis. At baseline, there was a strong correlation between CSF cryptococcal colony-forming unit counts and CSF cryptococcal antigen titers. During the first 2 weeks of therapy, CSF cryptococcal colony-forming unit counts decreased by >5 logs, and CSF cryptococcal antigen titers decreased by 1.5 dilutions. In individual patients, there was no correlation between the rate of decline in CSF cryptococcal colony-forming unit counts and that in CSF cryptococcal antigen titers.
Jiang, S; Lei, T-C; Xu, S-Z
Patients with systemic lupus erythematosus (SLE) have an increased susceptibility to bacterial, viral, fungal and parasitic infections. Cryptococcal infection of the central nervous system (CNS) is a rare but often fatal complication of SLE. Here, we describe a case of cryptococcal meningitis in a female patient with active SLE, who was successfully treated with amphotericin B. This case suggests that the clinical findings of SLE patients with cryptococcal meningitis are non-specific and misleading, and early use of amphotericin B has a good response.
Jiang, S; Lei, T-C; Xu, S-Z
Patients with systemic lupus erythematosus (SLE) have an increased susceptibility to bacterial, viral, fungal and parasitic infections. Cryptococcal infection of the central nervous system (CNS) is a rare but often fatal complication of SLE. Here we describe a case of cryptococcal meningitis in a female patient with active SLE, who was successfully treated with amphotericin B. This case suggests that the clinical findings of SLE patients with cryptococcal meningitis are non-specific and misleading, and early use of amphotericin B has a good response.
Carlson, Renee Donahue; Rolfes, Melissa A; Birkenkamp, Kate E; Nakasujja, Noeline; Rajasingham, Radha; Meya, David B; Boulware, David R
Cryptococcal meningitis is the most common cause of adult meningitis in Africa, yet neurocognitive outcomes are unknown. We investigated the incidence and predictors of neurologic impairment among cryptococcal survivors. HIV-infected, antiretroviral-naive Ugandans with cryptococcal meningitis underwent standardized neuropsychological testing at 1, 3, 6, and 12 months. A quantitative neurocognitive performance z-score (QNPZ) was calculated based on population z-scores from HIV-negative Ugandans (n = 100). Comparison was made with an HIV-infected, non-meningitis cohort (n = 110). Among 78 cryptococcal meningitis survivors with median CD4 count of 13 cells/μL (interquartile range: 6-44), decreased global cognitive function occurred through 12 months compared with the HIV-infected, non-cryptococcosis cohort (QNPZ-6 at 12 months, P = 0.036). Tests of performance in eight cognitive domains was impaired 1 month after cryptococcal diagnosis; however, cryptococcal meningitis survivors improved their global neurocognitive function over 12 months with residual impairment (mean z-scores < -1), only in domains of motor speed, gross motor and executive function at 12 months. There was no evidence that neurocognitive outcome was associated with initial demographics, HIV parameters, or meningitis severity. Paradoxically, persons with sterile CSF cultures after 14 days of induction amphotericin therapy had worse neurocognitive outcomes than those still culture-positive at 14 days (P = 0.002). Cryptococcal meningitis survivors have significant short-term neurocognitive impairment with marked improvement over the first 12 months. Few characteristics related to severity of cryptococcosis, including Cryptococcus burden, were associated with neurocognitive outcome.
Loyse, Angela; Thangaraj, Harry; Easterbrook, Philippa; Ford, Nathan; Roy, Monika; Chiller, Tom; Govender, Nelesh; Harrison, Thomas S; Bicanic, Tihana
Cryptococcal meningitis is the leading cause of adult meningitis in sub-Saharan Africa, and contributes up to 20% of AIDS-related mortality in low-income and middle-income countries every year. Antifungal treatment for cryptococcal meningitis relies on three old, off-patent antifungal drugs: amphotericin B deoxycholate, flucytosine, and fluconazole. Widely accepted treatment guidelines recommend amphotericin B and flucytosine as first-line induction treatment for cryptococcal meningitis. However, flucytosine is unavailable in Africa and most of Asia, and safe amphotericin B administration requires patient hospitalisation and careful laboratory monitoring to identify and treat common side-effects. Therefore, fluconazole monotherapy is widely used in low-income and middle-income countries for induction therapy, but treatment is associated with significantly increased rates of mortality. We review the antifungal drugs used to treat cryptococcal meningitis with respect to clinical effectiveness and access issues specific to low-income and middle-income countries. Each drug poses unique access challenges: amphotericin B through cost, toxic effects, and insufficiently coordinated distribution; flucytosine through cost and scarcity of registration; and fluconazole through challenges in maintenance of local stocks--eg, sustainability of donations or insufficient generic supplies. We advocate ten steps that need to be taken to improve access to safe and effective antifungal therapy for cryptococcal meningitis.
Desalermos, Athanasios; Kourkoumpetis, Themistoklis K; Mylonakis, Eleftherios
Despite recent improvements in the diagnosis and treatment of cryptococcosis, cryptococcal meningitis is responsible for > 600,000 deaths/year worldwide. The aim of this work is to provide an update on the developments in its epidemiology and management. Understanding the pathogenesis of Cryptococcus has improved, and new insights for the virulence of the fungus and the host response have enabled scientists to design new ways to confront this infection. Additionally, invertebrate model hosts have greatly facilitated the research in this field. Importantly, the epidemiology of Cryptococcus gattii has continued to evolve, and the emergence of this highly virulent species in immunocompetent populations, especially in Northwestern America and British Columbia, warrants increased awareness because delayed diagnosis and inappropriate antifungal therapy is associated with high mortality. Diagnosis remains a challenge, but new techniques for early and inexpensive identification of the pathogen are under development. Management can vary, based on the patient population (HIV-seropositive, organ transplant recipients or non-transplant/non-HIV). In most patients, amphotericin B with flucytosine continues to be the most appropriate induction therapy. However, in organ transplant recipients the use of liposomal amphotericin B improves mortality compared with deoxycholate amphotericin B. Also, the combination of amphotericin B with fluconazole seems to be a reasonable alternative, while fluconazole with flucytosine is superior to fluconazole monotherapy.
Ward, Melanie D; Jones, David E; Goldman, Myla D
Fingolimod (Gilenya, Novartis) is an oral sphingosine-1-phosphate analogue used in the treatment of relapsing multiple sclerosis (MS). Fingolimod treatment is associated with relative lymphopenia and was associated with an increased risk of herpes infection in clinical trials. In the post-marketing setting, fingolimod has been associated with several cases of cryptococcal meningitis, recently prompting an update to its prescribing information. To date, all cases have been associated with active treatment with fingolimod. In this report, we describe the first case of cryptococcal meningitis diagnosed after fingolimod discontinuation.
Rohatgi, Soma; Gohil, Shruti; Kuniholm, Mark H.; Schultz, Hannah; Dufaud, Chad; Armour, Kathryn L.; Badri, Sheila; Mailliard, Robbie B.; Pirofski, Liise-anne
ABSTRACT Cryptococcus neoformans is one of the most common causes of fungal disease in HIV-infected persons, but not all of those who are infected develop cryptococcal disease (CD). Although CD4+ T cell deficiency is a risk factor for HIV-associated CD, polymorphisms of phagocytic Fc gamma receptors (FCGRs) have been linked to CD risk in HIV-uninfected persons. To investigate associations between FCGR2A 131 H/R and FCGR3A 158 F/V polymorphisms and CD risk in HIV-infected persons, we performed PCR-based genotyping on banked samples from 164 men enrolled in the Multicenter AIDS Cohort Study (MACS): 55 who were HIV infected and developed CD and a matched control group of 54 who were HIV infected and 55 who were HIV uninfected. Using additive and allelic statistical models for analysis, the high-affinity FCGR3A 158V allele was significantly associated with CD status after adjusting for race/ethnicity (odds ratio [OR], 2.1; P = 0.005), as was the FCGR3A 158 VV homozygous genotype after adjusting for race/ethnicity, rate of CD4+ T cell decline, and nadir CD4+ T cell count (OR, 21; P = 0.005). No associations between CD and FCGR2A 131 H/R polymorphism were identified. In binding studies, human IgG (hIgG)-C. neoformans complexes exhibited more binding to CHO-K1 cells expressing FCGR3A 158V than to those expressing FCGR3A 158F, and in cytotoxicity assays, natural killer (NK) cells expressing FCGR3A 158V induced more C. neoformans-infected monocyte cytotoxicity than those expressing FCGR3A 158F. Together, these results show an association between the FCGR3A 158V allele and risk for HIV-associated CD and suggest that this polymorphism could promote C. neoformans pathogenesis via increased binding of C. neoformans immune complexes, resulting in increased phagocyte cargo and/or immune activation. PMID:23982074
To, Christina A; Hsieh, Robert W; McClellan, James Scott; Howard, Walter; Fischbein, Nancy J; Brown, Janice M Y; Felsher, Dean W; Fan, Alice C
The authors present the first case report of a patient with lymphoma who developed disseminated cryptococcal osteomyelitis and meningitis while being treated with the PEP-C (prednisone, etoposide, procarbazine and cyclophosphamide) chemotherapy regimen. During investigation of fever and new bony lesions, fungal culture from a rib biopsy revealed that the patient had cryptococcal osteomyelitis. Further evaluation demonstrated concurrent cryptococcal meningitis. The patient's disseminated cryptococcal infections completely resolved after a full course of antifungal treatment. Cryptococcal osteomyelitis is itself an extremely rare diagnosis, and the unique presentation with concurrent cryptococcal meningitis in our patient with lymphoma was likely due to his PEP-C treatment. It is well recognised that prolonged intensive chemotherapeutic regimens place patients at risk for atypical infections; yet physicians should recognise that even chronic low-dose therapies can put patients at risk for fungal infections. Physicians should consider fungal infections as part of the infectious investigation of a lymphopaenic patient on PEP-C.
To, Christina A; Hsieh, Robert W; McClellan, James Scott; Howard, Walter; Fischbein, Nancy J; Brown, Janice M Y; Felsher, Dean W; Fan, Alice C
The authors present the first case report of a patient with lymphoma who developed disseminated cryptococcal osteomyelitis and meningitis while being treated with the PEP-C (prednisone, etoposide, procarbazine and cyclophosphamide) chemotherapy regimen. During investigation of fever and new bony lesions, fungal culture from a rib biopsy revealed that the patient had cryptococcal osteomyelitis. Further evaluation demonstrated concurrent cryptococcal meningitis. The patient’s disseminated cryptococcal infections completely resolved after a full course of antifungal treatment. Cryptococcal osteomyelitis is itself an extremely rare diagnosis, and the unique presentation with concurrent cryptococcal meningitis in our patient with lymphoma was likely due to his PEP-C treatment. It is well recognised that prolonged intensive chemotherapeutic regimens place patients at risk for atypical infections; yet physicians should recognise that even chronic low-dose therapies can put patients at risk for fungal infections. Physicians should consider fungal infections as part of the infectious investigation of a lymphopaenic patient on PEP-C. PMID:22962380
Nasri, Hashem; Kabbani, Sarah; Bou Alwan, Melhim; Wang, Yun F; Rebolledo, Paulina A; Kraft, Colleen S; Nguyen, Minh L; Anderson, Albert M; Rouphael, Nadine
Background. Mortality for cryptococcal meningitis remains significant, in spite of available treatment. Resistance to first-line maintenance therapy, particularly fluconazole, has been reported. Methods. A retrospective chart review was performed on immunocompromised patients with cryptococcal meningitis, who had susceptibility testing performed between January 2001 and December 2011, at 3 hospitals in Atlanta, Georgia. Results. A total of 35 immunocompromised patients with cryptococcal meningitis were identified, 13 (37.1%) of whom had an elevated minimum inhibitory concentration (MIC) to fluconazole (MIC ≥16 µg/mL). Eighty percent of patients were males with African American predominance, the median age was 37 years, and 80% of the patients were human immunodeficiency virus (HIV) positive. Subsequent recurrence of cryptococcal meningitis was more likely in HIV patients compared with solid organ transplant patients (P = .0366). Overall, there was a statistically significant increase in an elevated MIC to fluconazole in patients who had a history of prior azole use (odds ratio, 10.12; 95% confidence interval, 2.04-50.16). Patients with an elevated MIC to fluconazole and those with a high cerebrospinal fluid cryptococcal antigen load (≥1:512) were more likely to have central nervous system complications (P = .0358 and P = .023, respectively). Although no association was observed between an elevated MIC to fluconazole and mortality, those who received voriconazole or high-dose fluconazole (≥800 mg) for maintenance therapy were more likely to survive (P = .0288). Conclusions. Additional studies are required to further investigate the morbidity and mortality associated with an elevated MIC to fluconazole in cryptococcal meningitis, to determine when it is appropriate to perform susceptibility testing, and to evaluate its cost effectiveness.
Ogaki, Kotaro; Noda, Kazuyuki; Fukae, Jiro; Furuya, Tsuyoshi; Hirayama, Takashi; Fujishima, Kenji; Hattori, Nobutaka; Okuma, Yasuyuki
Abstract An 81-year-old woman who had microscopic polyangiitis that was being treated with corticosteroids for 2 months was admitted to our department because of fever and clouding of consciousness. Neurological examination showed disturbance of consciousness and nuchal stiffness. Analysis of cerebrospinal fluid (CSF) revealed pleocytosis, low glucose level, and elevated protein levels. On the basis of the presence of Cryptococcus neoformans in CSF, the patient was diagnosed with cryptococcal meningitis. On the basis of established practice guidelines, liposomal amphotericin B (L-AMB) was administered to avoid the possible nephrotoxicity of amphotericin B. After the treatment was started, the patient's condition gradually improved. The results of CSF analysis also showed a gradual recovery. Because the cryptococcal antigen in CSF did not disappear completely, voriconazole (VRCZ) was administered orally; subsequently, the CSF cryptococcal antigen titer gradually decreased. During the course of the treatment with L-AMB and VRCZ, there were no severe side effects that required a change in treatment. To the best of our knowledge, in Japan, the combination of L-AMB and VRCZ has rarely been reported to be effective for the treatment of cryptococcal meningitis. The recovery of our patient indicates that the administration of L-AMB and VRCZ to elderly patients with cryptococcal meningitis and renal insufficiency is safe and leads to a successful outcome.
van Toorn, Ronald; Rabie, Helena
We describe a 10-year-old human immune deficiency virus (HIV) infected girl who presented with pseudocystic cryptococcal meningitis complicated by hydrocephalus secondary to aqueductal obstruction. The neuroradiological features of this case are presented and we also postulate on the pathogenesis of the type of hydrocephalus encountered.
Fang, Wenjie; Chen, Min; Liu, Jia; Hagen, Ferry; Ms, Abdullah; Al-Hatmi; Zhang, Peilian; Guo, Yun; Boekhout, Teun; Deng, Danqi; Xu, Jianping; Pan, Weihua; Liao, Wanqing
Cryptococcal meningitis is an important fungal infection among systemic lupus erythematosus patients. We conducted a pooled analysis and systematic review to describe the epidemiological and clinical profile of cryptococcal meningitis in systemic lupus erythematosus patients. From two hospitals in China and nine literature databases, cases and prevalence data were collected for pooled analysis and meta-analysis, respectively. Categorical variables of cases were compared using a χ(2)-test on the statistical program of SAS. A multiple regression analysis was performed to ascertain independent predictors significantly correlated with prognosis. Meta-analysis was conducted by the statistical program of R. The prevalence of cryptococcal meningitis in systemic lupus erythematosus patients was 0.5%. Patients were predominantly females and adults. A prednisone equivalent of more than 30 mg/day before infection was associated with higher mortality (odds ratio (OR)=9.69 (1.54, 60.73)). In all, 36.8-38.9% patients showed low lupus activity when they developed the crytococcal infection. Moreover, 38.2% of the patients were misdiagnosed. The estimated case-fatality rate was 23.6%. Our results suggest that more emphasis should be placed to further understand lupus-related cryptococcal meningitis and to develop better prophylaxis and management strategies to combat this condition.
Fang, Wenjie; Chen, Min; Liu, Jia; Hagen, Ferry; MS, Abdullah; Al-Hatmi; Zhang, Peilian; Guo, Yun; Boekhout, Teun; Deng, Danqi; Xu, Jianping; Pan, Weihua; Liao, Wanqing
Cryptococcal meningitis is an important fungal infection among systemic lupus erythematosus patients. We conducted a pooled analysis and systematic review to describe the epidemiological and clinical profile of cryptococcal meningitis in systemic lupus erythematosus patients. From two hospitals in China and nine literature databases, cases and prevalence data were collected for pooled analysis and meta-analysis, respectively. Categorical variables of cases were compared using a χ2-test on the statistical program of SAS. A multiple regression analysis was performed to ascertain independent predictors significantly correlated with prognosis. Meta-analysis was conducted by the statistical program of R. The prevalence of cryptococcal meningitis in systemic lupus erythematosus patients was 0.5%. Patients were predominantly females and adults. A prednisone equivalent of more than 30 mg/day before infection was associated with higher mortality (odds ratio (OR)=9.69 (1.54, 60.73)). In all, 36.8–38.9% patients showed low lupus activity when they developed the crytococcal infection. Moreover, 38.2% of the patients were misdiagnosed. The estimated case-fatality rate was 23.6%. Our results suggest that more emphasis should be placed to further understand lupus-related cryptococcal meningitis and to develop better prophylaxis and management strategies to combat this condition. PMID:27599471
Graham, Lisa M.; Schutz, Charlotte; Scriba, Thomas J.; Wilkinson, Robert J.; Boulware, David R.; Meintjes, Graeme; Lalloo, David G.; Urban, Britta C.
Fungal burden in the cerebrospinal fluid is an important determinant of mortality in cryptococcal meningitis, but its use in aiding clinical decision making is hampered by the time involved to perform quantitative cultures. Here, we demonstrate the potential of flow cytometry as a novel and rapid technique to address this issue. PMID:26719441
Leimann, Beatriz Consuelo Quinet; Koifman, Rosalina Jorge
The study aimed to compare the epidemiological profile of crytococcal meningitis in different information systems, thus assessing to what extent the profile available in the Sistema de Informação de Agravos de Notificação (Information System for Notifiable Diseases) reflected cryptococcal meningitis occurrences in the state of Rio de Janeiro, Southeastern Brazil, between 2002 and 2004. That database was compared to a new database comprised of cryptococcal meningitis cases from this System, from the Assessoria de Meningite da Secretaria de Saúde do Estado do Rio de Janeiro (State Department of Health Meningitis Advisory Committee), and from the Instituto Estadual de Infectologia São Sebastião (State Institute of Infectious Diseases) laboratory records. The System detected 65.7% of the cases present in the new database. The percentage of patients with AIDS as a pre-existing disease was similar in both databases (26% and 24.9%). Thus, even though cryptococcal meningitis incidence is underreported in the System, the profile of notified cases reflects the profile of the total number of cases.
Pettersen, Kenneth D; Pappas, Peter G; Chin-Hong, Peter; Baxi, Sanjiv M
Cryptococcal immune reconstitution inflammatory syndrome (C-IRIS) is an increasingly important manifestation among patients with HIV/AIDS, especially as the use of antiretroviral therapy (ART) is expanding worldwide. Cryptococcus and associated C-IRIS are common causes of meningitis. While intracranial lesions are common in HIV/AIDS, they are rarely due to cryptococcosis or C-IRIS. We describe two cases of paradoxical C-IRIS associated with the development of intracranial cryptococcomas in HIV/AIDS. Both patients had an initial episode of cryptococcal meningitis treated with antifungal therapy. At the time, they had initiated or modified ART with subsequent evidence of immune reconstitution. Two months later, they developed aseptic meningitis with intracranial lesions. After exhaustive work ups, both patients were diagnosed with paradoxical C-IRIS and biopsy confirmed intracranial cryptococcomas. We review the important clinical, diagnostic and therapeutic features of cryptococcomas associated with C-IRIS in HIV/AIDS.
Corti, Marcelo; Priarone, Maria; Negroni, Ricardo; Gilardi, Leonardo; Castrelo, Jimena; Arechayala, Alicia Irene; Messina, Fernando; Franze, Osvaldo
Cryptococcosis is an opportunistic mycosis, especially in patients that are human immunodeficiency virus (HIV)-positive, and frequently involves the central nervous system. We assessed the potential of ventriculoperitoneal shunting (VPS) in preventing mortality due to uncontrollable intracranial hypertension (ICH) in 15 patients with acquired immunodeficiency syndrome (AIDS)-related cryptococcal meningitis. After 2 weeks of antifungal therapy consisting of amphotericin B deoxycholate with or without fluconazole, patients with persistent ICH underwent VPS, despite having persistent Cryptococcus neoformans infection. In 12 patients, the uncontrollable ICH was resolved by VPS. Patients with cryptococcal meningoencephalitis who have ICH must be considered for VPS even with positive cerebrospinal fluid cultures.
Lee, Tae-Hee; Lee, Kee-Ook; Kim, Yong-Seok; Kim, Sun-Moon; Huh, Kyu-Chan; Choi, Young-Woo; Kang, Young-Woo
Various adverse events have been reported during combination therapy with pegylated (PEG)-interferon-α and ribavirin, although opportunistic infections, especially cryptococcal meningitis, are very rare. A 61-year-old woman complained of headaches and a fever during treatment of a chronic hepatitis C virus (HCV) infection. She had been treated for 7 months. Her headaches were refractory to analgesics, and she developed subtle nuchal rigidity. The cerebral spinal fluid (CSF) revealed a white blood cell count of 205/mm(3), 51 mg/dL protein, 35 mg/dL glucose, and negative Cryptococcus antigen. The CSF culture resulted in no growth. Five days later, the CSF was positive for Cryptococcus antigen. We administered amphotericin B and flucytosine, followed by fluconazole. Approximately 2 months later, she was discharged. For the first time, we report a case of cryptococcal meningitis during the treatment of chronic HCV with PEG-interferon-α and ribavirin.
Scriven, James E; Graham, Lisa M; Schutz, Charlotte; Scriba, Thomas J; Wilkinson, Katalin A; Wilkinson, Robert J; Boulware, David R; Urban, Britta C; Meintjes, Graeme; Lalloo, David G
Immune modulation may improve outcome in HIV-associated cryptococcal meningitis. Animal studies suggest alternatively activated macrophages are detrimental but human studies are limited. We performed a detailed assessment of the cerebrospinal fluid (CSF) immune response and examined immune correlates of disease severity and poor outcome, and the effects of antiretroviral therapy (ART). We enrolled persons ≥18 years with first episode of HIV-associated cryptococcal meningitis. CSF immune response was assessed using flow cytometry and multiplex cytokine analysis. Principal component analysis was used to examine relationships between immune response, fungal burden, intracranial pressure and mortality, and the effects of recent ART initiation (<12 weeks). CSF was available from 57 persons (median CD4 34/μL). CD206 (alternatively activated macrophage marker) was expressed on 54% CD14 and 35% CD14 monocyte-macrophages. High fungal burden was not associated with CD206 expression but with a paucity of CD4, CD8, and CD4CD8 T cells and lower interleukin-6, G-CSF, and interleukin-5 concentrations. High intracranial pressure (≥30 cm H2O) was associated with fewer T cells, a higher fungal burden, and larger Cryptococcus organisms. Mortality was associated with reduced interferon-gamma concentrations and CD4CD8 T cells but lost statistical significance when adjusted for multiple comparisons. Recent ART was associated with increased CSF CD4/CD8 ratio and a significantly increased macrophage expression of CD206. Paucity of CSF T cell infiltrate rather than alternative macrophage activation was associated with severe disease in HIV-associated cryptococcosis. ART had a pronounced effect on the immune response at the site of disease.
Mete, Bilgul; Saltoglu, Nese; Vanli, Ersin; Ozkara, Cigdem; Arslan, Ferhat; Mert, Ali; Ozaras, Resat; Tabak, Fehmi; Ozturk, Recep
Simultaneous central nervous system (CNS) infection with Cryptococcus and tuberculosis (TB) is very rare. Despite improved therapeutic options, treatment of CNS cryptococcosis is still difficult and needs invasive treatment modalities, such as intrathecal or intraventricular amphotericin B, in refractory cases. We describe a patient with systemic lupus erythematosus diagnosed with simultaneous cryptococcal and TB meningitis who had a poor response to intravenous liposomal amphotericin B and fluconazole, but was successfully treated with intraventricular amphotericin B, in addition to anti-TB therapy.
Tugume, L; Morawski, B M; Abassi, M; Bahr, N C; Kiggundu, R; Nabeta, H W; Hullsiek, K H; Taseera, K; Musubire, A K; Schutz, C; Muzoora, C; Williams, D A; Rolfes, M A; Meintjes, G; Rhein, J; Meya, D B; Boulware, D R
Anaemia represents a common toxicity with amphotericin B-based induction therapy in HIV-infected persons with cryptococcal meningitis. We sought to examine the impact of amphotericin-related anaemia on survival. We used data from Ugandan and South African trial participants to characterize the variation of haemoglobin concentrations from diagnosis to 12 weeks post-diagnosis. Anaemia severity was classified based on the haemoglobin concentration at cryptococcal meningitis diagnosis, and nadir haemoglobin values during amphotericin induction. Cox proportional hazard models were used to estimate 2- and 10-week mortality risk. We also estimated 10-week mortality risk among participants with nadir haemoglobin < 8.5 g/dL during amphotericin induction and who survived ≥ 2 weeks post-enrolment. The median haemoglobin concentration at meningitis diagnosis was 11.5 g/dL [interquartile range (IQR) 9.7-13 g/dL; n = 311] with a mean decline of 4.2 g/dL [95% confidence interval (CI) -4.6 to -3.8; P < 0.001; n = 148] from diagnosis to nadir value among participants with baseline haemoglobin ≥ 8.5 g/dL. The median haemoglobin concentration was 8.1 g/dL (IQR 6.5-9.5 g/dL) at 2 weeks, increasing to 9.4 g/dL (IQR 8.2-10.9 g/dL) by 4 weeks and continuing to increase to 12 weeks. Among participants with haemoglobin < 8.5 g/dL at diagnosis, mortality risk was elevated at 2 weeks [hazard ratio (HR) 2.7; 95% CI 1.5-4.9; P < 0.01] and 10 weeks (HR 1.8; 95% CI 1.1-2.2; P = 0.03), relative to those with haemoglobin ≥ 8.5 g/dL. New-onset anaemia occurring with amphotericin therapy did not have a statistically significant association with 10-week mortality (HR 2.0; 95% CI 0.5-9.1; P = 0.4). Amphotericin induced significant haemoglobin declines, which were mostly transient and did not impact 10-week mortality. Individuals with moderate to life-threatening anaemia at baseline had a higher mortality risk at 2 and 10 weeks post-enrolment. © 2016 British HIV Association.
Panackal, Anil A; Wuest, Simone C; Lin, Yen-Chih; Wu, Tianxia; Zhang, Nannan; Kosa, Peter; Komori, Mika; Blake, Andrew; Browne, Sarah K; Rosen, Lindsey B; Hagen, Ferry; Meis, Jacques; Levitz, Stuart M; Quezado, Martha; Hammoud, Dima; Bennett, John E; Bielekova, Bibi; Williamson, Peter R
The fungus Cryptococcus is a major cause of meningoencephalitis in HIV-infected as well as HIV-uninfected individuals with mortalities in developed countries of 20% and 30%, respectively. In HIV-related disease, defects in T-cell immunity are paramount, whereas there is little understanding of mechanisms of susceptibility in non-HIV related disease, especially that occurring in previously healthy adults. The present description is the first detailed immunological study of non-HIV-infected patients including those with severe central nervous system (s-CNS) disease to 1) identify mechanisms of susceptibility as well as 2) understand mechanisms underlying severe disease. Despite the expectation that, as in HIV, T-cell immunity would be deficient in such patients, cerebrospinal fluid (CSF) immunophenotyping, T-cell activation studies, soluble cytokine mapping and tissue cellular phenotyping demonstrated that patients with s-CNS disease had effective microbiological control, but displayed strong intrathecal expansion and activation of cells of both the innate and adaptive immunity including HLA-DR+ CD4+ and CD8+ cells and NK cells. These expanded CSF T cells were enriched for cryptococcal-antigen specific CD4+ cells and expressed high levels of IFN-γ as well as a lack of elevated CSF levels of typical T-cell specific Th2 cytokines -- IL-4 and IL-13. This inflammatory response was accompanied by elevated levels of CSF NFL, a marker of axonal damage, consistent with ongoing neurological damage. However, while tissue macrophage recruitment to the site of infection was intact, polarization studies of brain biopsy and autopsy specimens demonstrated an M2 macrophage polarization and poor phagocytosis of fungal cells. These studies thus expand the paradigm for cryptococcal disease susceptibility to include a prominent role for macrophage activation defects and suggest a spectrum of disease whereby severe neurological disease is characterized by immune-mediated host cell
Wu, Tianxia; Zhang, Nannan; Kosa, Peter; Komori, Mika; Blake, Andrew; Browne, Sarah K.; Rosen, Lindsey B.; Hagen, Ferry; Meis, Jacques; Levitz, Stuart M.; Quezado, Martha; Hammoud, Dima; Bennett, John E.; Bielekova, Bibi; Williamson, Peter R.
The fungus Cryptococcus is a major cause of meningoencephalitis in HIV-infected as well as HIV-uninfected individuals with mortalities in developed countries of 20% and 30%, respectively. In HIV-related disease, defects in T-cell immunity are paramount, whereas there is little understanding of mechanisms of susceptibility in non-HIV related disease, especially that occurring in previously healthy adults. The present description is the first detailed immunological study of non-HIV-infected patients including those with severe central nervous system (s-CNS) disease to 1) identify mechanisms of susceptibility as well as 2) understand mechanisms underlying severe disease. Despite the expectation that, as in HIV, T-cell immunity would be deficient in such patients, cerebrospinal fluid (CSF) immunophenotyping, T-cell activation studies, soluble cytokine mapping and tissue cellular phenotyping demonstrated that patients with s-CNS disease had effective microbiological control, but displayed strong intrathecal expansion and activation of cells of both the innate and adaptive immunity including HLA-DR+ CD4+ and CD8+ cells and NK cells. These expanded CSF T cells were enriched for cryptococcal-antigen specific CD4+ cells and expressed high levels of IFN-γ as well as a lack of elevated CSF levels of typical T-cell specific Th2 cytokines -- IL-4 and IL-13. This inflammatory response was accompanied by elevated levels of CSF NFL, a marker of axonal damage, consistent with ongoing neurological damage. However, while tissue macrophage recruitment to the site of infection was intact, polarization studies of brain biopsy and autopsy specimens demonstrated an M2 macrophage polarization and poor phagocytosis of fungal cells. These studies thus expand the paradigm for cryptococcal disease susceptibility to include a prominent role for macrophage activation defects and suggest a spectrum of disease whereby severe neurological disease is characterized by immune-mediated host cell
Nakae, Yoshiharu; Kudo, Yosuke; Yamamoto, Ryoo; Johkura, Ken
A pseudo-subarachnoid hemorrhage (pseudo-SAH) is a brain computed tomography (CT) finding that is seen as high-density areas along the basal cisterns, the sylvian vallecula/fissure, the tentorium cerebella, or the cortical sulci, although no SAH is found upon lumbar puncture or at autopsy. There is one report of cryptococcal meningitis presenting as pseudo-SAH, but the explanatory pathology is unknown. A 68-year-old woman with headache, fever, decreased hearing, and decreased vision was admitted to our hospital. Cerebrospinal fluid India ink staining was positive, and culture yielded Cryptococcus neoformans. Cryptococcus meningitis was diagnosed. Head CT and magnetic resonance imaging (MRI) showed no abnormality upon admission, but 1 month later, head CT showed iso- to high-density areas within the sulci, and fluid-attenuated inversion recovery MRI showed high signal intensity within the convexity sulci resembling an SAH. These areas were enhanced by gadolinium on T1-weighted images. Lumber puncture produced no evidence of bleeding. Biopsy of the left frontal lobe sulci was performed, and histopathological study revealed inflammation and granulation with capsules of C. neoformans. The inflammation and granulation at the convexity sulci induced by the C. neoformans infection explained the pseudo-SAH in this case. Physicians should be aware that cryptococcal meningitis-induced inflammation and granulation at the sulci can present as pseudo-SAH on CT and MRI.
Lee, Sunggeun; Collado, Anitsira; Singla, Montish; Carbajal, Roger; Chaudhari, Ashok; Baumstein, Donald
Hyponatremia is one of the most common electrolyte imbalances in HIV patients. The differential diagnosis may include hypovolemic hyponatremia, syndrome of inappropriate antidiuretic hormone secretion (SIADH), and adrenal insufficiency. Here, we describe a case of hyponatremia secondary to cerebral salt wasting syndrome (CSWS) in an HIV patient with cryptococcal meningitis. A 52-year-old man with a history of diabetes and HIV was admitted for headache and found to have cryptococcal meningitis. He was also found to have asymptomatic hyponatremia. He had signs of hypovolemia, such as orthostatic hypotension, dry mucosa, decreased skin turgor, hemoconcentration, contraction alkalosis, and high BUN/Cr ratio. The laboratory findings revealed sodium of 125 mmol/L, potassium of 5.5 mmol/L, urine osmolality of 522 mOsm/kg, urine sodium of 162 mmol/L, and urine chloride of 162 mmol/L. We started normal saline for hypovolemia, each 1 L prior and after amphotericin therapy. However, hypovolemia did not improve significantly despite IV fluid. Cosyntropin stimulation test was negative, and renin level was 0.25 ng·mL·h, with the aldosterone level of <1 ng/dL, the serum brain natriuretic peptide of 15 pg/mL, and serum uric acid of 2.8 mg/dL. The diagnosis of CSWS was suspected, fludrocortisone was tried, and hypovolemia and hyponatremia improved. Cryptococcal meningitis in HIV patients can present with CSWS, and the distinction between CSWS and SIADH is important because the treatment for CSWS is different than that of SIADH. Both share a similar clinical picture except that CSWS presents with constant hypovolemia despite volume replacement. Salt tablets, normal saline, or fludrocortisone can be used for treatment.
Kotwani, R N; Gokhale, P C; Bodhe, P V; Kirodian, B G; Kshirsagar, N A
Four patients with cryptococcal meningitis were successfully treated with liposomal amphotericin B prepared at our institute using Soya phosphatidylcholine and cholesterol. In one patient, response with 1 mg/kg/day treatment was poor. However, on increasing the dose to 2 mg/kg/day, a good response was observed with CSF becoming negative for Cryptococcus neoformans after seven days of this enhanced dose. L-AMP-LRC-1 was found to be well tolerated and a major advantage was observed in two renal transplant patients in whom it could be given safely.
Johnston, S R; Corbett, E L; Foster, O; Ash, S; Cohen, J
The clinical course of cryptococcal meningitis in AIDS shows some important differences from the features of the illness in non-AIDS patients. Complications such as raised intracranial pressure and visual impairment that are recognised in non-AIDS patients may be less frequent in those with AIDS. Persistent intracranial hypertension should be managed actively to prevent visual impairment. In AIDS patients, in whom ventriculo-peritoneal shunts carry additional risks, acetazolamide can be used successfully to lower the CSF pressure and prevent visual loss.
Zhang, Bingjun; Lv, Kefeng; Bao, Jian; Lu, Ciyong; Lu, Zhengqi
Objective It is difficult to make the differential diagnosis between tuberculous meningitis (TBM) and cryptococcal meningitis (CM) when the smear is negative. The objective of this study was to create a diagnostic rule for differentiating TBM from CM in adult HIV-negative patients based on clinical and laboratory features. Methods The clinical and laboratory data of 219 adult HIV-negative patients satisfying the diagnostic criteria for tuberculous (n=100) and cryptococcal (n=119) meningitis hospitalized at the Third Affiliated Hospital of Sun Yat-Sen University during the period 2000-2009 were retrospectively analyzed. Features found to be independently predictive of tuberculous meningitis were modeled using a multivariate logistic regression to create a diagnostic rule. The performance of the diagnostic rule was assessed using a prospective test data method. Results Six factors were found to be predictive of a diagnosis of tuberculous meningitis: gender, mental disorders, vision and/or hearing damage, proteins in the cerebrospinal fluid, the total cerebrospinal fluid white cell count and the coexistence of tuberculosis in peripheral organs. The diagnostic rule developed using these features exhibited 78.0% sensitivity, 95.2% specificity, 92.9% positive predictive value and 84.4% negative predictive value. The corresponding values for the diagnostic rule were 70.0% and 88.0% using prospective test data. Conclusion Clinical and laboratory features can be helpful in the differential diagnosis of tuberculous meningitis and cryptococcal meningitis in adult HIV-negative patients.
Xu, Nan; Gu, Julin; Zhu, Yuanjie; Wen, Hai; Ren, Qiushi; Chen, Jianghan
Amphotericin B deoxycholate (AmB), a classic antifungal drug, remains the initial treatment of choice for deep fungal infections, but it is not appropriate for treatment of cryptococcal meningitis due to its inability to pass through the blood–brain barrier (BBB). We examined the efficacy of amphotericin B-polybutylcyanoacrylate nanoparticles (AmB-PBCA-NPs) modified with polysorbate 80 that had a mean particle diameter less than 100 nanometers (69.0 ± 28.6 nm). AmB-PBCA-NPs were detected in the brain 30 minutes after systemic administration into BALB/c mice and had a higher concentration than systemically administered AmB liposome (AmB-L, P < 0.05); AmB was not detected in the brain. Following infection for 24 hours and then 7 days of treatment, the survival rate of mice in the AmB-PBCA-NP group (80%) was significantly higher than that of the AmB (0%) or AmB-L (60%) treatment groups. Fungal load was also lower when assessed by colony-forming unit counts obtained after plating infected brain tissue (P < 0.05). Our study indicates that AmB-PBCA-NPs with polysorbate 80 coating have the capacity to transport AmB across the BBB and is an efficient treatment against cryptococcal meningitis in a mouse model. PMID:21720503
Beale, Mathew A.; Sabiiti, Wilber; Robertson, Emma J.; Fuentes-Cabrejo, Karen M.; O’Hanlon, Simon J.; Jarvis, Joseph N.; Loyse, Angela; Meintjes, Graeme; Harrison, Thomas S.; May, Robin C.; Fisher, Matthew C.; Bicanic, Tihana
Cryptococcal meningitis is a major cause of mortality throughout the developing world, yet little is known about the genetic markers underlying Cryptococcal virulence and patient outcome. We studied a cohort of 230 Cryptococcus neoformans (Cn) isolates from HIV-positive South African clinical trial patients with detailed clinical follow-up using multi-locus sequence typing and in vitro phenotypic virulence assays, correlating these data with clinical and fungal markers of disease in the patient. South African Cn displayed high levels of genetic diversity and locus variability compared to globally distributed types, and we identified 50 sequence types grouped within the main molecular types VNI, VNII and VNB, with 72% of isolates typed into one of seven 'high frequency' sequence types. Spatial analysis of patients’ cryptococcal genotype was not shown to be clustered geographically, which might argue against recent local acquisition and in favour of reactivation of latent infection. Through comparison of MLST genotyping data with clinical parameters, we found a relationship between genetic lineage and clinical outcome, with patients infected with the VNB lineage having significantly worse survival (n=8, HR 3.35, CI 1.51-7.20, p=0.003), and this was maintained even after adjustment for known prognostic indicators and treatment regimen. Comparison of fungal genotype with in vitro phenotype (phagocytosis, laccase activity and CSF survival) performed on a subset of 89 isolates revealed evidence of lineage-associated virulence phenotype, with the VNII lineage displaying increased laccase activity (p=0.001) and ex vivo CSF survival (p=0.0001). These findings show that Cryptococcus neoformans is a phenotypically heterogeneous pathogen, and that lineage plays an important role in cryptococcal virulence during human infection. Furthermore, a detailed understanding of the genetic diversity in Southern Africa will support further investigation into how genetic diversity is
Beale, Mathew A; Sabiiti, Wilber; Robertson, Emma J; Fuentes-Cabrejo, Karen M; O'Hanlon, Simon J; Jarvis, Joseph N; Loyse, Angela; Meintjes, Graeme; Harrison, Thomas S; May, Robin C; Fisher, Matthew C; Bicanic, Tihana
Cryptococcal meningitis is a major cause of mortality throughout the developing world, yet little is known about the genetic markers underlying Cryptococcal virulence and patient outcome. We studied a cohort of 230 Cryptococcus neoformans (Cn) isolates from HIV-positive South African clinical trial patients with detailed clinical follow-up using multi-locus sequence typing and in vitro phenotypic virulence assays, correlating these data with clinical and fungal markers of disease in the patient. South African Cn displayed high levels of genetic diversity and locus variability compared to globally distributed types, and we identified 50 sequence types grouped within the main molecular types VNI, VNII and VNB, with 72% of isolates typed into one of seven 'high frequency' sequence types. Spatial analysis of patients' cryptococcal genotype was not shown to be clustered geographically, which might argue against recent local acquisition and in favour of reactivation of latent infection. Through comparison of MLST genotyping data with clinical parameters, we found a relationship between genetic lineage and clinical outcome, with patients infected with the VNB lineage having significantly worse survival (n=8, HR 3.35, CI 1.51-7.20, p=0.003), and this was maintained even after adjustment for known prognostic indicators and treatment regimen. Comparison of fungal genotype with in vitro phenotype (phagocytosis, laccase activity and CSF survival) performed on a subset of 89 isolates revealed evidence of lineage-associated virulence phenotype, with the VNII lineage displaying increased laccase activity (p=0.001) and ex vivo CSF survival (p=0.0001). These findings show that Cryptococcus neoformans is a phenotypically heterogeneous pathogen, and that lineage plays an important role in cryptococcal virulence during human infection. Furthermore, a detailed understanding of the genetic diversity in Southern Africa will support further investigation into how genetic diversity is
Background The central nervous system is considered a sanctuary site for HIV-1 replication. Variables associated with HIV cerebrospinal fluid (CSF) viral load in the context of opportunistic CNS infections are poorly understood. Our objective was to evaluate the relation between: (1) CSF HIV-1 viral load and CSF cytological and biochemical characteristics (leukocyte count, protein concentration, cryptococcal antigen titer); (2) CSF HIV-1 viral load and HIV-1 plasma viral load; and (3) CSF leukocyte count and the peripheral blood CD4+ T lymphocyte count. Methods Our approach was to use a prospective collection and analysis of pre-treatment, paired CSF and plasma samples from antiretroviral-naive HIV-positive patients with cryptococcal meningitis and assisted at the Francisco J Muñiz Hospital, Buenos Aires, Argentina (period: 2004 to 2006). We measured HIV CSF and plasma levels by polymerase chain reaction using the Cobas Amplicor HIV-1 Monitor Test version 1.5 (Roche). Data were processed with Statistix 7.0 software (linear regression analysis). Results Samples from 34 patients were analyzed. CSF leukocyte count showed statistically significant correlation with CSF HIV-1 viral load (r = 0.4, 95% CI = 0.13-0.63, p = 0.01). No correlation was found with the plasma viral load, CSF protein concentration and cryptococcal antigen titer. A positive correlation was found between peripheral blood CD4+ T lymphocyte count and the CSF leukocyte count (r = 0.44, 95% CI = 0.125-0.674, p = 0.0123). Conclusion Our study suggests that CSF leukocyte count influences CSF HIV-1 viral load in patients with meningitis caused by Cryptococcus neoformans.
Camara-Lemarroy, Carlos R; Flores-Cantu, Hazael; Calderon-Hernandez, Hector J; Diaz-Torres, Marco A; Villareal-Velazquez, Hector J
Patients with HIV are at risk of both primary and secondary haematological disorders. We report two cases of patients with HIV and cryptococcal meningitis who developed severe haemolytic anaemia, thrombocytopenia, renal failure and lactic acidosis while on treatment with amphotericin B and co-trimoxazole.
Hiesgen, J; Schutte, C; Olorunju, S; Retief, J
Aim This retrospective cohort study analyzes the impact of possible risk factors on the survival chance of patients with cryptococcal meningitis. These factors include the patient's socio-economic background, age, gender, presenting symptoms, comorbidities, laboratory findings and, in particular, non-adherence versus adherence to therapy. Methods Data were collected from all adult patients admitted to Kalafong Hospital with laboratory confirmed cryptococcal meningitis over a period of 24 months. We analyzed the data by the presentation of descriptive summary statistics, logistic regression was used to assess factors which showed association between outcome of measure and factor. Furthermore, multivariable logistic regression analysis using all the factors that showed significant association in the cross tabulation was applied to determine which factors had an impact on the patients' mortality risk. Results A total of 87 patients were identified. All except one were HIV-positive, of which 55.2% were antiretroviral therapy naïve. A history of previous tuberculosis was given by 25 patients (28.7%) and 49 (56.3%) were on tuberculosis treatment at admission or started during their hospital stay. In-hospital mortality was 31%. Statistical analysis showed that antiretroviral therapy naïve patients had 9.9 (CI 95% 1.2-81.2, p < 0.0032) times greater odds of dying compared to those on antiretroviral therapy, with 17 from 48 patients (35.4%) dying compared with 1 out of 21 patients (4.8%) on treatment. Defaulters had 14.7 (CI 95% 1.6-131.6, p < 0.016) times greater odds of dying, with 9 from 18 patients dying (50%), compared to the non-defaulters. In addition, patients who presented with nausea and vomiting had a 6.3 (95% CI 1.7-23.1, p < 0.005) times greater odds of dying (18/47, 38.3%); this remained significant when adjusted for antiretroviral therapy naïve patients and defaulters. Conclusion Cryptococcal meningitis is still a common opportunistic infection
Montezuma-Rusca, Jairo M.; Powers, John H.; Follmann, Dean; Wang, Jing; Sullivan, Brigit; Williamson, Peter R.
Background Cryptococcal meningitis (CM) is a leading cause of HIV-associated mortality. In clinical trials evaluating treatments for CM, biomarkers of early fungicidal activity (EFA) in cerebrospinal fluid (CSF) have been proposed as candidate surrogate endpoints for all- cause mortality (ACM). However, there has been no systematic evaluation of the group-level or trial-level evidence for EFA as a candidate surrogate endpoint for ACM. Methods We conducted a systematic review of randomized trials in treatment of CM to evaluate available evidence for EFA measured as culture negativity at 2 weeks/10 weeks and slope of EFA as candidate surrogate endpoints for ACM. We performed sensitivity analysis on superiority trials and high quality trials as determined by Cochrane measures of trial bias. Results Twenty-seven trials including 2854 patients met inclusion criteria. Mean ACM was 15.8% at 2 weeks and 27.0% at 10 weeks with no overall significant difference between test and control groups. There was a statistically significant group-level correlation between average EFA and ACM at 10 weeks but not at 2 weeks. There was also no statistically significant group-level correlation between CFU culture negativity at 2weeks/10weeks or average EFA slope at 10 weeks. A statistically significant trial-level correlation was identified between EFA slope and ACM at 2 weeks, but is likely misleading, as there was no treatment effect on ACM. Conclusions Mortality remains high in short time periods in CM clinical trials. Using published data and Institute of Medicine criteria, evidence for use of EFA as a surrogate endpoint for ACM is insufficient and could provide misleading results from clinical trials. ACM should be used as a primary endpoint evaluating treatments for cryptococcal meningitis. PMID:27490100
Crum-Cianflone, Nancy; Truett, April; R Wallace, Mark
Cryptococcal meningitis usually occurs among HIV-positive patients with CD4 counts less than 100 cells/mm(3) and manifests as headaches, fevers, and mental status changes. We present an unusual case of cryptococcal meningitis in a 34-year-old HIV-positive man presenting as a large abdominal cyst at the ventriculoperitoneal shunt site despite receiving highly active antiretroviral therapy (HAART) for more than 5 years and having a CD4 count more than 400 cells/mm(3).
Baallal, H; El Asri, A C; Eljebbouri, B; Akhaddar, A; Gazzaz, M; El Mostarchid, B; Boucetta, M
The fungus Cryptococcus neoformans can cause common opportunistic infection in acquired immune deficiency syndrome (AIDS) patients. But other conditions can be associated with sarcoidosis. Meningoencephalitis is the most common manifestation of this disease. One of the most important neurological complications is the development of intracranial hypertension (ICH), which may result in high morbidity and mortality. We report the case of a patient harboring a ventriculoperitoneal shunt, and having contracted a cryptococcal meningitis as a risk factor for pulmonary sarcoidosis. Brain MRI showed arachnoiditis, with a mass in contact with the right frontal horn. Indian ink staining of the cerebrospinal fluid (CSF) showed positivity that was confirmed by the identification of Cryptococcus neoformans after culture. The evolution was favorable under medical treatment with removal of material. The relationship between sarcoidosis and cryptococcosis, described in the literature is not coincidental but is a rare complication of sarcoidosis of potential severity (40% of mortality). Sarcoidosis is a common systemic disease that may increase host susceptibility to CNS cryptococcal infection without any other signs or symptoms of host immunosuppression. The diagnosis of cryptococcosis should be evoked as a differential diagnosis of neuro-sarcoidosis. Copyright © 2012 Elsevier Masson SAS. All rights reserved.
Cecchini, Diego M.; Cañizal, Ana M.; Rojas, Haroldo; Arechavala, Alicia; Negroni, Ricardo; Bouzas, María B.; Benetucci, Jorge A.
In order to determine HIV-1 kinetics in cerebrospinal fluid (CSF) and plasma in patients with cryptococcal meningitis (CM), we undertook a prospective collection of paired CSF/plasma samples from antiretroviral therapy-free HIV-infected patients with CM. Samples were obtained at baseline (S1) and at the second (S2) and third (S3) weeks of antifungal therapy. HIV-1 CSF concentrations were significantly lower in both S2 and S3 with respect to S1. Plasma concentrations remained stable. HIV-1 concentrations were higher in plasma than CSF in all cases. Patients who survived the episode of CM (but not those who died) showed a decrease in CSF viral load, what suggests different viral kinetics of HIV-1 in the CSF according to the clinical course of this opportunistic disease. PMID:24470944
Cecchini, Diego M; Cañizal, Ana M; Rojas, Haroldo; Arechavala, Alicia; Negroni, Ricardo; Bouzas, María B; Benetucci, Jorge A
In order to determine HIV-1 kinetics in cerebrospinal fluid (CSF) and plasma in patients with cryptococcal meningitis (CM), we undertook a prospective collection of paired CSF/plasma samples from antiretroviral therapy-free HIV-infected patients with CM. Samples were obtained at baseline (S1) and at the second (S2) and third (S3) weeks of antifungal therapy. HIV-1 CSF concentrations were significantly lower in both S2 and S3 with respect to S1. Plasma concentrations remained stable. HIV-1 concentrations were higher in plasma than CSF in all cases. Patients who survived the episode of CM (but not those who died) showed a decrease in CSF viral load, what suggests different viral kinetics of HIV-1 in the CSF according to the clinical course of this opportunistic disease.
Xu, Lie; Huang, Qin; Lin, Jin-Ran; Zhu, Cui-Yun; Li, Xin-Hua; Ye, Shan-Ke; Zhu, Ai-Hong; Chen, Dai-Hong; Zhang, Cheng-Feng; Chen, Liang; Ling, Yun
Cryptococcal meningitis (CM) is a global disease with significant morbidity and mortality. Although low peripheral blood cluster of differentiation 4 (CD4) cell counts are found to be related to a high burden of cryptococcus in HIV-infected patients, little is known about possible immune defects in previously healthy patients (PHPs). We performed a retrospective study of 41 CM patients treated from January 2005 to December 2014 who did not have HIV-infection. There were 33 PHPs and 8 not previously healthy patients (non-PHPs). We analyzed clinical test data pertaining to peripheral blood T cells, antibodies, inflammation markers, and cerebral spinal fluid (CSF) completed during the disease onset phase and 5 years following diagnosis. PHPs had significantly higher counts of cluster of differentiation 3 (CD3), cluster of differentiation 4 (CD4), and cluster of differentiation 45 (CD45) cells, and lower percentages of CD8 cells than non-PHPs (P < 0.05). Measurements of inflammatory markers and immunoglobulin in blood were comparable except for lower immunoglobulin A (IgA) levels in non-PHPs (P = 0.0410). Examination of CSF revealed lower white blood cell (WBC) counts in non-PHPs. Five-year mortality in PHPs was higher than in non-PHPs (22.0% vs 12.5%) but this was not statistically significant (P > 0.05). Multivariate analysis revealed that higher immunoglobulin G (IgG) levels in serum during disease onset may be an independent predictor of mortality (P = 0.015). In conclusion, PHPs demonstrate an immunophenotype that is distinct from that of non-PHPs, leading to an improved understanding of the immunology of cryptococcal meningitis.
Choi, Hye Mi; Jung, Gum Mo; Lee, Woong Ki; Lee, Hyeuk Soo; Kim, Byung Sun; Seong, Choong Sil; Yoon, So Hee; Cho, Yong Keun
Cryptococcus neoformans, an encapsulated fungus, is an important opportunistic pathogen that can cause meningitis in im-munocompromised patients. Since patients with cryptococcemia have high mortality, it is essential to make an early diagnosis and promptly initiate antifungal therapy. However, it is often very difficult to differentiate between cryptococcal meningitis and hepatic encephalopathy in patients with liver cirrhosis, and there is delay in making the diagnosis. Therefore, these patients have a particularly grave prognosis and consequently many patients die before culture results become available. In one study, starting antifungal therapy within 48 hours of the blood culture was associated with improved survival, but patients with liver cirrhosis were significantly less likely to receive antifungal therapy within 48 hours compared to those without liver cirrhosis. Recently, the authors experience a case of a 68-year-old woman with liver cirrhosis who presented with fever and a drowsy mental status. She had a previous history of having been admitted for infection-associated hepatic encephlopathy. Cryptococcal meningitis and cryptococcemia were diagnosed by spinal puncture and culture of cerebrospinal fluid. In spite of adequate treatment, the patient developed multi-system organ failure and eventually expired. Herein, we report a case of cryptococcal meningitis mimicking hepatic encephalopathy in a patient with liver cirrhosis.
Kuwahara, Hiroya; Tsuchiya, Kuniaki; Kobayashi, Zen; Inaba, Akira; Akiyama, Haruhiko; Mizusawa, Hidehiro
Cryptococcal meningitis is rarely complicated by immune-mediated leukoencephalopathy, but the precise pathomechanism is uncertain. A 72-year-old Japanese man treated with prednisolone for Sweet disease developed a subacute progression of meningitis, which was considered as neuro-Sweet disease. A treatment by methylprednisolone rapidly improved CSF findings with a remarkable decrease in lymphocyte numbers in the blood, but the patient's consciousness still worsened after the cessation of the treatment. The patient developed cryptococcal meningitis and MRI showed abnormal intensities predominantly in the cerebral deep white matter along with the recovery of lymphocyte numbers in the blood, which resulted in death. A postmortem examination of the brain revealed degenerative lesions, especially at the cerebral white matter and cortex adjacent to the leptomeninges abundantly infiltrated by Cryptococcus neoformans. In the affected cerebral deep white matter, perivascular infiltration of lymphocytes was prominent in coexistence with reactive astrocytes and vascular proliferation, but these findings were not observed in the subcortical and cortical lesions. Cryptococcus neoformans was not present within the brain parenchyma. This is the first report of a case suggesting that cryptococcal meningitis can accompany lymphocytic inflammation predominantly in cerebral deep white matter as a possible manifestation of immune reconstitution inflammatory syndrome.
Moodley, Anand; Rae, William; Bhigjee, Ahmed; Connolly, Cathy; Devparsad, Natasha; Michowicz, Andrew; Harrison, Thomas; Loyse, Angela
Cryptococcal induced visual loss is a devastating complication in survivors of cryptococcal meningitis (CM). Early detection is paramount in prevention and treatment. Subclinical optic nerve dysfunction in CM has not hitherto been investigated by electrophysiological means. We undertook a prospective study on 90 HIV sero-positive patients with culture confirmed CM. Seventy-four patients underwent visual evoked potential (VEP) testing and 47 patients underwent Humphrey's visual field (HVF) testing. Decreased best corrected visual acuity (BCVA) was detected in 46.5% of patients. VEP was abnormal in 51/74 (68.9%) right eyes and 50/74 (67.6%) left eyes. VEP P100 latency was the main abnormality with mean latency values of 118.9 (±16.5) ms and 119.8 (±15.7) ms for the right and left eyes respectively, mildly prolonged when compared to our laboratory references of 104 (±10) ms (p<0.001). Subclinical VEP abnormality was detected in 56.5% of normal eyes and constituted mostly latency abnormality. VEP amplitude was also significantly reduced in this cohort but minimally so in the visually unimpaired. HVF was abnormal in 36/47 (76.6%) right eyes and 32/45 (71.1%) left eyes. The predominant field defect was peripheral constriction with an enlarged blind spot suggesting the greater impact by raised intracranial pressure over that of optic neuritis. Whether this was due to papilloedema or a compartment syndrome is open to further investigation. Subclinical HVF abnormalities were minimal and therefore a poor screening test for early optic nerve dysfunction. However, early optic nerve dysfunction can be detected by testing of VEP P100 latency, which may precede the onset of visual loss in CM.
Moodley, Anand; Rae, William; Bhigjee, Ahmed; Connolly, Cathy; Devparsad, Natasha; Michowicz, Andrew; Harrison, Thomas; Loyse, Angela
Cryptococcal induced visual loss is a devastating complication in survivors of cryptococcal meningitis (CM). Early detection is paramount in prevention and treatment. Subclinical optic nerve dysfunction in CM has not hitherto been investigated by electrophysiological means. We undertook a prospective study on 90 HIV sero-positive patients with culture confirmed CM. Seventy-four patients underwent visual evoked potential (VEP) testing and 47 patients underwent Humphrey's visual field (HVF) testing. Decreased best corrected visual acuity (BCVA) was detected in 46.5% of patients. VEP was abnormal in 51/74 (68.9%) right eyes and 50/74 (67.6%) left eyes. VEP P100 latency was the main abnormality with mean latency values of 118.9 (±16.5) ms and 119.8 (±15.7) ms for the right and left eyes respectively, mildly prolonged when compared to our laboratory references of 104 (±10) ms (p<0.001). Subclinical VEP abnormality was detected in 56.5% of normal eyes and constituted mostly latency abnormality. VEP amplitude was also significantly reduced in this cohort but minimally so in the visually unimpaired. HVF was abnormal in 36/47 (76.6%) right eyes and 32/45 (71.1%) left eyes. The predominant field defect was peripheral constriction with an enlarged blind spot suggesting the greater impact by raised intracranial pressure over that of optic neuritis. Whether this was due to papilloedema or a compartment syndrome is open to further investigation. Subclinical HVF abnormalities were minimal and therefore a poor screening test for early optic nerve dysfunction. However, early optic nerve dysfunction can be detected by testing of VEP P100 latency, which may precede the onset of visual loss in CM. PMID:23285220
Vidal, Jose E; Boulware, David R
AIDS-related cryptococcal meningitis continues to cause a substantial burden of death in low and middle income countries. The diagnostic use for detection of cryptococcal capsular polysaccharide antigen (CrAg) in serum and cerebrospinal fluid by latex agglutination test (CrAg-latex) or enzyme-linked immunoassay (EIA) has been available for over decades. Better diagnostics in asymptomatic and symptomatic phases of cryptococcosis are key components to reduce mortality. Recently, the cryptococcal antigen lateral flow assay (CrAg LFA) was included in the armamentarium for diagnosis. Unlike the other tests, the CrAg LFA is a dipstick immunochromatographic assay, in a format similar to the home pregnancy test, and requires little or no lab infrastructure. This test meets all of the World Health Organization ASSURED criteria (Affordable, Sensitive, Specific, User friendly, Rapid/robust, Equipment-free, and Delivered). CrAg LFA in serum, plasma, whole blood, or cerebrospinal fluid is useful for the diagnosis of disease caused by Cryptococcus species. The CrAg LFA has better analytical sensitivity for C. gattii than CrAg-latex or EIA. Prevention of cryptococcal disease is new application of CrAg LFA via screening of blood for subclinical infection in asymptomatic HIV-infected persons with CD4 counts < 100 cells/mL who are not receiving effective antiretroviral therapy. CrAg screening of leftover plasma specimens after CD4 testing can identify persons with asymptomatic infection who urgently require pre-emptive fluconazole, who will otherwise progress to symptomatic infection and/or die.
VIDAL, Jose E.; BOULWARE, David R.
SUMMARY AIDS-related cryptococcal meningitis continues to cause a substantial burden of death in low and middle income countries. The diagnostic use for detection of cryptococcal capsular polysaccharide antigen (CrAg) in serum and cerebrospinal fluid by latex agglutination test (CrAg-latex) or enzyme-linked immunoassay (EIA) has been available for over decades. Better diagnostics in asymptomatic and symptomatic phases of cryptococcosis are key components to reduce mortality. Recently, the cryptococcal antigen lateral flow assay (CrAg LFA) was included in the armamentarium for diagnosis. Unlike the other tests, the CrAg LFA is a dipstick immunochromatographic assay, in a format similar to the home pregnancy test, and requires little or no lab infrastructure. This test meets all of the World Health Organization ASSURED criteria (Affordable, Sensitive, Specific, User friendly, Rapid/robust, Equipment-free, and Delivered). CrAg LFA in serum, plasma, whole blood, or cerebrospinal fluid is useful for the diagnosis of disease caused by Cryptococcus species. The CrAg LFA has better analytical sensitivity for C. gattii than CrAg-latex or EIA. Prevention of cryptococcal disease is new application of CrAg LFA via screening of blood for subclinical infection in asymptomatic HIV-infected persons with CD4 counts < 100 cells/mL who are not receiving effective antiretroviral therapy. CrAg screening of leftover plasma specimens after CD4 testing can identify persons with asymptomatic infection who urgently require pre-emptive fluconazole, who will otherwise progress to symptomatic infection and/or die. PMID:26465368
Rajasingham, Radha; Rolfes, Melissa A.; Birkenkamp, Kate E.; Meya, David B.; Boulware, David R.
Background Cryptococcal meningitis (CM) is the most common form of meningitis in Africa. World Health Organization guidelines recommend 14-d amphotericin-based induction therapy; however, this is impractical for many resource-limited settings due to cost and intensive monitoring needs. A cost-effectiveness analysis was performed to guide stakeholders with respect to optimal CM treatment within resource limitations. Methods and Findings: We conducted a decision analysis to estimate the incremental cost-effectiveness ratio (ICER) of six CM induction regimens: fluconazole (800–1,200 mg/d) monotherapy, fluconazole + flucytosine (5FC), short-course amphotericin (7-d) + fluconazole, 14-d of amphotericin alone, amphotericin + fluconazole, and amphotericin + 5FC. We computed actual 2012 healthcare costs in Uganda for medications, supplies, and personnel, and average laboratory costs for three African countries. A systematic review of cryptococcal treatment trials in resource-limited areas summarized 10-wk survival outcomes. We modeled one-year survival based on South African, Ugandan, and Thai CM outcome data, and survival beyond one-year on Ugandan and Thai data. Quality-adjusted life years (QALYs) were determined and used to calculate the cost-effectiveness ratio and ICER. The cost of hospital care ranged from $154 for fluconazole monotherapy to $467 for 14 d of amphotericin + 5FC. Based on 18 studies investigating outcomes for HIV-infected individuals with CM in resource-limited settings, the estimated mean one-year survival was lowest for fluconazole monotherapy, at 40%. The cost-effectiveness ratio ranged from $20 to $44 per QALY. Overall, amphotericin-based regimens had higher costs but better survival. Short-course amphotericin (1 mg/kg/d for 7 d) with fluconazole (1,200 mg/d for14 d) had the best one-year survival (66%) and the most favorable cost-effectiveness ratio, at $20.24/QALY, with an ICER of $15.11 per additional QALY over fluconazole monotherapy. The
Alves, Izabel Almeida; Staudt, Keli Jaqueline; Silva, Carolina de Miranda; Lock, Graziela de Araujo; Dalla Costa, Teresa; de Araujo, Bibiana Verlindo
To make advances in the treatment of cryptococcal meningitis, it is crucial to know a given drug's free fraction that reaches the biophase. In the present study, we applied microdialysis (μD) as a tool to determine the free levels reached by voriconazole (VRC) in the brains of healthy and Cryptococcus neoformans-infected rats. The infection was induced by the intravenous (i.v.) administration of 1 × 10(5) CFU of yeast. The dose administered was 5 mg/kg (of body weight) of VRC, given i.v. Plasma and microdialysate samples were analyzed by liquid chromatography-tandem mass spectrometry (LC-MS/MS) and LC-UV methods. The free brain/free plasma ratio (fT) and population pharmacokinetic (popPK) analyses were performed to evaluate the impact of infection on PK parameters of the drug. The brain penetration ratio showed an increase on brain exposure in infected animals (fThealthy = 0.85 versus fTinfected = 1.86). The structural PK model with two compartments and Michaelis-Menten (MM) elimination describes the VRC concentration-time profile in plasma and tissue simultaneously. The covariate infection was included in volume of distribution in the peripheral compartment in healthy animals (V2) and maximum rate of metabolism (VM ). The levels reached in infected tissues were higher than the values described for MIC of VRC for Cryptococccus neoformans (0.03 to 0.5 μg ml(-1)), indicating its great potential to treat meningitis associated with C. neoformans. Copyright © 2017 American Society for Microbiology.
Dyal, Jonathan; Akampurira, Andrew; Rhein, Joshua; Morawski, Bozena M; Kiggundu, Reuben; Nabeta, Henry W; Musubire, Abdu K; Bahr, Nathan C; Williams, Darlisha A; Bicanic, Tihana; Larsen, Robert A; Meya, David B; Boulware, David R
Quantitative cerebrospinal fluid (CSF) cultures provide a measure of disease severity in cryptococcal meningitis. The fungal clearance rate by quantitative cultures has become a primary endpoint for phase II clinical trials. This study determined the inter-assay accuracy of three different quantitative culture methodologies. Among 91 participants with meningitis symptoms in Kampala, Uganda, during August-November 2013, 305 CSF samples were prospectively collected from patients at multiple time points during treatment. Samples were simultaneously cultured by three methods: (1) St. George's 100 mcl input volume of CSF with five 1:10 serial dilutions, (2) AIDS Clinical Trials Group (ACTG) method using 1000, 100, 10 mcl input volumes, and two 1:100 dilutions with 100 and 10 mcl input volume per dilution on seven agar plates; and (3) 10 mcl calibrated loop of undiluted and 1:100 diluted CSF (loop). Quantitative culture values did not statistically differ between St. George-ACTG methods (P= .09) but did for St. George-10 mcl loop (P< .001). Repeated measures pairwise correlation between any of the methods was high (r≥0.88). For detecting sterility, the ACTG-method had the highest negative predictive value of 97% (91% St. George, 60% loop), but the ACTG-method had occasional (∼10%) difficulties in quantification due to colony clumping. For CSF clearance rate, St. George-ACTG methods did not differ overall (mean -0.05 ± 0.07 log10CFU/ml/day;P= .14) on a group level; however, individual-level clearance varied. The St. George and ACTG quantitative CSF culture methods produced comparable but not identical results. Quantitative cultures can inform treatment management strategies.
Badali, Hamid; Alian, Shahriar; Fakhim, Hamed; Falahatinejad, Mahsa; Moradi, Ali; Mohammad Davoudi, Mehrnaz; Hagen, Ferry; Meis, Jacques F
Cryptococcal meningitis is the most important opportunistic fungal infection with a high mortality in HIV-patients in less developed regions. Here, we report a case of cryptococcal meningitis in a 49-year-old HIV-positive female due to Cryptococcus neoformans (serotype A, mating-type alpha, genotype AFLP1/VNI) in Sari, Iran. In vitro antifungal susceptibility tests showed MICs of isavuconazole (0.016 μg ml(-1) ), voriconazole (0.031 μg ml(-1) ), posaconazole (0.031 μg ml(-1) ), itraconazole (0.063 μg ml(-1) ), amphotericin B (0.125 μg ml(-1) ) and fluconazole (8 μg ml(-1) ). Despite immediate antifungal therapy, the patient died 4 days later due to respiratory failure. Cryptococcal infections have been infrequently reported from Iran and therefore we analysed all published cases of cryptococcosis in Iran since the first reported case from 1969. © 2015 Blackwell Verlag GmbH.
Scriven, James E.; Rhein, Joshua; Hullsiek, Katherine Huppler; von Hohenberg, Maximilian; Linder, Grace; Rolfes, Melissa A.; Williams, Darlisha A.; Taseera, Kabanda; Meya, David B.; Meintjes, Graeme; Boulware, David R.
Introduction. Earlier antiretroviral therapy (ART) initiation in cryptococcal meningitis resulted in higher mortality compared with deferred ART initiation (1–2 weeks vs 5 weeks postmeningitis diagnosis). We hypothesized this was due to ART-associated immune pathology, without clinically recognized immune reconstitution inflammatory syndrome. Methods. Three macrophage activation markers and 19 cytokines/chemokines were measured from cryopreserved cerebrospinal fluid (CSF) and serum during the Cryptococcal Optimal ART Timing (COAT) trial. Comparisons were made between trial arms (early vs deferred) at 1, 8, 14, and 21 days following meningitis diagnosis. Results. More participants with early ART initiation had CSF white cell count (WCC) ≥5/µL at day 14 (58% vs 40%; P = .047), after a median of 6-days ART. Differences were mainly driven by participants with CSF WCC <5/µL at meningitis diagnosis: 28% (10/36) of such persons in the early ART group had CSF WCC ≥5/µL by day 14, compared with 0% (0/27) in the deferred arm (P = .002). Furthermore, Kampala participants (the largest site) receiving early ART had higher day-14 CSF levels of interleukin-13 (P = .04), sCD14 (P = .04), sCD163 (P = .02), and CCL3/MIP-1α (P = .02), suggesting increased macrophage/microglial activation. Conclusions. Early ART initiation in cryptococcal meningitis increased CSF cellular infiltrate, macrophage/microglial activation, and T helper 2 responses within the central nervous system. This suggests that increased mortality from early ART in the COAT trial was immunologically mediated. PMID:25651842
Crabtree Ramírez, B; Caro Vega, Y; Shepherd, B E; Le, C; Turner, M; Frola, C; Grinsztejn, B; Cortes, C; Padgett, D; Sterling, T R; McGowan, C C; Person, A
Cryptococcal meningitis (CM) is associated with substantial mortality in HIV-infected patients. Optimal timing of antiretroviral therapy (ART) in persons with CM represents a clinical challenge, and the burden of CM in Latin America has not been well described. Studies suggest that early ART initiation is associated with higher mortality, but data from the Americas are scarce. HIV-infected adults in care between 1985-2014 at participating sites in the Latin America (the Caribbean, Central and South America network (CCASAnet)) and the Vanderbilt Comprehensive Care Clinic (VCCC) and who had CM were included. Survival probabilities were estimated. Risk of death when initiating ART within the first 2 weeks after CM diagnosis versus initiating between 2-8 weeks was assessed using dynamic marginal structural models adjusting for site, age, sex, year of CM, CD4 count, and route of HIV transmission. 340 patients were included (Argentina 58, Brazil 138, Chile 28, Honduras 27, Mexico 34, VCCC 55) and 142 (42%) died during the observation period. Among 151 patients with CM prior to ART 56 (37%) patients died compared to 86 (45%) of 189 with CM after ART initiation (p=0.14). Patients diagnosed with CM after ART had a higher risk of death (p=0.03, log-rank test). The probability of survival was not statistically different between patients who started ART within 2 weeks of CM (7/24, 29%) vs. those initiating between 2-8 weeks (14/53, 26%) (p=0.96), potentially due to lack of power. In this large Latin-American cohort, patients with CM had very high mortality rates, especially those diagnosed after ART initiation. This study reflects the overwhelming burden of CM in HIV-infected patients in Latin America. Copyright © 2017 The Author(s). Published by Elsevier Ltd.. All rights reserved.
Tho, Dau Quang; Török, M Estée; Yen, Nguyen Thi Bich; Bang, Nguyen Duc; Lan, Nguyen Thi Ngoc; Kiet, Vo Sy; van Vinh Chau, Nguyen; Dung, Nguyen Huy; Day, Jeremy; Farrar, Jeremy; Wolbers, Marcel; Caws, Maxine
HIV-associated tuberculous meningitis (TBM) has high mortality. Aside from the devastating impact of multidrug resistance (MDR) on survival, little is understood about the influence of other bacterial factors on outcome. This study examined the influence of Mycobacterium tuberculosis drug resistance, bacterial lineage, and host vaccination status on outcome in patients with HIV-associated TBM. Mycobacterium tuberculosis isolates from the cerebrospinal fluid of 186 patients enrolled in two studies of HIV-associated TBM in Ho Chi Minh City, Vietnam, were tested for resistance to first-line antituberculosis drugs. Lineage genotyping was available for 122 patients. The influence of antituberculosis drug resistance and M. tuberculosis lineage on 9-month mortality was analyzed using Kaplan-Meier survival analysis and Cox multiple regression models. Isoniazid (INH) resistance without rifampin resistance was associated with increased mortality (adjusted hazard ratio [HR], 1.78, 95% confidence interval [CI], 1.18 to 2.66; P = 0.005), and multidrug resistance was uniformly fatal (n = 8/8; adjusted HR, 5.21, 95% CI, 2.38 to 11.42; P < 0.0001). The hazard ratio for INH-resistant cases was greatest during the continuation phase of treatment (after 3 months; HR, 5.05 [95% CI, 2.23 to 11.44]; P = 0.0001). Among drug-susceptible cases, patients infected with the "modern" Beijing lineage strains had lower mortality than patients infected with the "ancient" Indo-Oceanic lineage (HR, 0.29 [95% CI, 0.14 to 0.61]; P = 0.001). Isoniazid resistance, multidrug resistance, and M. tuberculosis lineage are important determinants of mortality in patients with HIV-associated TBM. Interventions which target these factors may help reduce the unacceptably high mortality in patients with TBM.
To, Kelvin K W; Cheng, Vincent C C; Tang, Bone S F; Fan, Yiu-Wah; Yuen, Kwok-Yung
This is the first report of a small-colony variant Cryptococcus neoformans isolated from the cerebrospinal fluid of a patient with cystopleural shunt associated chronic meningitis. Cryptococcal antigen testing of the cerebrospinal fluid and the serum were both negative. The atypical morphology and the false-negative test may lead to delay of diagnosis and treatment.
Stamm, A M; Diasio, R B; Dismukes, W E; Shadomy, S; Cloud, G A; Bowles, C A; Karam, G H; Espinel-Ingroff, A
A multicenter prospective randomized trial of four versus six weeks of amphotericin B, 0.3 mg/kg per day, plus flucytosine, 150 mg/kg per day, was performed with 194 patients with cryptococcal meningitis. One or more toxic drug reactions developed in 103 patients: azotemia (51), renal tubular acidosis (two), leukopenia (30), thrombocytopenia (22), diarrhea (26), nausea/vomiting (10), and hepatitis (13). The four- and six-week regimens were complicated by toxicity in 44 percent and 43 percent of cases, respectively. Toxicity appeared during the first two weeks of therapy in 56 percent and during the first four weeks in 87 percent. Azotemia did not occur more frequently in renal transplant recipients or diabetic patients. Cytopenias did not appear more often in patients with hematologic malignancies or those receiving immunosuppressive therapies. Toxic reactions that contributed to death developed in five patients (two with azotemia, one with pancytopenia, one with hepatitis, one with ileus). Amphotericin B-induced azotemia was not a significant risk factor for the subsequent development of bone marrow, gastrointestinal, or hepatic toxicity attributable to flucytosine. Flucytosine toxicity was associated with peak serum flucytosine levels of 100 micrograms/ml or more during two or more weeks of therapy (p = 0.005). Peak 5-fluorouracil levels were not predictive of toxicity. An initial dose of flucytosine is recommended based on the creatinine clearance: 150 mg/kg per day at a creatinine clearance above 50 ml/minute, 75 mg/kg per day at a creatinine clearance of 26 to 50 ml/minute, and 37 mg/kg per day at a creatinine clearance of 13 to 25 ml/minute. The serum creatinine level should be monitored twice weekly and the creatinine clearance weekly during therapy in order to anticipate changes in serum flucytosine concentration. In addition, it is recommended that the serum flucytosine level be determined two hours after an oral dose once a week, and that the dose be
Ganiem, Ahmad Rizal; Indrati, Agnes Rengga; Wisaksana, Rudi; Meijerink, Hinta; van der Ven, Andre; Alisjahbana, Bachti; van Crevel, Reinout
Introduction Previous studies, mostly from Africa, have shown that serum cryptococcal antigenemia may precede the development of cryptococcal meningitis and early death among patients with advanced HIV infection. We examined cryptococcal antigenemia as a risk factor for HIV-associated mortality in Indonesia, which is experiencing a rapidly growing HIV epidemic. Methods We included ART-naïve HIV patients with a CD4 cell count below 100 cells/μL and no signs of meningitis in an outpatient HIV clinic in Bandung, West Java, Indonesia. Baseline clinical data and follow-up were retrieved from a prospective database, and cryptococcal antigen was measured in stored serum samples using a semiquantitative lateral flow assay. Cox regression analysis was used to identify factors related to mortality. Results Among 810 patients (median CD4 cell count 22), 58 (7.1%) had a positive cryptococcal antigen test with a median titre of 1:80 (range: 1:1 to 1:2560). Cryptococcal antigenemia at baseline was strongly associated with the development of cryptococcal meningitis and early death and loss to follow-up. After one year, both death (22.4% vs. 11.6%; p=0.016; adjusted HR 2.19; 95% CI 1.78–4.06) and the combined endpoint of death or loss to follow-up (67.2% vs. 40.4%; p<0.001; adjusted HR 1.57; 95% CI 1.12–2.20) were significantly higher among patients with a positive cryptococcal antigen test. Conclusions Cryptococcal antigenemia is common and clinically relevant among patients with advanced HIV in this setting. Routine screening for cryptococcal antigen followed by lumbar puncture and pre-emptive antifungal treatment for those who are positive may help in reducing early mortality. PMID:24476751
Ganiem, Ahmad Rizal; Indrati, Agnes Rengga; Wisaksana, Rudi; Meijerink, Hinta; van der Ven, Andre; Alisjahbana, Bachti; van Crevel, Reinout
Previous studies, mostly from Africa, have shown that serum cryptococcal antigenemia may precede the development of cryptococcal meningitis and early death among patients with advanced HIV infection. We examined cryptococcal antigenemia as a risk factor for HIV-associated mortality in Indonesia, which is experiencing a rapidly growing HIV epidemic. We included ART-naïve HIV patients with a CD4 cell count below 100 cells/μL and no signs of meningitis in an outpatient HIV clinic in Bandung, West Java, Indonesia. Baseline clinical data and follow-up were retrieved from a prospective database, and cryptococcal antigen was measured in stored serum samples using a semiquantitative lateral flow assay. Cox regression analysis was used to identify factors related to mortality. Among 810 patients (median CD4 cell count 22), 58 (7.1%) had a positive cryptococcal antigen test with a median titre of 1:80 (range: 1:1 to 1:2560). Cryptococcal antigenemia at baseline was strongly associated with the development of cryptococcal meningitis and early death and loss to follow-up. After one year, both death (22.4% vs. 11.6%; p=0.016; adjusted HR 2.19; 95% CI 1.78-4.06) and the combined endpoint of death or loss to follow-up (67.2% vs. 40.4%; p<0.001; adjusted HR 1.57; 95% CI 1.12-2.20) were significantly higher among patients with a positive cryptococcal antigen test. Cryptococcal antigenemia is common and clinically relevant among patients with advanced HIV in this setting. Routine screening for cryptococcal antigen followed by lumbar puncture and pre-emptive antifungal treatment for those who are positive may help in reducing early mortality.
Chen, Min; Zhou, Jie; Li, Juan; Li, Meng; Sun, Jun; Fang, Wen J; Al-Hatmi, Abdullah M S; Xu, Jianping; Boekhout, Teun; Liao, Wan Q; Pan, Wei H
Cryptococcal meningitis (CM) is a life-threatening mycosis primarily occurring in HIV-infected individuals. Recently, non-HIV-infected hosts were increasingly reported to form a considerable proportion. However, the majority of the reported studies on the diagnosis of CM patients were performed on HIV-infected patients. For evaluation of various diagnostic approaches for CM in non-HIV-infected patients, a range of conventional and molecular assays used for diagnosis of CM were verified on 85 clinical CSFs from non-HIV-infected CM patients, including India ink staining, culture, a newly developed loop-mediated isothermal amplification (LAMP), the lateral flow assay (LFA) of cryptococcal antigen detection and a qPCR assay. The LFA had the highest positive detection rate (97.6%; 95% CI, 91.8-99.7%) in non-HIV-infected CM patients, followed by the LAMP (87.1%; 95% CI, 78.0-93.4%), the qPCR (80.0%; 95% CI, 69.9-87.9%), India ink staining (70.6%; 95% CI, 59.7-80.0%) and culture (35.3%; 95% CI, 25.2-46.4%). All culture positive specimens were correctly identified by the LFA.
Sloan, Derek; Dlamini, Sipho; Paul, Navin; Dedicoat, Martin
Despite the advent and increasingly wide availability of antiretroviral therapy, cryptococcal meningitis (CM) remains a significant cause of mortality and morbidity amongst individuals with HIV infection in resource-limited settings. The ideal management of CM remains unclear. The aim of this review is to assess the evidence for deciding on which antifungal regimen to use as well as other modalities of management to utilise especially resource poor settings in order to achieve the best possible outcome and enable an individual with CM to survive their acute illness and benefit from antiretroviral therapy. To determine the most effective initial and consolidation treatment strategy for CM in HIV infected adults. The Cochrane HIV/AIDS group search strategy was used. Key words in the search included, meningitis, cryptococcus neoformans, treatment, trial, human immunodeficiency virus, acquired immunodeficiency syndrome, antifungal agents, amphotericin, flucytosine, fluconazole, azole, lumbar puncture, cerebrospinal fluid (CSF) pressure and acetazolamide. Randomised of HIV-infected adults with a first episode of CM diagnosed on CSF examination, by India ink staining, CSF culture or cryptococcal antigen testing. Data were extracted using standardised forms and analysed using Rev Man 4.2.7 software. Six studies are included in the review. Five of the studies compared antifungal treatments and one study addressed lowering intracranial pressure. This study was stopped early due to excess adverse effects. The results of the other five studies as summarised as follows.Mayanja-Kizza 1998 compared fluconazole to fluconazole with 5 flucytosine. The dose of fluconazole used 200mg initially is lower than the recommended initial dose of 400mg. No survival advantage was found with the use of 5 flucytosine in addition to fluconazole.Two studies Brouwer 2004 and van der Horst 1997 compared Amphotericin (AmB) to AmB with 5 flucytosine. Both drugs were given at currently recommended
Kiggundu, Reuben; Morawski, Bozena M; Bahr, Nathan C; Rhein, Joshua; Musubire, Abdu K; Williams, Darlisha A; Abassi, Mahsa; Nabeta, Henry W; Hullsiek, Kathy Huppler; Meya, David B; Boulware, David R
The effect of tenofovir and amphotericin co-administration on kidney function is poorly characterized. We measured creatinine during induction therapy and at 4-weeks post-diagnosis in Ugandans undergoing cryptococcal meningitis therapy, and classified as not receiving antiretroviral therapy (ART), receiving non-tenofovir ART, or receiving tenofovir-based ART. Longitudinal creatinine changes and Grade 2-4 creatinine adverse events were evaluated across groups. Creatinine concentrations were similar across ART groups. At 4 weeks post-diagnosis, creatinine was 0.25mg/dL higher than at diagnosis, but similar across groups. Adverse event incidence was also similar across ART groups. Tenofovir and amphotericin co-administration did not increase the risk of kidney dysfunction. PMID:26334743
Kwan, Candice K; Leelawiwat, Wanna; Intalapaporn, Poj; Anekthananon, Thanomsak; Raengsakulrach, Boonyos; Peters, Philip J; McNicholl, Janet M; Park, Benjamin J; McConnell, Michelle S; Weidle, Paul J
Cryptococcal meningitis (CM) remains a significant HIV-associated opportunistic infection in Southeast Asia and Africa, with a high burden of disease and a high mortality rate despite the availability of antiretroviral therapy (ART). We retrospectively examined the utility of cryptococcal antigen screening to identify risk for CM among 211 Thai women initiating ART. Antigenemia prevalence was 11% (n = 9) among 84 women with a CD4 count <100 cells/mm(3). Screening identified all women who later developed CM. Cryptococcal antigen titers decreased over time with ART. Our study confirmed findings from previous studies in Thailand and South Africa and provided novel observational data regarding the course of cryptococcal antigenemia in patients initiating ART and the poor efficacy of low-dose fluconazole prophylaxis in preventing CM among patients with antigenemia.
Rhodes, Johanna; Beale, Mathew A.; Vanhove, Mathieu; Jarvis, Joseph N.; Kannambath, Shichina; Simpson, John A.; Ryan, Anthea; Meintjes, Graeme; Harrison, Thomas S.; Fisher, Matthew C.; Bicanic, Tihana
Recurrence of meningitis due to Cryptococcus neoformans after treatment causes substantial mortality in HIV/AIDS patients across sub-Saharan Africa. In order to determine whether recurrence occurred due to relapse of the original infecting isolate or reinfection with a different isolate weeks or months after initial treatment, we used whole-genome sequencing (WGS) to assess the genetic basis of infection in 17 HIV-infected individuals with recurrent cryptococcal meningitis (CM). Comparisons revealed a clonal relationship for 15 pairs of isolates recovered before and after recurrence showing relapse of the original infection. The two remaining pairs showed high levels of genetic heterogeneity; in one pair we found this to be a result of infection by mixed genotypes, while the second was a result of nonsense mutations in the gene encoding the DNA mismatch repair proteins MSH2, MSH5, and RAD5. These nonsense mutations led to a hypermutator state, leading to dramatically elevated rates of synonymous and nonsynonymous substitutions. Hypermutator phenotypes owing to nonsense mutations in these genes have not previously been reported in C. neoformans, and represent a novel pathway for rapid within-host adaptation and evolution of resistance to first-line antifungal drugs. PMID:28188180
Rhodes, Johanna; Beale, Mathew A; Vanhove, Mathieu; Jarvis, Joseph N; Kannambath, Shichina; Simpson, John A; Ryan, Anthea; Meintjes, Graeme; Harrison, Thomas S; Fisher, Matthew C; Bicanic, Tihana
Recurrence of meningitis due to Cryptococcus neoformans after treatment causes substantial mortality in HIV/AIDS patients across sub-Saharan Africa. In order to determine whether recurrence occurred due to relapse of the original infecting isolate or reinfection with a different isolate weeks or months after initial treatment, we used whole-genome sequencing (WGS) to assess the genetic basis of infection in 17 HIV-infected individuals with recurrent cryptococcal meningitis (CM). Comparisons revealed a clonal relationship for 15 pairs of isolates recovered before and after recurrence showing relapse of the original infection. The two remaining pairs showed high levels of genetic heterogeneity; in one pair we found this to be a result of infection by mixed genotypes, while the second was a result of nonsense mutations in the gene encoding the DNA mismatch repair proteins MSH2, MSH5, and RAD5 These nonsense mutations led to a hypermutator state, leading to dramatically elevated rates of synonymous and nonsynonymous substitutions. Hypermutator phenotypes owing to nonsense mutations in these genes have not previously been reported in C. neoformans, and represent a novel pathway for rapid within-host adaptation and evolution of resistance to first-line antifungal drugs.
Santos, Carlos A. Q.; Olsen, Margaret A.; Powderly, William G.
Abstract Background. Cryptococcosis is the third most common invasive fungal infection in solid organ transplant (SOT) recipients. There are no nationally representative data describing the incidence, risk factors, and outcomes of cryptococcosis after SOT. Methods. We assembled a large cohort of adult SOT recipients using Classification of Diseases, Ninth Revision, Clinical Modification billing data from Healthcare Cost and Utilization Project State Inpatient Databases of Florida (2006–2012), New York (2006–2011), and California (2004–2010). Demographics, comorbidities, death, and cryptococcal infections coded during hospitalization were identified. Results. A total of 42634 adults with SOT were identified during the study period. Cryptococcal disease was identified in 0.37% (n = 158), 44% of which had meningitis (n = 69). Median time to diagnosis of cryptococcosis was 464 days (range, 4–2393). The median time to onset of cryptococcosis was earlier for lung (191 days; range, 7.5–1816), heart (195 days; range, 4–1061), and liver (200 days; range, 4–1581) compared with kidney transplant recipients (616 days; range, 12–2393; P < .001, log rank test). Very early-onset disease (<30 days after transplantation) more frequently occurred in liver and lung transplant recipients. Lung transplant recipients had the highest risk of cryptococcosis (hazard ratio [HR], 2.10; 95% confidence interval [CI], 1.21–3.60). Cryptococcosis was associated with death (HR, 2.29; 95% CI, 1.68–3.11), after adjusting for age, type of SOT, and other comorbidities. Conclusions. Cryptococcosis is rare after SOT, but it is associated with significantly increased risk of death. Lung transplant recipients are at highest risk for cryptococcosis among SOTs. Nonkidney transplants have earlier onset of cryptococcosis and higher risk of death compared with kidney transplant recipients. PMID:28480277
Jarvis, Joseph N; Govender, Nelesh; Chiller, Tom; Park, Benjamin J; Longley, Nicky; Meintjes, Graeme; Bekker, Linda-Gail; Wood, Robin; Lawn, Stephen D; Harrison, Thomas S
HIV-associated cryptococcal meningitis (CM) is estimated to cause over half a million deaths annually in Africa. Many of these deaths are preventable. Screening patients for subclinical cryptococcal infection at the time of entry into antiretroviral therapy programs using cryptococcal antigen (CRAG) immunoassays is highly effective in identifying patients at risk of developing CM, allowing these patients to then be targeted with "preemptive" therapy to prevent the development of severe disease. Such CRAG screening programs are currently being implemented in a number of countries; however, a strong evidence base and clear guidance on how to manage patients with subclinical cryptococcal infection identified by screening are lacking. We review the available evidence and propose a treatment algorithm for the management of patients with asymptomatic cryptococcal antigenemia.
Nyazika, Tinashe K; Herkert, Patricia F; Hagen, Ferry; Mateveke, Kudzanai; Robertson, Valerie J; Meis, Jacques F
Cryptococcus neoformans is the leading cause of cryptococcosis in HIV-infected subjects worldwide. Treatment of cryptococcosis is based on amphotericin B, flucytosine, and fluconazole. In Zimbabwe, little is known about antifungal susceptibility of Cryptococcus. Sixty-eight genotyped Cryptococcus isolates were tested for antifungal profiles. Amphotericin B, isavuconazole, and voriconazole showed higher activity than other triazoles. Fluconazole and flucytosine were less effective, with geometric mean MICs of 2.24 and 2.67mg/L for C. neoformans AFLP1/VNI, 1.38 and 1.53mg/L for C. neoformans AFLP1A/VNB/VNII and AFLP1B/VNII, and 1.85 and 0.68mg/L for Cryptococcus tetragattii, respectively. A significant difference between flucytosine geometric mean MICs of C. neoformans and C. tetragattii was observed (P=0.0002). The majority of isolates (n=66/68; 97.1%) had a wild-type MIC phenotype of all antifungal agents. This study demonstrates a favorable situation with respect to the tested antifungals agents. Continued surveillance of antifungal susceptibility profiles is important due to the high burden of cryptococcosis in Africa.
Chou, Po-Han; Ouyang, Wen-Chen; Lan, Tsuo-Hung; Chan, Chin-Hong
We report a 78-year-old man without past psychiatric history who experienced his first manic episode successfully treated with quetiapine and lorazepam, but was ultimately found to have AIDS and Cryptococcus neoformans meningitis. Our presented case highlights the importance of comprehensive differential diagnoses to rule out secondary causes of psychiatric symptoms presenting for the first time in elderly patients.
Musabende, Marcellin; Mukabatsinda, Constance; Riviello, Elisabeth D; Ogbuagu, Onyema
A 61-year-old man living in rural Rwanda presented with a 2-month history of fevers, headaches, dry cough, weight loss and confusion. A cerebrospinal fluid analysis revealed neutrophilic pleocytosis, yeast and a positive cryptococcal antigen (CrAg). An HIV antibody test was negative. The patient's cough worsened while on antifungal induction therapy with intravenous conventional amphotericin B and high-dose oral fluconazole. Computerised tomography (CT) scan of the chest showed extensive miliary infiltrates. Bronchoalveolar lavage revealed acid-fast bacilli on smear and a positive GeneXpert test without rifampicin resistance. The patient improved with the addition of antitubercular therapy. In this case report, we describe an unusual presentation of two opportunistic infections occurring together in an HIV-negative man with no other known immunocompromising conditions. The case highlights the fact that, in disease endemic areas, multiple disseminated infections can occur in individuals without obvious immunocompromise.
Meda, John; Kalluvya, Samuel; Downs, Jennifer A; Chofle, Awilly A; Seni, Jeremiah; Kidenya, Benson; Fitzgerald, Daniel W; Peck, Robert N
Cryptococcal meningitis (CM) has a mortality rate of ∼70% among HIV-infected adults in low-income countries. Controlling intracranial pressure (ICP) is essential in CM, but it is difficult in low-income countries because manometers and practical ICP management protocols are lacking. As part of a continuous quality improvement project, our Tanzanian hospital initiated a new protocol for ICP management for CM. All adult inpatients with CM are included in a prospective patient registry. At the time of analysis, this registry included data from 2 years before the initiation of this new ICP management protocol and for a 9-month period after. ICP was measured at baseline and at days 3, 7, and 14 by both manometer and intravenous (IV) tubing set. All patients were given IV fluconazole according to Tanzanian treatment guidelines and were followed until 30 days after admission. Among adult inpatients with CM, 32 of 35 patients (91%) had elevated ICP on admission. Cerebrospinal fluid pressure measurements using the improvised IV tubing set demonstrated excellent agreement (r = 0.96) with manometer measurements. Compared with historical controls, the new ICP management protocol was associated with a significant reduction in 30-day mortality (16/35 [46%] vs. 48/64 [75%] in historical controls; hazard ratio = 2.1 [95% CI: 1.1 to 3.8]; P = 0.018]. Increased ICP is almost universal among HIV-infected adults admitted with CM in Tanzania. Intensive ICP management with a strict schedule of serial lumbar punctures reduced in-hospital mortality compared with historical controls. ICP measurement with IV tubing sets may be a good alternative in resource-limited health facilities where manometers are not available.
Rubio, Fernando Góngora; Zanon, Jeferson Rodrigo; de Almeida, Margarete Teresa Gottardo; de Góngora, Delzi Vinha Nunes
Several formulae have been developed in an attempt to reduce the toxicity of amphotericin B (AmB), but their high costs preclude widespread use. The aim of this study was to evaluate the efficacy of amphotericin B in a fat emulsion, i.e. Intralipid (AmB-IL), in 37 AIDS patients with cryptococcal meningitis (CM). We retrospectively reviewed data collected in a non-comparative open study between January 1999 and December 2001. The therapeutic cure was defined as complete resolution or improvement of the clinical symptoms or complete absence or improvement of the mycological alterations of the CSF. The outcomes were evaluated at 2 weeks, induction phase (IP), and at the end of treatment or consolidation phase (CP) with the last available CSF. Prior to the diagnosis of CM, 72% of patients had had one or more OI and 67.57% had a concomitant OI. The median CD4-cell count was 32 cells/mm(3), the median leukocyte count in the CSF was 29 cells/mm(3) and the median cumulative dose of AmB-IL was 1,200 mg (300-2,500). The therapeutic cure was 57.14% in the IP and 64.86% in the CP. During IP, 9 patients died (24.32%) and 4 (10.81%) during the CP (p=0.2). Thus, the overall mortality rate was 35.14%. AmB-IL, an inexpensive preparation, might be an alternative to conventional AmB. Some questions remain such as its compatibility, stability and level of toxicity. The benefit is especially important in developing countries, where no drugs other than AmB are available to treat systemic fungal infections.
Othman, Norlijah; Abdullah, Nor Atiqah Ng; Wahab, Zubaidah Abdul
An immunocompetent 5 year-old girl presented with pyrexia of unknown origin associated with headache. Initial investigations showed leukocytosis and an increased erythrocyte sedimentation rate. A Widal-Weil Felix test, blood film for malarial parasites, mycoplasma IgM antibody, cultures from blood and urine, full blood picture, Mantoux test, and chest x-ray were all negative. A lumbar puncture was done as part of a work-up for pyrexia of unknown origin. Cryptococcus neoformans was seen on India ink examination and confirmed on culture. She was treated with 10 weeks of intravenous amphotericin B and 8 weeks of fluconazole. Further immunological tests did not reveal any defect in the cell-mediated immune system. C. neoformans meningitis may present with non-specific symptoms and should be considered in a work-up for pyrexia of unknown origin.
Kumari, Sunita; Singh, Dharmendra Prasad; Yadav, Ramakant
Introduction The cases of cryptococcal meningitis and other forms of cryptococcosis have increased in recent time and the present scenario of the condition with significant morbidity and mortality is actually posing a serious threat to the community, so an early and prompt diagnosis is necessary to prevent serious complications and thus improving the overall disease outcome. Aim Comparison of diagnostic efficacy of nested Polymerase Chain Reaction (PCR) with Latex Agglutination Test (LAT) in the Cerebro Spinal Fluid (CSF) samples of the cases of meningitis in HIV positive and negative cases. Materials and Methods We have compared the diagnostic efficacy of Latex Agglutination Test (LAT) with nested Polymerase Chain Reaction (PCR) in 200 Cerebrospinal Fluid (CSF) samples, including 14 HIV positive also, in the cases of suspected cryptococcal meningitis. Nested PCR was done in all cases reporting positive by LAT and results were then compared with that of India ink and culture on Sabouraud Dextrose Agar (SDA), and the isolates were further identified by urease, nitrate and sugar assimilation tests. Results Of the 200 cases, including 14 HIV positive, LAT was positive in 46 cases while 154 were negative. Out of these 46 LAT positive cases, nested PCR was positive in 40 cases only, while culture and India ink was positive in 38 and 33 cases respectively. Majority of the cases, 30 (65.2%) were between age group 21-50 years, while 2 (4.3%) in 0-20, and 14 (30.4%) in 51-80 years age group. Conclusion Although negative staining like India ink and nigrosin are most widely used techniques, but these suffer with subjective error. Rapid method like LAT is available but it always has the scope of false positive and negative results. In such cases nested PCR can help in establishing final diagnosis. PMID:27190801
Meningitis Overview By Mayo Clinic Staff Meningitis is an inflammation of the membranes (meninges) surrounding your brain and spinal cord. The swelling from meningitis typically triggers symptoms such as ...
Mora, Delio José; Pedrosa, André Luiz; Rodrigues, Virmondes; Leite Maffei, Claudia Maria; Trilles, Luciana; Dos Santos Lazéra, Márcia; Silva-Vergara, Mario León
We molecularly characterized 81 cryptococcal isolates recovered from cerebrospinal fluid samples of 77 patients diagnosed between 1998 and 2007 as having cryptococcal meningitis in Uberaba Minas Gerais, Brazil. Fifty-seven (74%) were male with a mean age 35.6 years. Seventy-two (88.9%) of the isolates were from 68 AIDS patients and cryp-tococcosis was the first AIDS-defining condition in 38 (55.9%) patients. Cryptococcosis and AIDS were simultaneously diagnosed in 25 (65.8%) of these 38 patients. Genotypes were characterized through the use of URA5 restriction fragment length polymorphisms analysis, the genetic variability was determined using PCR-fingerprinting with the minisatellite-specific primer M13, and the mating type and serotypes were established by PCR. Seventy-six of the 81 isolates were Cryptococcus neoformans (93.8%), while the remaining five were C. gattii (6.1%), but all were mating type alpha. C. neoformans isolates were genotype VNI (serotype A), while C. gattii isolates were VGII. Four of the latter isolates were identical, but only two were from AIDS patients. Six of the nine isolates from non-AIDS patients were VNI. PCR fingerprints of the isolates from two of the three AIDS patients with clinical relapse were 100% identical. The predominance of VNI and mating type alpha is in accordance with data from other parts of the world. The occurrence of VGII in Minas Gerais indicates a geographical expansion within Brazil.
... One kind of bacterial meningitis is related to Lyme disease . Lyme meningitis is generally less severe than other forms ... to spend the full time in a hospital. Lyme meningitis is also treated with IV antibiotics. Doctors ...
... system, infecting the meninges and causing meningitis. continue Bacteria and Viruses Many viruses can cause viral meningitis. ... examined under a microscope to see if any bacteria, cells, or substances that indicate inflammation or infection ...
Garg, Ravindra Kumar; Sinha, Manish Kumar
Tuberculosis is the most common opportunistic infection in human immunodeficiency virus (HIV) infected persons. HIV-infected patients have a high incidence of tuberculous meningitis as well. The exact incidence and prevalence of tuberculous meningitis in HIV-infected patients are not known. HIV infection does not significantly alter the clinical manifestations, laboratory, radiographic findings, or the response to therapy. Still, some differences have been noted. For example, the histopathological examination of exudates in HIV-infected patients shows fewer lymphocytes, epithelioid cells, and Langhan's type of giant cells. Larger numbers of acid-fast bacilli may be seen in the cerebral parenchyma and meninges. The chest radiograph is abnormal in up to 46% of patients with tuberculous meningitis. Tuberculous meningitis is likely to present with cerebral infarcts and mass lesions. Cryptococcal meningitis is important in differential diagnosis. The recommended duration of treatment in HIV-infected patients is 9-12 months. The benefit of adjunctive corticosteroids is uncertain. Antiretroviral therapy and antituberculosis treatment should be initiated at the same time, regardless of CD4 cell counts. Tuberculous meningitis may be a manifestation of paradoxical tuberculosis-associated immune reconstitution inflammatory syndrome. Some studies have demonstrated a significant impact of HIV co-infection on mortality from tuberculous meningitis. HIV-infected patients with multidrug-resistant tuberculous meningitis have significantly higher mortality. The best way to prevent HIV-associated tuberculous meningitis is to diagnose and isolate infectious cases of tuberculosis promptly and administer appropriate treatment.
Vasant, Dipesh H.; Limdi, Jimmy K.; Borg-Bartolo, Simon P.; Bonington, Alec
Advanced age and associated comorbidities are-recognized predictors of life-threatening adverse outcomes, such as opportunistic infection following immunosuppressive therapy. We describe the case of an elderly patient with stricturing colonic Crohn’s disease and significant clinical comorbidities, initially controlled with corticosteroid induction followed by infliximab, whose course was complicated by fatal disseminated cryptococcal infection and posterior reversible encephalopathy syndrome. Our patient’s case highlights rare, but serious, complications of immunosuppression. In applying modern treatment paradigms to the elderly, the clinician must consider the potential for more pronounced adverse effects in this potentially vulnerable group, maximizing benefit and minimizing harm. PMID:27807560
Niyongabo, T; Aubry, P
The authors report a connection between a meningitis tuberculosis and a meningoencephalitis with cryptococcus in the case of an african VIH+. The diagnostic of a meningitis tuberculosis was retained on an indirect arguments, this of meningoencephalitis of direct arguments (antigen cryptococcus, cultivation on Sabouraud environment). The pulmonary tuberculosis and/or extrapulmonary tuberculosis is current in Central Africa during HIV infection, as well as the crytococcosis during AIDS. But, any observation on neuromeningitis strike of those two infections have been reported up to now.
Day, Jeremy N; Hoang, Thu N; Duong, Anh V; Hong, Chau T T; Diep, Pham T; Campbell, James I; Sieu, Tran P M; Hien, Tran T; Bui, Tien; Boni, Maciej F; Lalloo, David G; Carter, Dee; Baker, Stephen; Farrar, Jeremy J
Cryptococcal disease most commonly occurs in patients with an underlying immune deficit, most commonly HIV infection, and is due to Cryptococcus neoformans var. grubii. Occasionally disease due to this variety occurs in apparently immunocompetent patients. The relationship between strains infecting immunosuppressed and immunocompetent patients is not clear. Amplified fragment length polymorphism (AFLP) analysis was used to characterize the relationship between strains infecting HIV-infected and uninfected patients. Isolates from 51 HIV-uninfected patients and 100 HIV-infected patients with cryptococcal meningitis were compared. C. neoformans var. grubii VNI was responsible for infections in 73% of HIV-uninfected and 100% of HIV-infected patients. AFLP analysis defined two distinct clusters, VNIγ and VNIδ. The majority (84%) of isolates from HIV-uninfected patients were VNIγ, compared with only 38% of isolates from HIV-infected patients (odds ratio, 8.30; 95% confidence interval [CI], 3.04 to 26.6; P < 0.0001). In HIV-uninfected patients, underlying disease was less frequent in those with VNIγ infections. Two clusters of C. neoformans var. grubii VN1 are responsible for the majority of cases of cryptococcal meningitis in Vietnam. The distribution of these clusters differs according to the immune status of the host.
Comparison of 2 doses of liposomal amphotericin B and conventional amphotericin B deoxycholate for treatment of AIDS-associated acute cryptococcal meningitis: a randomized, double-blind clinical trial of efficacy and safety.
Hamill, Richard J; Sobel, Jack D; El-Sadr, Wafaa; Johnson, Philip C; Graybill, John R; Javaly, Kedarnath; Barker, David E
BACKGROUND. It is generally acknowledged that amphotericin B is the most effective treatment for cryptococcal meningitis. However, administration of this drug is accompanied by substantial adverse effects. This double-blind study, performed before the routine availability of highly active antiretroviral therapy, was designed to compare the efficacy and safety of liposomal amphotericin B to conventional amphotericin deoxycholate in patients with acquired immunodeficiency syndrome (AIDS) and acute cryptococcal meningitis. METHODS. Patients were randomized (ratio, 1:1:1) from multiple sites in the United States and Canada to receive either amphotericin B at 0.7 mg/kg/day (n = 87), liposomal amphotericin B at 3 mg/kg/day (n = 86), or liposomal amphotericin B at 6 mg/kg/day (n = 94). RESULTS. Efficacy was similar among all 3 treatment groups. The overall incidence of infusion-related reactions was significantly lower for both the 3 mg/kg/day and 6 mg/kg/day dosages of liposomal amphotericin B, compared with conventional amphotericin B (P < .001). Significantly fewer patients who received the 3 mg/kg/day dosage of liposomal amphotericin B developed nephrotoxicity, indicated by a doubling of the serum creatinine value, compared with recipients of conventional amphotericin B (P = .004). Overall mortality at 10 weeks was 11.6%, with no significant differences among the treatment groups. CONCLUSIONS. Liposomal amphotericin B provides an equally efficacious alternative to conventional amphotericin B deoxycholate in patients with AIDS and acute cryptococcal meningitis. Liposomal amphotericin B at a dosage of 3 mg/kg/day is accompanied by significantly fewer adverse effects.
Fortuin-de Smidt, Melony; Kularatne, Ranmini; Dawood, Halima; Govender, Nelesh P.
Background We aimed to establish the prevalence of amphotericin B deoxycholate (AmBd)-related toxicities among South African patients with cryptococcosis and determine adherence to international recommendations to prevent, monitor and manage AmBd-related toxicities. Methods Clinical data were collected from cases of laboratory-confirmed cryptococcosis at 25 hospitals, October 2012 –February 2013. Anemia was defined as hemoglobin (Hb) concentration <10 g/dl, hypokalemia as serum potassium (K) <3.4 mEq/L and nephrotoxicity as an increase in serum creatinine (Cr) to >1.1 times the upper limit of normal. To determine adherence to toxicity prevention recommendations, we documented whether baseline Hb, K and Cr tests were performed, whether pre-emptive hydration and IV potassium chloride (KCl) was administered prior to 80% and 60% of AmBd doses and whether daily oral KCl supplementation was given ≥60% of the time. To determine adherence to monitoring recommendations, we ascertained whether a daily fluid chart was completed, Hb was monitored weekly and K or Cr were monitored bi-weekly. Results Of 846 patients, clinical data were available for 76% (642/846), 82% (524/642) of whom received AmBd. Sixty-four per cent (n = 333) had documented baseline laboratory tests, 40% (n = 211) were given pre-emptive hydration and 14% (n = 72) and 19% (n = 101) received intravenous and oral KCl. While on AmBd, 88% (n = 452) had fluid monitoring; 27% (n = 142), 45% (n = 235) and 44% (n = 232) had Hb, K and Cr levels monitored. Toxicities developed frequently during treatment: anemia, 16% (86/524); hypokalemia, 43% (226/524) and nephrotoxicity, 32% (169/524). Conclusion AmBd-related toxicities occurred frequently but were potentially preventable with adequate monitoring, supplemental fluid and electrolyte therapies. PMID:27467556
... be caused by: Chemical irritation Drug allergies Fungi Parasites Tumors Many types of viruses can cause meningitis: Enteroviruses: These are viruses that also can cause intestinal illness. Herpes viruses: These are the same viruses ...
... type of meningitis because it's not caused by bacteria). The doctor will recommend as much rest as possible to help the recovery, and also may also recommend medication to help relieve any ... For Teens For Kids ...
Hinchey, W W; Someren, A
A case of granulomatous prostatitis due to Cryptococcus neoformans is reported. The patient, who had a history of diabetes mellitus and chronic active hepatitis, had symptoms of prostatic hypertrophy. Tissue obtained from surgery showed granulomatous prostatitis, and a cryptococcal organism was identified by special stains. Postoperative cultures grew Cryptococcus neoformans, and the patient was treated successfully with surgery and a short course of amphotericin B. After nine months of follow-up, there is no evidence of systemic infection.
Ezeanolue, Echezona E; Nwizu, Chidi; Greene, Gregory S; Amusu, Olatilewa; Chukwuka, Chinwe; Ndembi, Nicaise; Smith, Rachel M; Chiller, Tom; Pharr, Jennifer; Kozel, Thomas R
Worldwide, HIV-associated cryptococcal meningitis affects approximately 1 million persons and causes 600,000 deaths each year mostly in sub-Saharan Africa. Limited data exist on cryptococcal meningitis and antigenemia in Nigeria, and most studies are geographically restricted. We determined the prevalence of cryptococcal antigenemia (CrAg) among HIV-infected, treatment-naive individuals in Nigeria. This was a retrospective, cross-sectional study across 4 geographic regions in Nigeria. We performed CrAg testing using a lateral flow immunoassay on archived whole-blood samples collected from HIV-infected participants at US President's Emergency Plan for AIDS Relief (PEPFAR)-supported sites selected to represent the major geographical and ethnic diversity in Nigeria. Eligible samples were collected from consenting patients (>15 years) naive to antiretroviral therapy with CD4 count less than 200 cells per cubic millimeter and were stored in an -80°C freezer. A total of 2752 stored blood samples were retrospectively screened for CrAg. Most of the samples were from participants aged 30-44 years (57.6%), and 1570 (57.1%) were from women. The prevalence of CrAg positivity in specimens with CD4 <200 cells per cubic millimeter was 2.3% (95% confidence interval: 1.8% to 3.0%) and varied significantly across the 4 regions (P < 0.001). At 4.4% (3.2% to 5.9%), the South East contained the highest prevalence. The significant regional variation in CrAg prevalence found in Nigeria should be taken into consideration as plans are made to integrate routine screening into clinical care for HIV-infected patients.
Ganiem, A. Rizal; Dian, Sofiati; Indriati, Agnes; Chaidir, Lidya; Wisaksana, Rudi; Sturm, Patrick; Melchers, Willem; van der Ven, Andre; Parwati, Ida; van Crevel, Reinout
Background HIV-associated subacute meningitis is mostly caused by tuberculosis or cryptococcosis, but often no etiology can be established. In the absence of CT or MRI of the brain, toxoplasmosis is generally not considered as part of the differential diagnosis. Methodology/Principal Findings We performed cerebrospinal fluid real time PCR and serological testing for Toxoplasma gondii in archived samples from a well-characterized cohort of 64 HIV-infected patients presenting with subacute meningitis in a referral hospital in Indonesia. Neuroradiology was only available for 6 patients. At time of presentation, patients mostly had newly diagnosed and advanced HIV infection (median CD4 count 22 cells/mL), with only 17.2% taking ART, and 9.4% PJP-prophylaxis. CSF PCR for T. Gondii was positive in 21 patients (32.8%). Circulating toxoplasma IgG was present in 77.2% of patients tested, including all in whom the PCR of CSF was positive for T. Gondii. Clinically, in the absence of neuroradiology, toxoplasmosis was difficult to distinguish from tuberculosis or cryptococcal meningitis, although CSF abnormalities were less pronounced. Mortality among patients with a positive CSF T. Gondii PCR was 81%, 2.16-fold higher (95% CI 1.04–4.47) compared to those with a negative PCR. Conclusions/Significance Toxoplasmosis should be considered in HIV-infected patients with clinically suspected subacute meningitis in settings where neuroradiology is not available. PMID:23326616
Ganiem, A Rizal; Dian, Sofiati; Indriati, Agnes; Chaidir, Lidya; Wisaksana, Rudi; Sturm, Patrick; Melchers, Willem; van der Ven, Andre; Parwati, Ida; van Crevel, Reinout
HIV-associated subacute meningitis is mostly caused by tuberculosis or cryptococcosis, but often no etiology can be established. In the absence of CT or MRI of the brain, toxoplasmosis is generally not considered as part of the differential diagnosis. We performed cerebrospinal fluid real time PCR and serological testing for Toxoplasma gondii in archived samples from a well-characterized cohort of 64 HIV-infected patients presenting with subacute meningitis in a referral hospital in Indonesia. Neuroradiology was only available for 6 patients. At time of presentation, patients mostly had newly diagnosed and advanced HIV infection (median CD4 count 22 cells/mL), with only 17.2% taking ART, and 9.4% PJP-prophylaxis. CSF PCR for T. Gondii was positive in 21 patients (32.8%). Circulating toxoplasma IgG was present in 77.2% of patients tested, including all in whom the PCR of CSF was positive for T. Gondii. Clinically, in the absence of neuroradiology, toxoplasmosis was difficult to distinguish from tuberculosis or cryptococcal meningitis, although CSF abnormalities were less pronounced. Mortality among patients with a positive CSF T. Gondii PCR was 81%, 2.16-fold higher (95% CI 1.04-4.47) compared to those with a negative PCR. Toxoplasmosis should be considered in HIV-infected patients with clinically suspected subacute meningitis in settings where neuroradiology is not available.
Katchanov, Juri; Zimmermann, Ulrike; Branding, Gordian; Tintelnot, Kathrin; Müller, Markus; Arastéh, Keikawus; Stocker, Hartmut
We report a case of cryptococcal immune reconstitution inflammatory syndrome affecting the lungs, and 10 months later the cervical lymph nodes, in the absence of cryptococcal meningitis, in advanced HIV infection. Our report demonstrates the organ-specificity of the timing of the inflammatory response and illustrates the organ-specific interplay of immunity and infection in cryptococcal disease. Copyright © 2013 The Authors. Published by Elsevier Ltd.. All rights reserved.
Sabiiti, Wilber; Robertson, Emma; Beale, Mathew A.; Johnston, Simon A.; Brouwer, Annemarie E.; Loyse, Angela; Jarvis, Joseph N.; Gilbert, Andrew S.; Fisher, Matthew C.; Harrison, Thomas S.; May, Robin C.; Bicanic, Tihana
Background. Cryptococcal meningitis (CM) is a leading cause of HIV-associated mortality globally. High fungal burden in cerebrospinal fluid (CSF) at diagnosis and poor fungal clearance during treatment are recognized adverse prognostic markers; however, the underlying pathogenic factors that drive these clinical manifestations are incompletely understood. We profiled a large set of clinical isolates for established cryptococcal virulence traits to evaluate the contribution of C. neoformans phenotypic diversity to clinical presentation and outcome in human cryptococcosis. Methods. Sixty-five C. neoformans isolates from clinical trial patients with matched clinical data were assayed in vitro to determine murine macrophage uptake, intracellular proliferation rate (IPR), capsule induction, and laccase activity. Analysis of the correlation between prognostic clinical and host immune parameters and fungal phenotypes was performed using Spearman’s r, while the fungal-dependent impact on long-term survival was determined by Cox regression analysis. Results. High levels of fungal uptake by macrophages in vitro, but not the IPR, were associated with CSF fungal burden (r = 0.38, P = 0.002) and long-term patient survival (hazard ratio [HR] 2.6, 95% CI 1.2–5.5, P = 0.012). High-uptake strains were hypocapsular (r = –0.28, P = 0.05) and exhibited enhanced laccase activity (r = 0.36, P = 0.003). Fungal isolates with greater laccase activity exhibited heightened survival ex vivo in purified CSF (r = 0.49, P < 0.0001) and resistance to clearance following patient antifungal treatment (r = 0.39, P = 0.003). Conclusion. These findings underscore the contribution of cryptococcal-phagocyte interactions and laccase-dependent melanin pathways to human clinical presentation and outcome. Furthermore, characterization of fungal-specific pathways that drive clinical manifestation provide potential targets for the development of therapeutics and the management of CM. Funding. This work
Brouwer, Annemarie E; Siddiqui, Asna A; Kester, Maartje I; Sigaloff, Kim C E; Rajanuwong, Adul; Wannapasni, Saran; Chierakul, Wirongrong; Harrison, Thomas S
The pathophysiology of meningitis caused by Cryptococcus gattii in apparently immunocompetent individuals remains unclear. We measured multiple cytokines in CSF from a HIV-seronegative, apparently immunocompetent, Thai patient with C. gattii meningitis, over the first 2 weeks of antifungal therapy. Levels of proinflammatory IFN-gamma, TNF-alpha, and IL-6 were very low compared to patients with HIV-related Cryptococcus neoformans meningitis and of IL-10 very high. While patients with C. gattii meningitis may be a heterogeneous group, these data suggest in this case a maladapted immune response to cryptococcal exposure had allowed progression to clinical cryptococcal disease.
Yamaguchi, Hiromichi; Komase, Yuko; Ikehara, Mizuki; Yamamoto, Takahito; Shinagawa, Toshihito
A 23-year-old man with no recent medical history was hospitalized complaining of high fever and cough. In addition to very marked eosinophilia, chest X-ray revealed extensive bronchovascular bundle thickening. Transbronchial lung biopsy (TBLB) showed moderate eosinophil infiltration. Cryptococcus neoformans infection was diagnosed, based on blood culture, cerebrospinal fluid culture, urine culture, and lung biopsy specimens. The eosinophilia was successfully alleviated by treatment for cryptococcal meningitis. Furthermore, cryptococcal sepsis resolved with amphotericin B and 5-flucytosine treatment. Eosinophilia commonly occurs following chronic Aspergillus infection, but the present case suggests the involvement of Cryptococcus in another mechanism for eosinophilia.
Zhou, Li; Saksena, Nitin K.
Human immunodeficiency virus type 1 is associated with the development of neurocognitive disorders in many infected individuals, including a broad spectrum of motor impairments and cognitive deficits. Despite extensive research, the pathogenesis of HIV-associated neurocognitive disorders (HAND) is still not clear. This review provides a comprehensive view of HAND, including HIV neuroinvasion, HAND diagnosis and different level of disturbances, influence of highly-active antiretroviral therapy to HIV-associated dementia (HAD), possible pathogenesis of HAD, etc. Together, this review will give a thorough and clear understanding of HAND, especially HAD, which will be vital for future research, diagnosis and treatment. PMID:24470972
Tang, Michele W; Clemons, Karl V; Katzenstein, David A; Stevens, David A
Cryptococcal meningitis is a devastating HIV-related opportunistic infection, affecting nearly 1 million individuals and causing over 500 000 deaths each year. The burden of disease is greatest in sub-Saharan Africa and Southeast Asia, where cryptococcal disease is the most common cause of meningitis. Rapid, accurate and affordable diagnosis of cryptococcal disease has been lacking in many of the most heavily affected areas. Here, we review a point-of-care assay for cryptococcal disease, the dipstick-formatted cryptococcal antigen lateral flow assay (LFA) (IMMY, Norman, OK). In comparison to culture, the assay is 99.5% sensitive and 98% specific. In comparison to other commercially available tests for cryptococcal antigen, the LFA has equal or superior sensitivity and specificity in CSF, plasma and serum samples. We discuss potential applications for the use of the assay in resource-limited settings, including what is likely to be an important role of the LFA in screening for early cryptococcal infection before clinical disease and in evaluating pre-emptive treatment.
Fica, Alberto; Soto, Andrés; Dabanch, Jeannette P; Pinilla, Jorge; Porte, Lorena
Cryptococcal infections are classically associated to HIV/AIDS patients without therapy, but its presence among other immunosuppressed patients is less recognized. We report 3 lethal cases in non HIV-patients. Two of them presented with meningitis associated to renal transplant or corticosteroid use and, the third, with a necrotic skin infection in the context of progressive liver cirrhosis. In the former two patients, meningeal infection was suspected late, and in the latter, the diagnosis was established postmortem. Cryptococcal infections in non-HIV immunosupressed patients can affect different sites, are suspected late and have a high case-fatality ratio.
Zamora Bastidas, Tomas Omar; Potosí García, Jorge Andrés; Díaz Idrobo, Bairon
Abstract Introduction: Cryptococcosis is an opportunistic fungal infection whose etiology is Cryptococcus neofromans / C. gattii, complex which affects immunocompromised patients mainly. Meningeal infection is one of the most common presentations, but cerebellar affection is rare. Case Description: Male patient with 65 old years, from an area of subtropical climate with chronic exposure to poultry, without pathological antecedents, who presented clinical picture consistent with headache, fever, seizures and altered mental status. Clinical findings and diagnostic methods: Initially without menigeal signs or intracranial hypertension and normal neurological examination. Later, the patient developed ataxia, dysdiadochokinesia and limb loss. By lumbar punction and image of nuclear magnetic resonance (NMR) cerebellitis cryptococcal was diagnosticated. Treatment: Antifungal therapy with amphotericin B and fluconazole was performed, however the patient died. Clinical Relevance: The cryptococcosis has different presentations, it´s a disease whose incidence has been increasing since the advent of the HIV / AIDS pandemy, however the commitment of the encephalic parenchyma and in particular the cerebellum is considered rare. In this way we are facing the first case of cryptococcal cerebellitis in our midst.
Kondo, Reiichiro; Sugita, Yasuo; Arakawa, Kenji; Nakashima, Shinji; Umeno, Yumi; Todoroki, Keita; Yoshida, Tomoko; Takase, Yorihiko; Kage, Masayoshi; Oshima, Koichi; Yano, Hirohisa
Neurogenic pulmonary edema (NPE) is a clinical syndrome characterized by the acute onset of pulmonary edema following a significant central nervous system insult. Only a few cases of NPE after Cryptococcal meningitis have been reported. We report a case of NPE following Cryptococcal meningoencephalitis. A 40-year-old man with no medical history was hospitalized for disturbance of consciousness. Blood glucose level was 124 mg/dL. Non-contrast head computed tomography showed no abnormalities. Lumbar puncture revealed a pressure of over 300 mm H2 O and cerebrospinal fluid (CSF) confirmed a white blood cell count of 65/mm(3) . The CSF glucose level was 0 mg/dL. The patient was empirically started on treatment for presumptive bacterial and viral meningitis. Four days after, the patient died in a sudden severe pulmonary edema. Autopsy was performed. We found at autopsy a brain edema with small hemorrhage of the right basal ganglia, severe pulmonary edema and mild cardiomegaly. Histologically, dilated Virchow-Robin spaces, crowded with Cryptococci were observed. In the right basal ganglia, Virchow-Robin spaces were destroyed with hemorrhage and Cryptococci spread to parenchyma of the brain. No inflammatory reaction of the lung was seen. Finally, acute pulmonary edema in this case was diagnosed as NPE following Cryptococcal meningoencephalitis. After autopsy, we found that he was positive for serum antibodies to human immunodeficiency virus. © 2015 Japanese Society of Neuropathology.
Viereck, Matthew J; Chalouhi, Nohra; Krieger, David I; Judy, Kevin D
The standard treatment of hydrocephalus is placement of a ventriculoperitoneal (VP) shunt. While infection is a common complication, rarely are fungal organisms implicated. Cryptococcus neoformans has been reported in only nine cases of shunt infection to our knowledge. The timing from shunt placement to symptom onset varies widely from 10 days to 15 months. We present a patient who developed a cryptococcal infection of his VP shunt more than two decades following shunt placement.
Rajasingham, Radha; Rhein, Joshua; Klammer, Kate; Musubire, Abdu; Nabeta, Henry; Akampurira, Andrew; Mossel, Eric C.; Williams, Darlisha A.; Boxrud, Dave J.; Crabtree, Mary B.; Miller, Barry R.; Rolfes, Melissa A.; Tengsupakul, Supatida; Andama, Alfred O.; Meya, David B.; Boulware, David R.
There is limited understanding of the epidemiology of meningitis among human immunodeficiency virus (HIV)-infected populations in sub-Saharan Africa. We conducted a prospective cohort study of HIV-infected adults with suspected meningitis in Uganda, to comprehensively evaluate the etiologies of meningitis. Intensive cerebrospiral fluid (CSF) testing was performed to evaluate for bacterial, viral, fungal, and mycobacterial etiologies, including neurosyphilis,16s ribosomal DNA (rDNA) polymerase chain reaction (PCR) for bacteria, Plex-ID broad viral assay, quantitative-PCR for HSV-1/2, cytomegalovirus (CMV), Epstein–Barr virus (EBV), and Toxoplasma gondii; reverse transcription-PCR (RT-PCR) for Enteroviruses and arboviruses, and Xpert MTB/RIF assay. Cryptococcal meningitis accounted for 60% (188 of 314) of all causes of meningitis. Of 117 samples sent for viral PCR, 36% were EBV positive. Among cryptococcal antigen negative patients, the yield of Xpert MTB/RIF assay was 22% (8 of 36). After exclusion of cryptococcosis and bacterial meningitis, 61% (43 of 71) with an abnormal CSF profile had no definitive diagnosis. Exploration of new TB diagnostics and diagnostic algorithms for evaluation of meningitis in resource-limited settings remains needed, and implementation of cryptococcal diagnostics is critical. PMID:25385864
Rajasingham, Radha; Rhein, Joshua; Klammer, Kate; Musubire, Abdu; Nabeta, Henry; Akampurira, Andrew; Mossel, Eric C; Williams, Darlisha A; Boxrud, Dave J; Crabtree, Mary B; Miller, Barry R; Rolfes, Melissa A; Tengsupakul, Supatida; Andama, Alfred O; Meya, David B; Boulware, David R
There is limited understanding of the epidemiology of meningitis among human immunodeficiency virus (HIV)-infected populations in sub-Saharan Africa. We conducted a prospective cohort study of HIV-infected adults with suspected meningitis in Uganda, to comprehensively evaluate the etiologies of meningitis. Intensive cerebrospiral fluid (CSF) testing was performed to evaluate for bacterial, viral, fungal, and mycobacterial etiologies, including neurosyphilis,16s ribosomal DNA (rDNA) polymerase chain reaction (PCR) for bacteria, Plex-ID broad viral assay, quantitative-PCR for HSV-1/2, cytomegalovirus (CMV), Epstein-Barr virus (EBV), and Toxoplasma gondii; reverse transcription-PCR (RT-PCR) for Enteroviruses and arboviruses, and Xpert MTB/RIF assay. Cryptococcal meningitis accounted for 60% (188 of 314) of all causes of meningitis. Of 117 samples sent for viral PCR, 36% were EBV positive. Among cryptococcal antigen negative patients, the yield of Xpert MTB/RIF assay was 22% (8 of 36). After exclusion of cryptococcosis and bacterial meningitis, 61% (43 of 71) with an abnormal CSF profile had no definitive diagnosis. Exploration of new TB diagnostics and diagnostic algorithms for evaluation of meningitis in resource-limited settings remains needed, and implementation of cryptococcal diagnostics is critical. © The American Society of Tropical Medicine and Hygiene.
Senadim, Songul; Alpaydin Baslo, Sezin; Tekin Güveli, Betül; Dedei Daryan, Metin; Kantaroglu, Elif; Ozturk, Oya; Atakli, Dilek
Cryptococcal meningoencephalitis (CM) is a serious central nervous system infection caused by Cryptococcus neoformans, seen mostly in immunocompromised hosts and less in immunocompetent patients. The vast majority of cryptococcosis cases are seen as human immunodeficiency virus infections with advanced immunosuppression. Meningitis and meningoencephalitis are the most common clinical manifestations. Nevertheless, immunocompetent patients with CM are rarely reported. Cerebral venous sinus thrombosis is a rare complication of CM. Here, we report an immunocompetent patient with CM from a non-endemic area, who presented with an acute onset and atypical symptoms associated with cerebral venous thrombosis.
Bahr, Nathan C; Nuwagira, Edwin; Evans, Emily E; Cresswell, Fiona V; Bystrom, Philip V; Byamukama, Adolf; Bridge, Sarah C; Bangdiwala, Ananta S; Meya, David B; Denkinger, Claudia M; Muzoora, Conrad; Boulware, David R
WHO recommends Xpert MTB/RIF as initial diagnostic testing for tuberculous meningitis. However, diagnosis remains difficult, with Xpert sensitivity of about 50-70% and culture sensitivity of about 60%. We evaluated the diagnostic performance of the new Xpert MTB/RIF Ultra (Xpert Ultra) for tuberculous meningitis. We prospectively obtained diagnostic cerebrospinal fluid (CSF) specimens during screening for a trial on the treatment of HIV-associated cryptococcal meningitis in Mbarara, Uganda. HIV-infected adults with suspected meningitis (eg, headache, nuchal rigidity, altered mental status) were screened consecutively at Mbarara Regional Referral Hospital. We centrifuged CSF, resuspended the pellet in 2 mL of CSF, and tested 0·5 mL with mycobacteria growth indicator tube culture, 1 mL with Xpert, and cryopreserved 0·5 mL, later tested with Xpert Ultra. We assessed diagnostic performance against uniform clinical case definition or a composite reference standard of any positive CSF tuberculous test. From Feb 27, 2015, to Nov 7, 2016, we prospectively evaluated 129 HIV-infected adults with suspected meningitis for tuberculosis. 23 participants were classified as probable or definite tuberculous meningitis by uniform case definition, excluding Xpert Ultra results. Xpert Ultra sensitivity was 70% (95% CI 47-87; 16 of 23 cases) for probable or definite tuberculous meningitis compared with 43% (23-66; 10/23) for Xpert and 43% (23-66; 10/23) for culture. With composite standard, we detected tuberculous meningitis in 22 (17%) of 129 participants. Xpert Ultra had 95% sensitivity (95% CI 77-99; 21 of 22 cases) for tuberculous meningitis, which was higher than either Xpert (45% [24-68]; 10/22; p=0·0010) or culture (45% [24-68]; 10/22; p=0·0034). Of 21 participants positive by Xpert Ultra, 13 were positive by culture, Xpert, or both, and eight were only positive by Xpert Ultra. Of those eight, three were categorised as probable tuberculous meningitis, three as possible
Helbok, R; Pongpakdee, S; Yenjun, S; Dent, W; Beer, R; Lackner, P; Bunyaratvej, P; Prasert, B; Vejjajiva, A; Schmutzhard, E
The charts of 114 consecutive patients with chronic meningitis admitted to a general hospital in Bangkok, Thailand, between 1993 and 1999 were retrospectively reviewed. The most common causative agents were Cryptococcus neoformans (54%) and Mycobacterium tuberculosis (37%). HIV and other underlying diseases had a major impact on the presentation of chronic cryptococcal meningitis patients. Compared to HIV-negative cryptococcal meningitis patients (21%), HIV-positives (79%) had a significantly lower incidence of focal signs (p = 0.02), hydrocephalus (p = 0.03) and seizures (p = 0.001) during hospital stay, furthermore, a lower leucocyte level, a significantly higher glucose level (p = 0.02) and a lower protein level (p = 0.03) in the first cerebrospinal fluid examination. Of the 43 patients with chronic tuberculous meningitis, only 3 were HIV positive. Focal neurologic deficits were found more frequently in tuberculous meningitis patients (p = 0.001) when compared to cryptococcal meningitis patients without HIV. Cerebral infarction on cerebral CT was indicative of tuberculous meningitis. Cryptococcal meningitis patients with HIV infection had a worse outcome compared to non-AIDS patients. Advanced stage of the disease on admission, decreased level of consciousness prior to and on the admission day and raised intracranial pressure above 40 cm H(2)O at any given time were predictive of a poor outcome in tuberculous meningitis patients.
Musubire, A K; Meya, B D; Mayanja-Kizza, H; Lukande, R; Wiesner, L D; Bohjanen, P; R Boulware, R D
In many resource-limited settings, cryptococcal meningitis (CM) contributes up to 20% of all deaths with further complications due to Immune Reconstitution Inflammatory Syndrome (IRIS). We present a case report on a patient who developed CM-IRIS and then subsequent CM-relapse with a fluconazole-resistant organism and then later CM-IRIS once again, manifesting as cystic cryptococcomas, hydrocephalus, and sterile CSF. In this case we, demonstrate that CM-IRIS and persistent low level cryptococcal infection are not mutually exclusive phenomena. The management of IRIS with corticosteroids may increase the risk of culture positive CM-relapse which may further increase the risk of recurrent IRIS and resulting complications including death. We also highlight the role of imaging and fluconazole resistance testing in patients with recurrent meningitis and the importance of CSF cultures in guiding treatment decisions.
McKenney, Jennie; Smith, Rachel M; Chiller, Tom M; Detels, Roger; French, Audrey; Margolick, Joseph; Klausner, Jeffrey D
Cryptococcal meningitis (CM) is one of the leading opportunistic infections associated with human immunodeficiency virus (HIV) infection. The worldwide burden of CM among persons living with HIV/acquired immunodeficiency syndrome (AIDS) was estimated in 2009 to be 957,900 cases, with approximately 624,700 deaths annually. The high burden of CM globally comes despite the fact that cryptococcal antigen (CrAg) is detectable weeks before the onset of symptoms, allowing screening for cryptococcal infection and early treatment to prevent CM and CM-related mortality (2). However, few studies have been conducted in the United States to assess the prevalence of cryptococcal infection. To quantify the prevalence of undiagnosed cryptococcal infection in HIV-infected persons in the United States during 1986-2012, stored sera from 1,872 participants in the Multicenter AIDS Cohort Study and the Women's Interagency HIV Study with CD4 T-cell counts <100 cells/µL were screened for CrAg, using the CrAg Lateral Flow Assay (LFA) (Immy, Inc.). This report describes the results of that analysis, which indicated the overall prevalence of CrAg positivity in this population to be 2.9% (95% confidence interval [CI] = 2.2%-3.7%).
... causes meningitis. Causes Pneumococcal meningitis is caused by Streptococcus pneumoniae bacteria (also called pneumococcus, or S pneumoniae ). This type ... Saunders; 2015:chap 89. Wood JB, Peters TR. Streptococcus pneumoniae (pneumococcus). In: Kliegman RM, Stanton BF, St. Geme ...
Huang, Laurence; Cattamanchi, Adithya; Davis, J Lucian; den Boon, Saskia; Kovacs, Joseph; Meshnick, Steven; Miller, Robert F; Walzer, Peter D; Worodria, William; Masur, Henry
During the past 30 years, major advances have been made in our understanding of HIV/AIDS and Pneumocystis pneumonia (PCP), but significant gaps remain. Pneumocystis is classified as a fungus and is host-species specific, but an understanding of its reservoir, mode of transmission, and pathogenesis is incomplete. PCP remains a frequent AIDS-defining diagnosis and is a frequent opportunistic pneumonia in the United States and in Europe, but comparable epidemiologic data from other areas of the world that are burdened with HIV/AIDS are limited. Pneumocystis cannot be cultured, and bronchoscopy with bronchoalveolar lavage is the gold standard procedure to diagnose PCP, but noninvasive diagnostic tests and biomarkers show promise that must be validated. Trimethoprim-sulfamethoxazole is the recommended first-line treatment and prophylaxis regimen, but putative trimethoprim-sulfamethoxazole drug resistance is an emerging concern. The International HIV-associated Opportunistic Pneumonias (IHOP) study was established to address these knowledge gaps. This review describes recent advances in the pathogenesis, epidemiology, diagnosis, and management of HIV-associated PCP and ongoing areas of clinical and translational research that are part of the IHOP study and the Longitudinal Studies of HIV-associated Lung Infections and Complications (Lung HIV).
... influenzae meningitis; H. flu meningitis; Haemophilus influenzae type b meningitis ... influenzae meningitis is caused by Haemophilus influenzae type b bacteria. This illness is not the same as ...
Ghosh, Gopal Chandra; Sharma, Brijesh; Gupta, B B
Tuberculous and Cryptococcal meningitis are common in HIV patients. A highly specific and sensitive rapid test for diagnosis of Tuberculous meningitis especially in setting of HIV is not available in developing countries where the burden of disease is high. We measured ADA (adenosine deaminase) levels using spectrophotometric method in the CSF of HIV patients with meningitis to differentiate Tuberculous meningitis from meningitis due to other causes. Kruskal-Wallis test was used to compare ADA values between tuberculous meningitis (TBM) and nontuberculous (non-TB) meningitis patients and a receiver-operating characteristic (ROC) analysis curve was drawn from these values. Levels of ADA in the CSF of patients with TBM were significantly higher than those in patients with meningitis due to other causes. CSF ADA level determination with a cut-off value of 6 IU/L was found to be highly specific and fairly sensitive test for the diagnosis of TBM in HIV positive patients.
Bowen, Lauren N; Smith, Bryan; Reich, Daniel; Quezado, Martha; Nath, Avindra
Nearly 30 years after the advent of antiretroviral therapy (ART), CNS opportunistic infections remain a major cause of morbidity and mortality in HIV-positive individuals. Unknown HIV-positive disease status, antiretroviral drug resistance, poor drug compliance, and recreational drug abuse are factors that continue to influence the morbidity and mortality of infections. The clinical and radiographic pattern of CNS opportunistic infections is unique in the setting of HIV infection: opportunistic infections in HIV-positive patients often have characteristic clinical and radiological presentations that can differ from the presentation of opportunistic infections in immunocompetent patients and are often sufficient to establish the diagnosis. ART in the setting of these opportunistic infections can lead to a paradoxical worsening caused by an immune reconstitution inflammatory syndrome (IRIS). In this Review, we discuss several of the most common CNS opportunistic infections: cerebral toxoplasmosis, progressive multifocal leukoencephalopathy (PML), tuberculous meningitis, cryptococcal meningitis and cytomegalovirus infection, with an emphasis on clinical pearls, pathological findings, MRI findings and treatment. Moreover, we discuss the risk factors, pathophysiology and management of IRIS. We also summarize the challenges that remain in management of CNS opportunistic infections, which includes the lack of phase II and III clinical trials, absence of antimicrobials for infections such as PML, and controversy regarding the use of corticosteroids for treatment of IRIS.
Goldman, D L; Casadevall, A; Cho, Y; Lee, S C
The primary clinical manifestation of Cryptococcus neoformans infection in humans is meningoencephalitis. To study the defense mechanisms that participate in the host response against C. neoformans infection of the central nervous system (CNS), we have developed a new model of cryptococcal meningitis in rats. Intracisternal inoculation of C. neoformans produced a granulomatous meningitis with minimal brain parenchymal involvement, resembling cryptococcal meningitis in immunocompetent patients. The granulomas were composed of T cells (CD4+ and CD8+) and macrophages (CD11b/c+); a subpopulation of the macrophages expressed inducible nitric oxide synthase (NOS2). In this model, C. neoformans disseminated to systemic organs early in the course of infection and provoked granuloma formation and NOS2 expression. The temporal profile of inflammation indicated that the CNS inflammatory response is delayed relative to that in the lung and the spleen, which suggests that the effective inflammatory response within the CNS may follow activation of T cells in the periphery and their subsequent entry into the CNS. Inflammation in the meninges was associated with signs of subpial and subependymal glial activation, including enhanced expression of CD11b/c and CD4 in microglia and glial fibrillary acidic protein in astrocytes. Neither cells, however, expressed NOS2. Although C. neoformans invasion to the brain parenchyma was rare, soluble polysaccharide was commonly associated with reactive glial cells. Necrosis was not a feature of C. neoformans granulomas, but, instead, inflammatory cells underwent apoptosis in inflamed organs. The current rat intrathecal cryptococcosis model has several unique advantages for the study of human cryptococcal meningoencephalitis that include close resemblance of histopathologic changes to those in humans, easy accessibility to the cerebrospinal fluid compartment, and no requirement of immunosuppressive agents for establishment of infection.
Rhein, Joshua; Bahr, Nathan C; Hemmert, Andrew C; Cloud, Joann L; Bellamkonda, Satya; Oswald, Cody; Lo, Eric; Nabeta, Henry; Kiggundu, Reuben; Akampurira, Andrew; Musubire, Abdu; Williams, Darlisha; Meya, David B; Boulware, David R
Meningitis remains a worldwide problem, and rapid diagnosis is essential to optimize survival. We evaluated the utility of a multiplex PCR test in differentiating possible etiologies of meningitis. Cerebrospinal fluid (CSF) from 69 HIV-infected Ugandan adults with meningitis was collected at diagnosis (n=51) and among persons with cryptococcal meningitis during therapeutic lumbar punctures (n=68). Cryopreserved CSF specimens were analyzed with BioFire FilmArray® Meningitis/Encephalitis panel, which targets 17 pathogens. The panel detected Cryptococcus in the CSF of patients diagnosed with a first-episode of cryptococcal meningitis by fungal culture with 100% sensitivity and specificity, and differentiated between fungal relapse and paradoxical immune reconstitution inflammatory syndrome in recurrent episodes. A negative FilmArray result was predictive of CSF sterility on follow-up lumbar punctures for cryptococcal meningitis. EBV was frequently detected in this immunosuppressed population (n=45). Other pathogens detected included: CMV (n=2), VZV (n=2), HHV-6 (n=1), and Streptococcus pneumoniae (n=1). The FilmArray Meningitis/Encephalitis panel offers a promising platform for rapid meningitis diagnosis. PMID:26711635
Rhein, Joshua; Bahr, Nathan C; Hemmert, Andrew C; Cloud, Joann L; Bellamkonda, Satya; Oswald, Cody; Lo, Eric; Nabeta, Henry; Kiggundu, Reuben; Akampurira, Andrew; Musubire, Abdu; Williams, Darlisha A; Meya, David B; Boulware, David R
Meningitis remains a worldwide problem, and rapid diagnosis is essential to optimize survival. We evaluated the utility of a multiplex PCR test in differentiating possible etiologies of meningitis. Cerebrospinal fluid (CSF) from 69 HIV-infected Ugandan adults with meningitis was collected at diagnosis (n=51) and among persons with cryptococcal meningitis during therapeutic lumbar punctures (n=68). Cryopreserved CSF specimens were analyzed with BioFire FilmArray® Meningitis/Encephalitis panel, which targets 17 pathogens. The panel detected Cryptococcus in the CSF of patients diagnosed with a first episode of cryptococcal meningitis by fungal culture with 100% sensitivity and specificity and differentiated between fungal relapse and paradoxical immune reconstitution inflammatory syndrome in recurrent episodes. A negative FilmArray result was predictive of CSF sterility on follow-up lumbar punctures for cryptococcal meningitis. EBV was frequently detected in this immunosuppressed population (n=45). Other pathogens detected included: cytomegalovirus (n=2), varicella zoster virus (n=2), human herpes virus 6 (n=1), and Streptococcus pneumoniae (n=1). The FilmArray Meningitis/Encephalitis panel offers a promising platform for rapid meningitis diagnosis. Copyright © 2015 Elsevier Inc. All rights reserved.
Gish, Stacey R.; Maier, Ezekiel J.; Haynes, Brian C.; Santiago-Tirado, Felipe H.; Srikanta, Deepa L.; Ma, Cynthia Z.; Li, Lucy X.; Williams, Matthew; Crouch, Erika C.; Khader, Shabaana A.
ABSTRACT Cryptococcus neoformans is a ubiquitous, opportunistic fungal pathogen that kills over 600,000 people annually. Here, we report integrated computational and experimental investigations of the role and mechanisms of transcriptional regulation in cryptococcal infection. Major cryptococcal virulence traits include melanin production and the development of a large polysaccharide capsule upon host entry; shed capsule polysaccharides also impair host defenses. We found that both transcription and translation are required for capsule growth and that Usv101 is a master regulator of pathogenesis, regulating melanin production, capsule growth, and capsule shedding. It does this by directly regulating genes encoding glycoactive enzymes and genes encoding three other transcription factors that are essential for capsule growth: GAT201, RIM101, and SP1. Murine infection with cryptococci lacking Usv101 significantly alters the kinetics and pathogenesis of disease, with extended survival and, unexpectedly, death by pneumonia rather than meningitis. Our approaches and findings will inform studies of other pathogenic microbes. PMID:27094327
Clifford, David B; Ances, Beau M
Neurological involvement in HIV is often associated with cognitive impairment. Although severe and progressive neurocognitive impairment has become rare in HIV clinics in the era of potent antiretroviral therapy, most patients with HIV worldwide have poor outcomes on formal neurocognitive tests. In this Review, we describe the manifestations of HIV-associated neurocognitive disorder in the era of effective HIV therapy, outline diagnosis and treatment recommendations, and explore the research questions that remain. Although comorbid disorders, such as hepatitis C infection or epilepsy, might cause some impairment, their prevalence is insufficient to explain the frequency with which it is encountered. HIV disease markers, such as viral load and CD4 cell counts, are not strongly associated with ongoing impairment on treatment, whereas cardiovascular disease markers and inflammatory markers are. New cerebrospinal fluid and neuroimaging biomarkers are needed to detect and follow impairment. Ongoing research efforts to optimise HIV therapy within the CNS, and potentially to intervene in downstream mechanisms of neurotoxicity, remain important avenues for future investigation. Ultimately, the full control of virus in the brain is a necessary step in the goal of HIV eradication. Copyright © 2013 Elsevier Ltd. All rights reserved.
... to the spinal cord. Unlike the fungi above, Candida , which can also cause meningitis, is usually acquired ... weights are also at increased risk for getting Candida blood stream infection, which may spread to the ...
... consultations Fact sheets Fact files Questions & answers Features Multimedia Contacts Meningococcal meningitis Fact sheet N°141 Updated ... result in brain damage, hearing loss or a learning disability in 10% to 20% of survivors. A ...
... Resources for Healthcare Professionals Related Links Vaccine Schedules Preteen & Teen Vaccines Meningococcal Disease Sepsis Viral Meningitis Language: ... Arboviruses Lymphocytic Choriomeningitis Virus Related Links Vaccine Schedules Preteen & Teen ... Disease Sepsis Language: English Spanish ...
Boulware, David R; Rolfes, Melissa A; Rajasingham, Radha; von Hohenberg, Maximilian; Qin, Zhenpeng; Taseera, Kabanda; Schutz, Charlotte; Kwizera, Richard; Butler, Elissa K; Meintjes, Graeme; Muzoora, Conrad; Bischof, John C; Meya, David B
Cryptococcal meningitis is common in sub-Saharan Africa. Given the need for data for a rapid, point-of-care cryptococcal antigen (CRAG) lateral flow immunochromatographic assay (LFA), we assessed diagnostic performance of cerebrospinal fluid (CSF) culture, CRAG latex agglutination, India ink microscopy, and CRAG LFA for 832 HIV-infected persons with suspected meningitis during 2006-2009 (n = 299) in Uganda and during 2010-2012 (n = 533) in Uganda and South Africa. CRAG LFA had the best performance (sensitivity 99.3%, specificity 99.1%). Culture sensitivity was dependent on CSF volume (82.4% for 10 μL, 94.2% for 100 μL). CRAG latex agglutination test sensitivity (97.0%-97.8%) and specificity (85.9%-100%) varied between manufacturers. India ink microscopy was 86% sensitive. Laser thermal contrast had 92% accuracy (R = 0.91, p<0.001) in quantifying CRAG titers from 1 LFA strip to within <1.5 dilutions of actual CRAG titers. CRAG LFA is a major advance for meningitis diagnostics in resource-limited settings.
Rolfes, Melissa A.; Rajasingham, Radha; von Hohenberg, Maximilian; Qin, Zhenpeng; Taseera, Kabanda; Schutz, Charlotte; Kwizera, Richard; Butler, Elissa K.; Meintjes, Graeme; Muzoora, Conrad; Bischof, John C.; Meya, David B.
Cryptococcal meningitis is common in sub-Saharan Africa. Given the need for data for a rapid, point-of-care cryptococcal antigen (CRAG) lateral flow immunochromatographic assay (LFA), we assessed diagnostic performance of cerebrospinal fluid (CSF) culture, CRAG latex agglutination, India ink microscopy, and CRAG LFA for 832 HIV-infected persons with suspected meningitis during 2006–2009 (n = 299) in Uganda and during 2010–2012 (n = 533) in Uganda and South Africa. CRAG LFA had the best performance (sensitivity 99.3%, specificity 99.1%). Culture sensitivity was dependent on CSF volume (82.4% for 10 μL, 94.2% for 100 μL). CRAG latex agglutination test sensitivity (97.0%–97.8%) and specificity (85.9%–100%) varied between manufacturers. India ink microscopy was 86% sensitive. Laser thermal contrast had 92% accuracy (R = 0.91, p<0.001) in quantifying CRAG titers from 1 LFA strip to within <1.5 dilutions of actual CRAG titers. CRAG LFA is a major advance for meningitis diagnostics in resource-limited settings. PMID:24378231
Refractory Cryptococcus neoformans Meningoencephalitis in an Immunocompetent Patient: Paradoxical Antifungal Therapy-Induced Clinical Deterioration Related to an Immune Response to Cryptococcal Organisms.
Nakajima, Hideto; Takayama, Ayami; Fujiki, Yohei; Ito, Takumi; Kitaoka, Haruko
We present a case of refractory Cryptococcus neoformans meningoencephalitis in an immunocompetent woman. Her clinical symptoms did not improve with 6 months of antifungal therapy, and MRI abnormalities, indicating severe meningeal and cerebral inflammation, persisted despite a decreasing cryptococcal antigen titer. The patient continued to deteriorate despite antifungal therapy, and her condition clearly improved following treatment with adjunctive corticosteroid. We postulate that the paradoxical antifungal therapy-related clinical deterioration was due to an immune response to cryptococcal organisms, which responded to corticosteroids. These observations provide rationale for a further evaluation of corticosteroids in the management of select cases of C. neoformans central nervous system infection.
Kessler, Bernhard; Bally, Frank; Hewer, Ekkehard; Sendi, Parham
Cryptococcus spp. commonly causes infection in immunocompromised hosts. Clinical presentation of cryptococcal meningoencephalitis (CM) is variable, but headache, fever and a high intracranial pressure should suggest the diagnosis. The cryptococcal antigen test is a specific and sensitive rapid test that can be performed on blood or cerebrospinal fluid. We report a case of CM in a patient with previously undetected lymphocytopenia. Because cryptococcal antigen test results were negative, diagnosis and treatment were delayed.
Kammalac Ngouana, T; Dongtsa, J; Kouanfack, C; Tonfack, C; Fomena, S; Mallié, M; Delaporte, E; Boyom, F-Fekam; Bertout, S
Cryptococcal meningitis is a mycosis encountered especially in patients with Acquired Immunodeficiency Syndrome and is fatal in the absence of treatment. Information on epidemiology, diagnosis and susceptibility profile to antifungal drugs, are scarce in Cameroon. Authors evaluated the diagnosis possibilities of the cryptococcal meningitis in Cameroon, and studied the antifungal susceptibility of isolated strains to fluconazole, used as first line treatment of the disease in Cameroon. Between December 2009 and July 2011, 146 cerebrospinal fluids obtained from HIV patients with suspicion of meningitis were analysed. The diagnosis procedure involved macroscopic and cyto-chemical analysis, India ink test, culture on Sabouraud chloramphenicol medium and antigen latex agglutination test. Antifungal susceptibility testing of isolated strains to fluconazole was done by the E-test(®) method. The diagnosis of cryptococcal meningitis gave 28.08% positive cases. Among these patients, 80% were at stages III and IV and 20% at stage I of the HIV infection, according to the WHO previous classification. Cyto-chemical analysis showed current findings in the case of cryptococcal meningitis. India ink test and latex agglutination test exhibited very high sensitivity and specificity (>94%). Fluconazole antifungal susceptibility testing gave MICs lower than 32μg/mL to 92.7% of isolated strains and MICs greater than this value to 7.3% of isolates. These results showed that cryptococcal meningitis remains a real problem among HIV infected patients in Yaoundé. The emergence of fluconazole reduced susceptibility strains is worrying. Nevertheless, efficacy of rapid detection tests is interesting because this will help in rapid diagnosis and treatment of patients.
... tis cause death in up to 90% of people. For most kinds of meningitis, the risk of dying is about 30%. Neurologic problems can also occur from the men- ingitis. For instance, some people have hearing prob- lems or trouble thinking, which ...
Oladele, Rita O.; Akanmu, Alani S.; Nwosu, Augustina O.; Ogunsola, Folasade T.; Richardson, Malcolm D.; Denning, David W.
Background. Cryptococcal meningitis has a high mortality in human immunodeficiency virus (HIV)-infected persons in Africa. This is preventable with early screening and preemptive therapy. We evaluated the prevalence of cryptococcal disease by antigen testing, possible associated factors, and outcomes in HIV-infected patients being managed in a tertiary hospital in Lagos, Nigeria. Methods. Sera were collected from 214 consenting HIV-infected participants with CD4+ counts <250 cells/mm3, irrespective of their antiretroviral therapy (ART) status, between November 2014 and May 2015. A cryptococcal antigen (CrAg) lateral flow assay was used for testing. Pertinent clinical data were obtained from patients and their case notes. Results. Of the 214 participants, females (124; 57.9%) outnumbered males. Mean age was 41.3 ± 9.4 (standard deviation) years. The majority (204; 95.3%) were ART experienced. The median CD4+ cell count was 160 cells/mm3 (interquartile range, 90–210). The overall seroprevalence of cryptococcal antigenemia was 8.9% (19 of 214); 6 of 61 (9.8%) in those with CD4+ cell counts <100 cells/mm3, 4 of 80 (5.0%) in the 100–200 group, and 9 of 73 (12.3%) in 200–250 cells/mm3 group. Among ART-naive patients, 1 of 10 (10%) was CrAg positive. Twenty-seven of 214 (12.6%) had associated oral thrush. Potential baseline meningitis symptoms (3 of 214 [1.4%] experienced neck pain or stiffness and 21 of 214 [9.8%] experienced headache) were common in the study group, but the result was not statistically significant in relation to CrAg positivity. Two of 19 (10.5%) CrAg-positive patients died, 10 of 19 (52.6%) were lost to follow up, and 7 of 19 (36.8%) were alive. Empirical fluconazole was routinely given to those with low CD4 counts <100 cells/mm3, which was unrelated to CrAg positivity (P = .018). Conclusions. We report a prevalence of 8.9% cryptococcal antigenemia in a setting where first-line antifungals are not readily available. We recommend Cr
Oladele, Rita O; Akanmu, Alani S; Nwosu, Augustina O; Ogunsola, Folasade T; Richardson, Malcolm D; Denning, David W
Background. Cryptococcal meningitis has a high mortality in human immunodeficiency virus (HIV)-infected persons in Africa. This is preventable with early screening and preemptive therapy. We evaluated the prevalence of cryptococcal disease by antigen testing, possible associated factors, and outcomes in HIV-infected patients being managed in a tertiary hospital in Lagos, Nigeria. Methods. Sera were collected from 214 consenting HIV-infected participants with CD4(+) counts <250 cells/mm(3), irrespective of their antiretroviral therapy (ART) status, between November 2014 and May 2015. A cryptococcal antigen (CrAg) lateral flow assay was used for testing. Pertinent clinical data were obtained from patients and their case notes. Results. Of the 214 participants, females (124; 57.9%) outnumbered males. Mean age was 41.3 ± 9.4 (standard deviation) years. The majority (204; 95.3%) were ART experienced. The median CD4(+) cell count was 160 cells/mm(3) (interquartile range, 90-210). The overall seroprevalence of cryptococcal antigenemia was 8.9% (19 of 214); 6 of 61 (9.8%) in those with CD4(+) cell counts <100 cells/mm(3), 4 of 80 (5.0%) in the 100-200 group, and 9 of 73 (12.3%) in 200-250 cells/mm(3) group. Among ART-naive patients, 1 of 10 (10%) was CrAg positive. Twenty-seven of 214 (12.6%) had associated oral thrush. Potential baseline meningitis symptoms (3 of 214 [1.4%] experienced neck pain or stiffness and 21 of 214 [9.8%] experienced headache) were common in the study group, but the result was not statistically significant in relation to CrAg positivity. Two of 19 (10.5%) CrAg-positive patients died, 10 of 19 (52.6%) were lost to follow up, and 7 of 19 (36.8%) were alive. Empirical fluconazole was routinely given to those with low CD4 counts <100 cells/mm(3), which was unrelated to CrAg positivity (P = .018). Conclusions. We report a prevalence of 8.9% cryptococcal antigenemia in a setting where first-line antifungals are not readily available. We
Montgomery, Martha P; Nakasujja, Noeline; Morawski, Bozena M; Rajasingham, Radha; Rhein, Joshua; Nalintya, Elizabeth; Williams, Darlisha A; Huppler Hullsiek, Kathy; Kiragga, Agnes; Rolfes, Melissa A; Donahue Carlson, Renee; Bahr, Nathan C; Birkenkamp, Kate E; Manabe, Yukari C; Bohjanen, Paul R; Kaplan, Jonathan E; Kambugu, Andrew; Meya, David B; Boulware, David R
HIV-infected persons with detectable cryptococcal antigen (CrAg) in blood have increased morbidity and mortality compared with HIV-infected persons who are CrAg-negative. This study examined neurocognitive function among persons with asymptomatic cryptococcal antigenemia. Participants from three prospective HIV cohorts underwent neurocognitive testing at the time of antiretroviral therapy (ART) initiation. Cohorts included persons with cryptococcal meningitis (N = 90), asymptomatic CrAg + (N = 87), and HIV-infected persons without central nervous system infection (N = 125). Z-scores for each neurocognitive test were calculated relative to an HIV-negative Ugandan population with a composite quantitative neurocognitive performance Z-score (QNPZ-8) created from eight tested domains. Neurocognitive function was measured pre-ART for all three cohorts and additionally after 4 weeks of ART (and 6 weeks of pre-emptive fluconazole) treatment among asymptomatic CrAg + participants. Cryptococcal meningitis and asymptomatic CrAg + participants had lower median CD4 counts (17 and 26 cells/μL, respectively) than the HIV-infected control cohort (233 cells/μL) as well as lower Karnofsky performance status (60 and 70 vs. 90, respectively). The composite QNPZ-8 for asymptomatic CrAg + (-1.80 Z-score) fell between the cryptococcal meningitis cohort (-2.22 Z-score, P = 0.02) and HIV-infected controls (-1.36, P = 0.003). After four weeks of ART and six weeks of fluconazole, the asymptomatic CrAg + cohort neurocognitive performance improved (-1.0 Z-score, P < 0.001). Significant deficits in neurocognitive function were identified in asymptomatic CrAg + persons with advanced HIV/AIDS even without signs or sequelae of meningitis. Neurocognitive function in this group improves over time after initiation of pre-emptive fluconazole treatment and ART, but short term adherence support may be necessary.
Britz, Erika; Perovic, Olga; von Mollendorf, Claire; von Gottberg, Anne; Iyaloo, Samantha; Quan, Vanessa; Chetty, Verushka; Sriruttan, Charlotte; Ismail, Nazir A.; Nanoo, Ananta; Musekiwa, Alfred; Reddy, Carl; Viljoen, Karien; Cohen, Cheryl; Govender, Nelesh P.
Introduction Meningitis is a major cause of mortality in southern Africa. We aimed to describe the aetiologies and frequencies of laboratory-confirmed fungal and bacterial meningitis among adults in a South African province with an 11% HIV prevalence, over 4 years. Methods We conducted a retrospective, observational study of secondary laboratory data, extracted on all cerebrospinal fluid (CSF) specimens submitted to public-sector laboratories in Gauteng province from 2009 through 2012. We calculated cause-specific incidence rates in the general and HIV-infected populations and used Poisson regression to determine if trends were significant. Results We identified 11,891 (10.7%) incident cases of meningitis from 110,885 CSF specimens. Cryptococcal meningitis, tuberculous meningitis and pneumococcal meningitis accounted for 62.3% (n = 7,406), 24.6% (n = 2,928) and 10.1% (n = 1,197) of cases over the four-year period. The overall incidence (cases per 100,000 persons) of cryptococcal meningitis declined by 23% from 24.4 in 2009 to 18.7 in 2012 (p <0.001) and decreased by 19% among HIV-infected persons from 178.2 to 144.7 (p <0.001). Tuberculous meningitis decreased by 40% from 11.3 in 2009 to 6.8 in 2012 (p <0.001) and decreased by 36% among HIV-infected persons from 54.4 to 34.9 (p <0.001). Pneumococcal meningitis decreased by 41% from 4.2 in 2009 to 2.5 in 2012 (p <0.001) and decreased by 38% among HIV-infected persons from 28.0 to 17.5 (p <0.001). Among cases of other bacterial meningitis (248/11,891, 2.1%), Neisseria meningitidis (n = 93), Escherichia coli (n = 72) and Haemophilus influenzae (n = 20) were the most common organisms identified. Conclusions In this high HIV-prevalence province, cryptococcal meningitis was the leading cause of laboratory-confirmed meningitis among adults. Over a 4-year period, there was a significant decrease in incidence of cryptococcal, tuberculous and pneumococcal meningitis. This coincided with expansion of the national
... spinal cord (meninges) and of the fluid-filled space between the meninges (subarachnoid space) that develops over days to a few weeks. ... three layers of tissue called meninges. The subarachnoid space is located between the middle layer and the ...
Vidal, José E; Toniolo, Carolina; Paulino, Adriana; Colombo, Arnaldo; Dos Anjos Martins, Marilena; da Silva Meira, Cristina; Pereira-Chioccola, Vera Lucia; Figueiredo-Mello, Claudia; Barros, Tiago; Duarte, Jequelie; Fonseca, Fernanda; Alves Cunha, Mirella; Mendes, Clara; Ribero, Taiana; Dos Santos Lazera, Marcia; Rajasingham, Radha; Boulware, David R
To determine the prevalence of asymptomatic cryptococcal antigen (CRAG) using lateral flow assay (LFA) in hospitalised HIV-infected patients with CD4 counts <200 cells/μl. Hospitalised HIV-infected patients were prospectively recruited at Instituto de Infectologia Emilio Ribas, a tertiary referral hospital to HIV-infected patients serving the São Paulo State, Brazil. All patients were >18 years old without prior cryptococcal meningitis, without clinical suspicion of cryptococcal meningitis, regardless of antiretroviral (ART) status, and with CD4 counts <200 cells/μl. Serum CRAG was tested by LFA in all patients, and whole blood CRAG was tested by LFA in positive cases. We enrolled 163 participants of whom 61% were men. The duration of HIV diagnosis was a median of 8 (range, 1-29) years. 26% were antiretroviral (ART)-naïve, and 74% were ART-experienced. The median CD4 cell count was 25 (range, 1-192) cells/μl. Five patients (3.1%; 95%CI, 1.0-7.0%) were asymptomatic CRAG-positive. Positive results cases were cross-verified by performing LFA in whole blood. 3.1% of HIV-infected inpatients with CD4 <200 cells/μl without symptomatic meningitis had cryptococcal antigenemia in São Paulo, suggesting that routine CRAG screening may be beneficial in similar settings in South America. Our study reveals another targeted population for CRAG screening: hospitalised HIV-infected patients with CD4 <200 cells/μl, regardless of ART status. Whole blood CRAG LFA screening seems to be a simple strategy to prevention of symptomatic meningitis. © 2016 John Wiley & Sons Ltd.
Thiruchelvan, N; Wuu, K Y; Arseculeratne, S N; Ashraful-Haq, J
Wet India ink mounts of cerebrospinal fluid (CSF) are useful in the laboratory diagnosis of cryptococcal meningitis. Pseudo-cryptococcal artefacts in such mounts have been attributed to leucocytes in CSF but their mode of formation has not been explained. This report describes the reproduction of such an artefact in cryptococcus free CSF-leucocyte mixtures that had been subjected to high speed centrifugation. The viscosity of DNA that could provide a morphological pseudo-capsule, and the yellow-green fluorescence of the pseudo-capsular material on staining with acridine-orange, suggest that lymphocytic nuclear DNA, which possibly leaked out after damage to the lymphocyte membrane by centrifugation, was responsible for this artefact.
Beno, Pavol; Kaiglova, Alzbeta; Samohyl, Martin
HIV Infection resulting in AIDS remains serious global public health problem. In the fight with the global health problem plays a key role a simple, reliable and fast diagnostics. An important method in diagnostics is the identification and detection of viral capside p24 antigen levels. Fourth generation tests for the diagnostics of HIV infection simultaneously detect the presence of HIV antibodies and p24 antigen. Based on the monitoring of CD4 count, we can estimate the stage in which the infection is, and we can also suggest a therapeutic approach. Cerebral toxoplasmosis is the most common neurological opportunistic disease manifested in HIV infected patients. Cryptococcal meningitis is the second most common cause of the opportunistic neuroinfections. Despite of significant advances in the diagnostics and treatment of HIV infection, this disease is still unable to get completely under control. The future perspective in HIV diagnostics are biosensors.
Mittal, N; Vatsa, S; Minz, Aka
Cryptococcal meningitis in immunocompetent post-partum women has been rarely reported. Immune restoration during post-partum period leads to unmasking of many opportunistic infections that may have been acquired during pregnancy but manifest itself in the post-partum period due to immune reconstitution inflammatory syndrome. This case highlights the importance of considering opportunistic pathogens in immunocompetent patients who may be undergoing immune restoration. We report here a fatal case of post-partum immunocompetent women who presented with clinical features of meningitis. Prognosis of the cryptococcal meningitis not only depends on the immune status of the patient but also on how early the disease is diagnosed in the course of illness.
Navabi, Nazlee; Montebatsi, Milton; Scott, Michelle; Gluckman, Stephen J; Reid, Michael J A
A case of false-negative serum latex agglutination cryptococcal antigen (CRAG) test in a 45-year-old HIV-positive male with Cryptococcus-positive culture is described. The patient was presented to a hospital in Botswana, with breathlessness and a diffuse papular rash. His CD4 count was 25 cells/μL. Despite the suspicion for disseminated cryptococcal disease, an initial serum CRAG latex test was negative. Results of subsequent Indian ink staining, culture of cerebrospinal fluid and skin scrapings, and serum lateral flow immunoassay (LFA) were all positive for Cryptococcus neoformans. There are several possible explanations for the false-negative CRAG latex test. Given the positive LFA result, we speculate that disease may have been caused by Cryptococcus gattii, which is estimated to be responsible for between 15% and 30% of all cryptococcal diseases in Botswana. Reduced sensitivity of CRAG latex assays for detecting C gattii may lead to underdiagnosis of cryptococcal infection.
Onyebujoh, Philip Chukwuka; Ribeiro, Isabela; Whalen, Christopher Curtis
The vicious interaction between the human immunodeficiency virus (HIV) infection and tuberculosis (TB) pandemics poses special challenges to national control programs and individual physicians. Although recommendations for the treatment of TB in HIV-infected patients do not significantly differ from those for HIV-uninfected patients, the appropriate management of HIV-associated TB is complicated by health system issues, diagnostic difficulties, adherence concerns, overlapping adverse-effect profiles and drug interactions, and the occurrence of paradoxical reactions after the initiation of effective antiretroviral therapy. In this article, recommended treatment strategies and novel approaches to the management of HIV-associated TB are reviewed, including adjuvant treatment and options for treatment simplification. A focused research agenda is proposed in the context of the limitations of the current knowledge framework. PMID:17726832
Veltman, Jennifer A; Bristow, Claire C; Klausner, Jeffrey D
Introduction Meningitis is one of the leading causes of death among patients living with HIV in sub-Saharan Africa. There is no widespread tracking of the incidence rates of causative agents among patients living with HIV, yet the aetiologies of meningitis are different than those of the general population. Methods We reviewed the scientific literature published in PubMed to determine the incidence rates of meningitis among hospitalized people living with HIV in sub-Saharan Africa and report our findings from seven studies across sub-Saharan Africa. Results We found high rates of cryptococcal meningitis (19–68%). Tuberculous meningitis was lower (1–36%), although some centres included possible cases as “other” meningitis; therefore, this may not be a true representation of the total cases. Pyogenic meningitis ranged from 6 to 30% and “other” meningitis ranged from 7 to 28% of all reported cases of meningitis. Mortality rates ranged from 25 to 68%. This review describes the most common aetiologies and provides practical diagnostic, treatment and prevention considerations as they apply to the individual living with HIV in sub-Saharan Africa. Conclusions Diagnosis is often limited, and wider availability of accurate and low-cost laboratory diagnostics is desperately needed for prompt diagnosis and initiation of appropriate treatment. Wider acceptance and adoption of available preventative modalities can decrease the incidence of potentially fatal central nervous system infections in African patients living with HIV. PMID:25308903
Veltman, Jennifer A; Bristow, Claire C; Klausner, Jeffrey D
Meningitis is one of the leading causes of death among patients living with HIV in sub-Saharan Africa. There is no widespread tracking of the incidence rates of causative agents among patients living with HIV, yet the aetiologies of meningitis are different than those of the general population. We reviewed the scientific literature published in PubMed to determine the incidence rates of meningitis among hospitalized people living with HIV in sub-Saharan Africa and report our findings from seven studies across sub-Saharan Africa. We found high rates of cryptococcal meningitis (19-68%). Tuberculous meningitis was lower (1-36%), although some centres included possible cases as "other" meningitis; therefore, this may not be a true representation of the total cases. Pyogenic meningitis ranged from 6 to 30% and "other" meningitis ranged from 7 to 28% of all reported cases of meningitis. Mortality rates ranged from 25 to 68%. This review describes the most common aetiologies and provides practical diagnostic, treatment and prevention considerations as they apply to the individual living with HIV in sub-Saharan Africa. Diagnosis is often limited, and wider availability of accurate and low-cost laboratory diagnostics is desperately needed for prompt diagnosis and initiation of appropriate treatment. Wider acceptance and adoption of available preventative modalities can decrease the incidence of potentially fatal central nervous system infections in African patients living with HIV.
Spina-Tensini, Tallulah; Muro, Marisol Dominguez; Queiroz-Telles, Flávio; Strozzi, Isabella; Moraes, Samia Talise; Petterle, Ricardo Rasmussen; Vettorello, Marcelo; Staudacher, Claudia; Miguez, Luiz Alberto Lopes; de Almeida, Sérgio Monteiro
Cryptococcal meningitis is mainly caused by members of the C. neoformans/C. gattii species complexes. The ecological niches of Cryptococcus species have extensively been studied, but its epidemiological relationship with meningitis cases is still unknown. In this study, we estimate the relationship between cryptococcal meningitis cases and tree and pigeon populations, the classical niches of members of C. neoformans/C. gattii sensu lato. We analysed the records of every patient whose cerebrospinal fluid culture yielded Cryptococcus spp. during the last 30 years at Clinical Hospital of Curitiba. Data about Curitiba's pigeon and tree distribution were obtained from Curitiba's Secretaries of Zoonosis and Environment archives. We used ArcGis9 software to plot the distribution of the pigeon and tree populations in this city as well as cryptococcal meningitis cases, distinguishing them according to the causal agent in C. neoformans or C. gattii s.l. In total, 489 cryptococcal cultures were documented, with 140 corresponding to patients eligible for this study (134 affected by C. neoformans s.l. and 6 by C. gattii s.l.). The map showed a relationship between C. neoformans s.l. patients and pigeon population. C. gattii s.l. patients were associated with neither tree nor pigeon populations, but lived close to large unbuilt, unforested areas.
Tenor, Jennifer L; Oehlers, Stefan H; Yang, Jialu L; Tobin, David M; Perfect, John R
The human fungal pathogen Cryptococcus neoformans is capable of infecting a broad range of hosts, from invertebrates like amoebas and nematodes to standard vertebrate models such as mice and rabbits. Here we have taken advantage of a zebrafish model to investigate host-pathogen interactions of Cryptococcus with the zebrafish innate immune system, which shares a highly conserved framework with that of mammals. Through live-imaging observations and genetic knockdown, we establish that macrophages are the primary immune cells responsible for responding to and containing acute cryptococcal infections. By interrogating survival and cryptococcal burden following infection with a panel of Cryptococcus mutants, we find that virulence factors initially identified as important in causing disease in mice are also necessary for pathogenesis in zebrafish larvae. Live imaging of the cranial blood vessels of infected larvae reveals that C. neoformans is able to penetrate the zebrafish brain following intravenous infection. By studying a C. neoformans FNX1 gene mutant, we find that blood-brain barrier invasion is dependent on a known cryptococcal invasion-promoting pathway previously identified in a murine model of central nervous system invasion. The zebrafish-C. neoformans platform provides a visually and genetically accessible vertebrate model system for cryptococcal pathogenesis with many of the advantages of small invertebrates. This model is well suited for higher-throughput screening of mutants, mechanistic dissection of cryptococcal pathogenesis in live animals, and use in the evaluation of therapeutic agents. Cryptococcus neoformans is an important opportunistic pathogen that is estimated to be responsible for more than 600,000 deaths worldwide annually. Existing mammalian models of cryptococcal pathogenesis are costly, and the analysis of important pathogenic processes such as meningitis is laborious and remains a challenge to visualize. Conversely, although
Bahr, Nathan C; Boulware, David R
Infectious meningitis may be due to bacterial, mycobacterial, fungal or viral agents. Diagnosis of meningitis must take into account numerous items of patient history and symptomatology along with regional epidemiology and basic cerebrospinal fluid testing (protein, etc.) to allow the clinician to stratify the likelihood of etiology possibilities and rationally select additional diagnostic tests. Culture is the mainstay for diagnosis in many cases, but technology is evolving to provide more rapid, reliable diagnosis. The cryptococcal antigen lateral flow assay (Immuno-Mycologics) has revolutionized diagnosis of cryptococcosis and automated nucleic acid amplification assays hold promise for improving diagnosis of bacterial and mycobacterial meningitis. This review will focus on a holistic approach to diagnosis of meningitis as well as recent technological advances. PMID:25402579
Kinjo, K; Satake, S; Ohama, T
A 64-year-old male on regular hemodialysis who was a human T lymphotrophic virus Type I (HTLV-I) carrier developed cryptococcal pleuritis. The initial manifestations of the present case were a persistent cough and the accumulation of unilateral pleural effusion. A culture of the pleural fluid of the patient grew cryptococcus neoformans and a test for antigens against cryptococcus neoformans in the pleural fluid was also positive, therefore, cryptococcal pleuritis was diagnosed. Pleural cryptococcosis per se is rare and it is extremely rare for a dialysis patient to develop pleural cryptococcosis. To our knowledge, only a few cases of cryptococcal pleuritis have so far been reported in patients on dialysis. Furthermore, an isolated occurrence of cryptococcal pleuritis with no cryptococcal pulmonary parenchymal lesions, as was seen in the present case, is rare because cryptococcal pleuritis is usually associated with underlying cryptococcal pulmonary parenchymal lesions. Patients on chronic dialysis are susceptible to developing pleural effusion from many etiologies such as congestive heart failure, infection (tuberculosis, bacterial, viral, parasitic, fungal), collagen vascular disease, drug reaction, metastasis, or uremia itself. Cryptococcal pleuritis developing in a dialysis patient is extremely rare, but physicians should consider cryptococcal infection as a possible cause when pleural effusion develops in a dialysis patient and no other cause is identified, as occurred in the present case.
Boulware, David R; von Hohenberg, Maximilian; Rolfes, Melissa A; Bahr, Nathan C; Rhein, Joshua; Akampurira, Andrew; Williams, Darlisha A; Taseera, Kabanda; Schutz, Charlotte; McDonald, Tami; Muzoora, Conrad; Meintjes, Graeme; Meya, David B; Nielsen, Kirsten; Huppler Hullsiek, Katherine
Background. Cerebrospinal fluid (CSF) cryptococcal glucuronoxylomannan antigen (CrAg) titers generally correlate with quantitative fungal culture burden; however, correlation is not precise. Some patients have higher CrAg titers with lower fungal burdens and vice versa. We hypothesized that the relative discordancy between CrAg titer and quantitative culture burden reflects the relative degree of CrAg shedding by Cryptococcus neoformans and is associated with human immune responses. Methods. One hundred ninety human immunodeficiency virus-infected individuals with cryptococcal meningitis were enrolled in Uganda and South Africa. We compared initial CSF CrAg titers relative to their CSF quantitative cultures to determine low (n = 58), intermediate (n = 68), or high (n = 64) CrAg shedders. We compared cytokines measured by Luminex multiplex assay on cryopreserved CSF and 10-week mortality across shedding groups using linear and logistic regression and distribution of genotypes by multilocus sequence typing. Results. The relative degree of CrAg shedding was positively associated with increasing CSF levels of the following: interleukin (IL)-6, IL-7, IL-8, and tumor necrosis factor-α (each P < 0.01), which are all secreted by antigen-presenting cells and negatively associated with vascular endothelial growth factor (P = .01). In addition, IL-5, IL-13, granulocyte colony-stimulating factor, and macrophage chemotactic protein were decreased in low-CrAg shedders compared with intermediate shedders (each P ≤ .01). Type 1 T-helper cells (Th1) cytokine responses and 10-week mortality did not differ between the shedding groups. Cryptococcal genotypes were equally distributed across shedding groups. Conclusions. Discordancy between CrAg shedding and expected shedding based on quantitative fungal burden is associated with detectable immunologic differences in CSF, primarily among secreted cytokines and chemokines produced by antigen-presenting cells and Th2.
Morris, B; Chan, Y F; Reddy, J; Woodgyer, A
A 50-year-old diabetic woman with end-stage renal disease, who had been on continuous ambulatory peritoneal dialysis for 8 months, developed peritonitis caused by Cryptococcus neoformans var. neoformans. The patient was completely asymptomatic and infection was confirmed by detection of budding yeast cells in Gram-stained smears of turbid peritoneal fluid. The infection was cleared after intravenous fluconazole with delayed removal of the catheter. Fluconazole may be a suitable alternative drug in treating cryptococcal peritonitis.
Shah, Vinaya B; Patil, Pallavi A; Agrawa, Vipul; Kaswan, Harish K
Cryptococcosis is a well recognized infection in immunocompromised patients. Cryptococcal infection primarily involves the lung and is hematogeneously spread to other organs. Sometimes it might affect the genitourinary tract. The prostate gland is a rare site of primary infection due to cryptococcus neoformans. We report a case of granulomatous inflammation in the prostate as a result of crypyococcus neoformans infection in a 70 year old immunocompetent patient, a non diabetic, which was diagnosed by transrectal ultrasound guided biopsy.
Seo, Ill Young; Jeong, Hee Jong; Yun, Ki Jung; Rim, Joung Sik
Cryptococcal infection primarily involves the lung and is hematogenously spread to other organs. Sometimes it might affect the genitourinary tract, and rare cases have been reported involving the prostate without systemic infection. We report a case of granulomatous prostatitis as a result of Cryptococcus neoformans yeast in an immunocompromised patient with alcoholic liver cirrhosis, which was diagnosed by transrectal ultrasound guided biopsy and treated with antifungal medication.
... May 2014) 14 Adult Vaccine-Preventable Diseases Infographic Meningitis Myths and Facts Myth: Meningococcal disease is easy ... infected person, such as shaking hands. Fact: Meningococcal meningitis is spread through air droplets and direct contact ...
Matsunaga, Akihiro; Hishima, Tsunekazu; Tanaka, Noriko; Yamasaki, Maria; Yoshida, Lui; Mochizuki, Makoto; Tanuma, Junko; Oka, Shinichi; Ishizaka, Yukihito; Shimura, Mari; Hagiwara, Shotaro
HIV-positive patients have a 60-fold to 200-fold increased incidence of non-Hodgkin lymphomas, including Burkitt lymphoma, diffuse large B-cell lymphoma, and primary central nervous system lymphoma. HIV-associated lymphomas frequently have features such as extranodal involvement, decreased responses to standard chemotherapy, and high relapse rates, which indicate a poor prognosis. General pathological features do not clearly differentiate HIV-associated lymphomas from non-HIV lymphomas. To investigate the features of HIV-associated lymphomas, we performed genome-wide DNA methylation profiling of HIV and non-HIV lymphomas using Illumina GoldenGate Methylation Cancer Panel I and Illumina Infinium HumanMethylation450 BeadChip microarrays. DNA methylation profiles in HIV-associated and non-HIV lymphomas were characterized using unsupervised hierarchical clustering analyses. The analyses of promoter regions revealed unique DNA methylation profiles in HIV-associated lymphomas, suggesting profile differences compared with non-HIV lymphomas, which implies specific gene regulation in HIV-associated lymphoma involving DNA methylation. Based on HumanMethylation450 BeadChip data, 2541 target sites were selected as differing significantly in comparisons between HIV-associated and non-HIV-associated lymphomas using Wilcoxon's rank-sum test (P <0.05) and Δβ values more than 0.30. Recurrent cases of HIV-associated lymphoma had different profiles compared with nonrecurrent HIV lymphomas. DNA methylation profiling indicated that 2541 target sites differed significantly in HIV-associated lymphoma, which may partly explain the poor prognosis. Our data indicate that the methylation profiles of target genes have potential in elucidating HIV-associated lymphomagenesis and can serve as new prognostic markers.
Elbirt, Daniel; Mahlab-Guri, Keren; Bezalel-Rosenberg, Shira; Gill, Harpreet; Attali, Malka; Asher, Ilan
Neurocognitive impairment still occurs in the era of HAART, though its onset appears to be delayed and its severity reduced, while HIV-infected individuals live longer with the infection. HAND defines three categories of disorders according to standardized measures of dysfunction: asymptomatic neurocognitive impairment (ANI), mild neurocognitive disorder (MND), and HIV-associated dementia (HAD). The pathogenic mechanisms underlying HAND involve host and virus characterizations and interactions and seem to depend heavily on the overall condition of the immune system. Since there are insufficient data at this point to determine the best therapeutic approach, and since HAART apparently is not sufficient to prevent or reverse HAND, therapy with a combination of drugs with high CPE should be considered while adjunctive and alternative therapies are being explored.
Reddy, Deepa; Mitsuyasu, Ronald
HIV-associated multicentric Castleman disease (HIV MCD) is a rare lymphoproliferative disorder, the incidence of which appears to be increasing in the highly active antiretroviral therapy era. Current knowledge of the disease is limited and this review will discuss what is known about the pathophysiology, diagnosis, management, and prognosis of HIV MCD. HIV MCD has been shown to be associated with infection with human herpesvirus-8. Vascular endothelial growth factor and the cytokine interleukin-6 (IL-6) are also thought to play a role in the pathogenesis of MCD. Currently, rituximab is often used alone or in combination with chemotherapy for treatment of MCD. Novel monoclonal antibodies targeting IL-6 and the IL-6 receptor are also being studied for the management of this disease. Because HIV MCD is an uncommon diagnosis, comprehensive clinical studies have not been done, and understanding of the disease is incomplete. Further studies are needed to make definitive conclusions regarding optimal treatment of HIV MCD.
Noguera-Julian, Marc; Guillén, Yolanda; Peterson, Jessica; Reznik, David; Harris, Erica V.; Joseph, Sandeep J.; Rivera, Javier; Kannanganat, Sunil; Amara, Rama; Nguyen, Minh Ly; Mutembo, Simon; Paredes, Roger; Read, Timothy D.; Marconi, Vincent C.
Abstract HIV-associated periodontal diseases (PD) could serve as a source of chronic inflammation. Here, we sought to characterize the oral microbial signatures of HIV+ and HIV– individuals at different levels of PD severity. This cross-sectional study included both HIV+ and HIV– patients with varying degrees of PD. Two tooth, 2 cheek, and 1 saliva samples were obtained for microbiome analysis. Mothur/SILVADB were used to classify sequences. R/Bioconductor (Vegan, PhyloSeq, and DESeq2) was employed to assess overall microbiome structure differences and differential abundance of bacterial genera between groups. Polychromatic flow cytometry was used to assess immune activation in CD4 and CD8 cell populations. Around 250 cheek, tooth, and saliva samples from 50 participants (40 HIV+ and 10 HIV–) were included. Severity of PD was classified clinically as None/Mild (N), Moderate (M), and Severe (S) with 18 (36%), 16 (32%), and 16 (32%) participants in each category, respectively. Globally, ordination analysis demonstrated clustering by anatomic site (R2 = 0.25, P < 0.001). HIV status and PD severity showed a statistically significant impact on microbiome composition but only accounted for a combined 2% of variation. HIV+ samples were enriched in genera Abiotrophia, Neisseria, Kingella, and unclassified Neisseriaceae and depleted in Leptotrichia and Selenomonas. The Neisseria genus was consistently enriched in HIV+ participants regardless of sampling site and PD level. Immune markers were altered in HIV+ participants but did not show association with the oral microbiome. HIV-associated changes in oral microbiome result in subtle microbial signatures along different stages of PD that are common in independent oral anatomic sites. PMID:28328799
Noguera-Julian, Marc; Guillén, Yolanda; Peterson, Jessica; Reznik, David; Harris, Erica V; Joseph, Sandeep J; Rivera, Javier; Kannanganat, Sunil; Amara, Rama; Nguyen, Minh Ly; Mutembo, Simon; Paredes, Roger; Read, Timothy D; Marconi, Vincent C
HIV-associated periodontal diseases (PD) could serve as a source of chronic inflammation. Here, we sought to characterize the oral microbial signatures of HIV+ and HIV- individuals at different levels of PD severity.This cross-sectional study included both HIV+ and HIV- patients with varying degrees of PD. Two tooth, 2 cheek, and 1 saliva samples were obtained for microbiome analysis. Mothur/SILVADB were used to classify sequences. R/Bioconductor (Vegan, PhyloSeq, and DESeq2) was employed to assess overall microbiome structure differences and differential abundance of bacterial genera between groups. Polychromatic flow cytometry was used to assess immune activation in CD4 and CD8 cell populations.Around 250 cheek, tooth, and saliva samples from 50 participants (40 HIV+ and 10 HIV-) were included. Severity of PD was classified clinically as None/Mild (N), Moderate (M), and Severe (S) with 18 (36%), 16 (32%), and 16 (32%) participants in each category, respectively. Globally, ordination analysis demonstrated clustering by anatomic site (R2 = 0.25, P < 0.001). HIV status and PD severity showed a statistically significant impact on microbiome composition but only accounted for a combined 2% of variation. HIV+ samples were enriched in genera Abiotrophia, Neisseria, Kingella, and unclassified Neisseriaceae and depleted in Leptotrichia and Selenomonas. The Neisseria genus was consistently enriched in HIV+ participants regardless of sampling site and PD level. Immune markers were altered in HIV+ participants but did not show association with the oral microbiome.HIV-associated changes in oral microbiome result in subtle microbial signatures along different stages of PD that are common in independent oral anatomic sites.
Salavert, M; Carrasco, R; Roig, P; Nieto, A; Cervelló, A; Navarro, V
We report a case of Candida albicans meningitis in a male with human immunodeficiency virus (HIV) infection. This finding has seldom been reported, both in this group of patients and in those with other causes of immunosuppression or other underlying diseases. We discuss the clinical presentation and the features of cerebrospinal fluid, which showed only a mild inflammatory reaction as found in other fungal meningitis (basically cryptococcal) in AIDS patients. Finally, we emphasize the ineffectiveness of amphotericin therapy to achieve a complete microbiological cure and to prevent the relapse of meningitis in this patient. We also stress the need to make an early diagnosis in cases of fungal meningitis in patients with VIH infection, so that appropriate therapy is begun as soon as possible.
Zunt, Joseph R; Baldwin, Kelly J
This article describes the background, clinical presentation, diagnosis, and treatment of selected etiologies of subacute and chronic meningitis. Key diagnostic considerations when evaluating a patient presenting with chronic inflammation of the CNS are discussed, and several specific infectious, neoplastic, and autoimmune etiologies are reviewed in detail. With recent advancement in serologic and CSF diagnostic testing, specific infectious, neoplastic, or autoimmune etiologies of chronic meningitis can be identified. Eliminating previous diagnostic uncertainty of chronic inflammation in the CNS has led to rapid and specific treatment regimens that ultimately improve patient outcomes. Recent advances in imaging have also aided clinicians in both their diagnostic approach and the detection of inflammatory complications such as hydrocephalus, hemorrhage, and ischemic stroke. Meningitis is defined as inflammation involving the meninges of the brain and spinal cord. Meningitis can be categorized as acute, subacute, or chronic based on duration of inflammation. This article focuses on the most common causes of subacute and chronic meningitis. Chronic meningitis is commonly defined as inflammation evolving during weeks to months without resolution of CSF abnormalities. Determining the time course of meningitis is important for creating a differential diagnosis. Most organisms causing acute meningitis rarely persist more than a few weeks. Although numerous etiologies of subacute and chronic meningitis have been identified, this article focuses on the most common etiologies: (1) infectious, (2) autoimmune, and (3) neoplastic.
Swanson, Barbara; Keithley, Joyce K.; Johnson, Angela; Fogg, Louis; Adeyemi, Oluwatoyin; Sha, Beverly E.; Snell, Kimberly A.
Background. HIV infection is associated with systemic inflammation that can increase risk for cardiovascular events. Acupuncture has been shown to have immunomodulatory effects and to improve symptoms in persons with inflammatory conditions. Objective. To test the anti-inflammatory effects of an acupuncture protocol that targets the cholinergic anti-inflammatory pathway (CAIP), a neural mechanism whose activation has been shown to reduce the release of proinflammatory cytokines, in persons with HIV-associated inflammation. Design, Setting, Participants, and Interventions. Double-blind, placebo-controlled clinical trial conducted in an outpatient clinic located in a medically underserved urban neighborhood. Twenty-five clinically-stable HIV-infected persons on antiretroviral therapy were randomized to receive once weekly CAIP-based acupuncture or sham acupuncture. Main Outcome Measures. Outcomes included plasma concentrations of high sensitivity C-reactive protein and D-dimer and fasting lipids. Results. Twenty-five participants completed the protocol (treatment group n = 12, control group n = 13). No adverse events related to the acupuncture protocol were observed. Compared to baseline values, the two groups did not significantly differ in any outcome measures at the end of the acupuncture protocol. Conclusions. CAIP-based acupuncture did not favorably modulate inflammatory or lipid parameters. Additional studies are warranted of CAIP-based protocols of different frequencies/durations. PMID:25922615
Kronauer, C M; Schär, G; Barben, M; Bühler, H
We report on an HIV positive patient with a disseminated Penicillium marneffei infection. A 35-year-old Swiss homosexual male with HIV-associated immunodeficiency with a CD4 cell count of 90/mm3 presented with a two-month history of malaise, intermittent fever, loss of weight, unproductive cough and widespread molluscum contagiosum-like skin lesions, mainly on the face. The patient had travelled extensively and had last visited Thailand 19 months before admission. The chest X-ray showed bilateral diffuse reticulonodular markings. The diagnosis was suspected in bronchoalveolar lavage, which showed round-to-oval intracellular yeast cells but also elongated sausage-shaped extracellular forms. The diagnosis was confirmed on culture. Penicillium marneffei was further isolated from the following specimens: blood cultures, bone marrow, stool, skin and tracheal mucosa biopsy. Intravenous amphotericin B therapy led to a complete subsidence of all symptoms and the skin lesions healed without leaving a scar. The infection, with its clinical presentation, epidemiology, diagnostic problems and therapy is reviewed. We stress that since Penicillium marneffei is an increasingly important pathogen in HIV positive patients in Southeast Asia, this fungus can also be imported to Europe by travellers. If immunocompromised patients have molluscum contagiosum-like skin lesions, pneumonitis and a history of travelling in Southeast Asia, disseminated Penicillium marneffei infection should be considered in differential diagnosis.
Reddy, Deepa; Mitsuyasu, Ronald
Purpose of review HIV-associated multicentric Castleman disease (HIV MCD) is a rare lymphoproliferative disorder, the incidence of which appears to be increasing in the highly active antiretroviral therapy (HAART) era. Current knowledge of the disease is limited and this review will discuss what is known about the pathophysiology, diagnosis, management, and prognosis of HIV MCD. Recent findings HIV MCD has been shown to be associated with infection with human herpervirus-8 (HHV8). Vascular endothelial growth factor and the cytokine interleukin-6 (IL-6) are also thought to play a role in the pathogenesis of MCD. Currently, rituximab is often used alone or in combination with chemotherapy for treatment of MCD. Novel monoclonal antibodies targeting IL-6 and the IL-6 receptor are also being studied for the management of this disease. Summary Because HIV MCD is an uncommon diagnosis, comprehensive clinical studies have not been done, and understanding of the disease is incomplete. Further studies are needed to make definitive conclusions regarding optimal treatment of HIV MCD. PMID:21760504
Wearne, Nicola; Okpechi, Ikechi G
The cause of the human immunodeficiency virus (HIV) epidemic in South Africa (SA) was worsened by the denial by key political players that HIV causes acquired immunodeficiency syndrome (AIDS). South Africa continues to have the highest rate of HIV world-wide, which has had a huge impact on the development of both chronic kidney disease and acute kidney injury. Fortunately, there is now an effective antiretroviral therapy (ART) roll-out program. SA is also dealing with a collision of epidemics of HIV, tuberculosis, and non-communicable disease, particularly hypertension and diabetes. This has been evidenced by recent data seen in the reinstated SA renal registry. There is also an unacceptably high rate of tuberculosis in regions of SA, this has led to high rates of granulomatous interstitial nephritis (GIN) and case reports of TB-GIN immune reconstitution inflammatory syndrome (IRIS). HIV-associated nephropathy (HIVAN) remains common in SA and responds well to ART. The definitive diagnosis requires a renal biopsy, which is often not possible in many regions of sub-Saharan Africa. Unfortunately, there is still a high rate of HIVAN in SA due to late presentation and lack of effective screening for renal disease in HIV-positive patients. Transplantation for HIV-positive donors to positive recipients offers a unique and encouraging way forward for these patients.
Swanson, Barbara; Keithley, Joyce K; Johnson, Angela; Fogg, Louis; Adeyemi, Oluwatoyin; Sha, Beverly E; Snell, Kimberly A
Background. HIV infection is associated with systemic inflammation that can increase risk for cardiovascular events. Acupuncture has been shown to have immunomodulatory effects and to improve symptoms in persons with inflammatory conditions. Objective. To test the anti-inflammatory effects of an acupuncture protocol that targets the cholinergic anti-inflammatory pathway (CAIP), a neural mechanism whose activation has been shown to reduce the release of proinflammatory cytokines, in persons with HIV-associated inflammation. Design, Setting, Participants, and Interventions. Double-blind, placebo-controlled clinical trial conducted in an outpatient clinic located in a medically underserved urban neighborhood. Twenty-five clinically-stable HIV-infected persons on antiretroviral therapy were randomized to receive once weekly CAIP-based acupuncture or sham acupuncture. Main Outcome Measures. Outcomes included plasma concentrations of high sensitivity C-reactive protein and D-dimer and fasting lipids. Results. Twenty-five participants completed the protocol (treatment group n = 12, control group n = 13). No adverse events related to the acupuncture protocol were observed. Compared to baseline values, the two groups did not significantly differ in any outcome measures at the end of the acupuncture protocol. Conclusions. CAIP-based acupuncture did not favorably modulate inflammatory or lipid parameters. Additional studies are warranted of CAIP-based protocols of different frequencies/durations.
Zhang, Nannan; Park, Yoon-Dong; Williamson, Peter R.
Rapid advances in molecular biology and genome sequencing have enabled the generation of new technology and resources for cryptococcal research. RNAi-mediated specific gene knock down has become routine and more efficient by utilizing modified shRNA plasmids and convergent promoter RNAi constructs. This system was recently applied in a high-throughput screen to identify genes involved in host-pathogen interactions. Gene deletion efficiencies have also been improved by increasing rates of homologous recombination through a number of approaches, including a combination of double-joint PCR with split-marker transformation, the use of dominant selectable markers and the introduction of Cre-Loxp systems into Cryptococcus. Moreover, visualization of cryptococcal proteins has become more facile using fusions with codon-optimized fluorescent tags, such as green or red fluorescent proteins or, mCherry. Using recent genome-wide analytical tools, new transcriptional factors and regulatory proteins have been identified in novel virulence-related signaling pathways by employing microarray analysis, RNA-sequencing and proteomic analysis. PMID:25460849
Zhang, Nannan; Park, Yoon-Dong; Williamson, Peter R
Rapid advances in molecular biology and genome sequencing have enabled the generation of new technology and resources for cryptococcal research. RNAi-mediated specific gene knock down has become routine and more efficient by utilizing modified shRNA plasmids and convergent promoter RNAi constructs. This system was recently applied in a high-throughput screen to identify genes involved in host-pathogen interactions. Gene deletion efficiencies have also been improved by increasing rates of homologous recombination through a number of approaches, including a combination of double-joint PCR with split-marker transformation, the use of dominant selectable markers and the introduction of Cre-Loxp systems into Cryptococcus. Moreover, visualization of cryptococcal proteins has become more facile using fusions with codon-optimized fluorescent tags, such as green or red fluorescent proteins or, mCherry. Using recent genome-wide analytical tools, new transcriptional factors and regulatory proteins have been identified in novel virulence-related signaling pathways by employing microarray analysis, RNA-sequencing and proteomic analysis.
Mouchrif, Issam; Berdaii, Adnane; Labib, Ismail; Harrandou, Moustapha
Meningitis is a rare but serious complication of epidural and spinal anesthesia. Bacterial meningitis is mainly caused by Gram-positive cocci, implying an exogenous contamination which suggests a lack of asepsis. The evolution is usually favorable after treatment, but at the expense of increased health care costs and, sometimes, of significant neurological sequelae. We report a case of bacterial meningitis after spinal anesthesia for caesarean section.
Garvey, Lucy; Winston, Alan; Walsh, John; Post, Frank; Porter, Kholoud; Gazzard, Brian; Fisher, Martin; Leen, Clifford; Pillay, Deenan; Hill, Teresa; Johnson, Margaret; Gilson, Richard; Anderson, Jane; Easterbrook, Philippa; Bansi, Loveleen; Orkin, Chloe; Ainsworth, Jonathan; Phillips, Andrew N; Sabin, Caroline A
Data describing the incidence and survival of HIV-related central nervous system diseases (CNS-D) in recent years are sparse. Between 1996 and 2007, adult subjects without previous CNS-D within a large UK cohort were included (n=30,954). CNS-D were HIV encephalopathy (HIVe), progressive multifocal leucoencephalopathy (PML), cerebral toxoplasmosis (TOXO) and cryptococcal meningitis (CRYP). Associations between demographic, clinical and laboratory parameters with incidence and survival of CNS-D were evaluated using Poisson regression analysis and Kaplan-Meier techniques. Six hundred and thirteen new CNS-D occurred in 574 subjects (HIVe:187, PML:113, TOXO:184, CRYP:129). Incidence of all CNS-D declined from 13.1 per 1000 PY in 1996/1997 to 1.0 per 1000 PY in 2006/2007 (P=0.0001). Current CD4+ cell count below 200 cells/ul and plasma HIV RNA above 100,000 copies/ml were independently associated with the development of CNS-D. Calendar year 1996/1997, older age, prior AIDS diagnosis and PML diagnosis were significantly associated with shorter survival. An ongoing decline in the incidence of CNS-D has been observed in very recent years. Mortality following such a diagnosis remains high. © 2010 The Author(s). European Journal of Neurology © 2010 EFNS.
Chen, Yuan; Toffaletti, Dena L; Tenor, Jennifer L; Litvintseva, Anastasia P; Fang, Charles; Mitchell, Thomas G; McDonald, Tami R; Nielsen, Kirsten; Boulware, David R; Bicanic, Tihana; Perfect, John R
Cryptococcus neoformans is the leading cause of fungal meningitis worldwide. Previous studies have characterized the cryptococcal transcriptome under various stress conditions, but a comprehensive profile of the C. neoformans transcriptome in the human host has not been attempted. Here, we extracted RNA from yeast cells taken directly from the cerebrospinal fluid (CSF) of two AIDS patients with cryptococcal meningitis prior to antifungal therapy. The patients were infected with strains of C. neoformans var. grubii of molecular type VNI and VNII. Using RNA-seq, we compared the transcriptional profiles of these strains under three environmental conditions (in vivo CSF, ex vivo CSF, and yeast extract-peptone-dextrose [YPD]). Although we identified a number of differentially expressed genes, single nucleotide variants, and novel genes that were unique to each strain, the overall expression patterns of the two strains were similar under the same environmental conditions. Specifically, yeast cells obtained directly from each patient's CSF were more metabolically active than cells that were incubated ex vivo in CSF. Compared with growth in YPD, some genes were identified as significantly upregulated in both in vivo and ex vivo CSF, and they were associated with genes previously recognized for contributing to pathogenicity. For example, genes with known stress response functions, such as RIM101, ENA1, and CFO1, were regulated similarly in the two clinical strains. Conversely, many genes that were differentially regulated between the two strains appeared to be transporters. These findings establish a platform for further studies of how this yeast survives and produces disease. Cryptococcus neoformans, an environmental, opportunistic yeast, is annually responsible for an estimated million cases of meningitis and over 600,000 deaths, mostly among HIV-infected patients in sub-Saharan Africa and Asia. Using RNA-seq, we analyzed the gene expression of two strains of C
Rick, Fernanda; Niyibizi, Aline Aurore; Shroufi, Amir; Onami, Kazumi; Steele, Sarah-Jane; Kuleile, Malehlohonolo; Muleya, Innocent; Chiller, Tom; Walker, Tiffany; Van Cutsem, Gilles
Cryptococcal meningitis is one of the leading causes of death among people with HIV in Africa, primarily due to delayed presentation, poor availability and high cost of treatment. Routine cryptococcal antigen (CrAg) screening of patients with a CD4 count less than 100 cells/mm3, followed by pre-emptive therapy if positive, might reduce mortality in high prevalence settings. Using the cryptococcal antigen (CrAg) lateral flow assay (LFA), screening is possible at the point of care (POC). However, critical shortages of health staff may limit adoption. This study investigates the feasibility of lay counsellors conducting CrAg LFA screening in rural primary care clinics in Lesotho. From May 2014 to June 2015, individuals who tested positive for HIV were tested for CD4 count and those with CD4 <100 cells/mm3 were screened with CrAg LFA. All tests were performed by lay counsellors. CrAg-positive asymptomatic patients received fluconazole, while symptomatic patients were referred to hospital. Lay counsellors were trained and supervised by a laboratory technician and counsellor activity supervisor. Additionally, nurses and doctors were trained on CrAg screening and appropriate treatment. During the study period, 1,388 people were newly diagnosed with HIV, of whom 129 (9%) presented with a CD4 count <100 cells/mm3. Of these, 128 (99%) were screened with CrAg LFA and 14/128 (11%) tested positive. Twelve of the 14 (86%) were asymptomatic, and received outpatient fluconazole. All commenced ART with a median time to initiation of 15.5 days [IQR: 14-22]. Of the asymptomatic patients, nine (75%) remained asymptomatic after a median time of 5 months [IQR; 3-6] of follow up. One (8%) became co-infected with tuberculosis and died and two were transferred out. The two patients with symptomatic cryptococcal meningitis (CM) were referred to hospital, where they later died. CrAg LFA screening by lay counsellors followed by pre-emptive fluconazole treatment for asymptomatic cases, or
Santiago-Tirado, Felipe H; Peng, Tao; Yang, Meng; Hang, Howard C; Doering, Tamara L
Cryptococcus neoformans is an opportunistic yeast that kills over 625,000 people yearly through lethal meningitis. Host phagocytes serve as the first line of defense against this pathogen, but fungal engulfment and subsequent intracellular proliferation also correlate with poor patient outcome. Defining the interactions of this facultative intracellular pathogen with host phagocytes is key to understanding the latter's opposing roles in infection and how they contribute to fungal latency, dissemination, and virulence. We used high-content imaging and a human monocytic cell line to screen 1,201 fungal mutants for strains with altered host interactions and identified multiple genes that influence fungal adherence and phagocytosis. One of these genes was PFA4, which encodes a protein S-acyl transferase (PAT), one of a family of DHHC domain-containing proteins that catalyzes lipid modification of proteins. Deletion of PFA4 caused dramatic defects in cryptococcal morphology, stress tolerance, and virulence. Bioorthogonal palmitoylome-profiling identified Pfa4-specific protein substrates involved in cell wall synthesis, signal transduction, and membrane trafficking responsible for these phenotypic alterations. We demonstrate that a single PAT is responsible for the modification of a subset of proteins that are critical in cryptococcal pathogenesis. Since several of these palmitoylated substrates are conserved in other pathogenic fungi, protein palmitoylation represents a potential avenue for new antifungal therapeutics.
Santiago-Tirado, Felipe H.; Peng, Tao; Yang, Meng; Hang, Howard C.; Doering, Tamara L.
Cryptococcus neoformans is an opportunistic yeast that kills over 625,000 people yearly through lethal meningitis. Host phagocytes serve as the first line of defense against this pathogen, but fungal engulfment and subsequent intracellular proliferation also correlate with poor patient outcome. Defining the interactions of this facultative intracellular pathogen with host phagocytes is key to understanding the latter’s opposing roles in infection and how they contribute to fungal latency, dissemination, and virulence. We used high-content imaging and a human monocytic cell line to screen 1,201 fungal mutants for strains with altered host interactions and identified multiple genes that influence fungal adherence and phagocytosis. One of these genes was PFA4, which encodes a protein S-acyl transferase (PAT), one of a family of DHHC domain-containing proteins that catalyzes lipid modification of proteins. Deletion of PFA4 caused dramatic defects in cryptococcal morphology, stress tolerance, and virulence. Bioorthogonal palmitoylome-profiling identified Pfa4-specific protein substrates involved in cell wall synthesis, signal transduction, and membrane trafficking responsible for these phenotypic alterations. We demonstrate that a single PAT is responsible for the modification of a subset of proteins that are critical in cryptococcal pathogenesis. Since several of these palmitoylated substrates are conserved in other pathogenic fungi, protein palmitoylation represents a potential avenue for new antifungal therapeutics. PMID:25970403
Simms, Kelley M; Kortepeter, Cindy; Avigan, Mark
The purpose of this case series is to characterize a recently identified association of the antiepileptic drug (AED) lamotrigine with aseptic meningitis based on cases reported to the Food and Drug Administration (FDA)'s Adverse Event Reporting System (AERS) database. We performed a data mining analysis of 9 AEDs from the FDA's AERS database. We applied the multi-item gamma Poisson shrinker (MGPS) algorithm to the entire AERS database through November 2, 2009, to generate empirical Bayes geometric mean (EBGM) values with corresponding confidence intervals for 9 AEDs and the adverse event code "meningitis aseptic." The AERS database was also searched for postmarketing reports of aseptic meningitis associated with lamotrigine and a detailed review of each case was performed. Forty AERS cases were identified in this review. Findings from the AERS reports revealed CSF profiles with features of both bacterial as well as viral meningitis. Fifteen cases documented a positive rechallenge; the median time to onset of symptoms upon rechallenge was only 60 minutes. Data mining analysis of several anticonvulsants resulted in disproportionate reporting solely for lamotrigine. There appears to be an association between lamotrigine use and aseptic meningitis. It is notable that nearly 40% of cases in this case series reported a positive rechallenge. Lamotrigine-associated aseptic meningitis should be considered in the differential diagnosis of culture-negative meningitis. This case series highlights the need for continued pharmacovigilance and the importance of systematic monitoring of patients treated with antiepileptic medications.
Greene, Greg; Sriruttan, Charlotte; Le, Thuy; Chiller, Tom; Govender, Nelesh P
As HIV treatment programmes scale up to meet the UNAIDS 90-90-90 goals, care must be taken to start antiretroviral treatment safely in patients with advanced disease (CD4 counts <200 cells/μl) who are simultaneously at risk for opportunistic infections and immune reconstitution inflammatory syndrome. Invasive fungal diseases pose a great threat at this critical time point, though the development of inexpensive and highly accurate rapid diagnostic tests has changed the approach HIV programmes are taking to reduce the high mortality associated with these opportunistic infections. This article summarizes recent advances and findings in fungal opportunistic infection diagnostics with a focus on screening to prevent cryptococcal meningitis. Cryptococcal antigen (CrAg) screening using a lateral flow assay platform is cost-effective and feasible to implement as either a laboratory reflex or point-of-care test. Recent CrAg screening pilots have elucidated the varying prevalence of cryptococcal antigenemia across geographic regions, which may aid programme planning. Evidence from recently completed clinical trials provides a strong motivation for the use of CrAg titer to refine treatment options for patients with subclinical cryptococcal disease. Although several operational barriers to programme effectiveness still need to be addressed, the utility of CrAg screening using inexpensive and accurate antigen assays has been demonstrated in real-world HIV programmes, paving the way for development and testing of other fungal opportunistic infection screening strategies and for an integrated advanced HIV disease testing package to reduce AIDS mortality and ensure safe antiretroviral treatment initiation.
Nonnemacher, Michael R.; Wigdahl, Brian
HIV-associated neurologic disease continues to be a significant complication in the era of highly active antiretroviral therapy. A substantial subset of the HIV-infected population shows impaired neuropsychological performance as a result of HIV-mediated neuroinflammation and eventual central nervous system (CNS) injury. CNS compartmentalization of HIV, coupled with the evolution of genetically isolated populations in the CNS, is responsible for poor prognosis in patients with AIDS, warranting further investigation and possible additions to the current therapeutic strategy. This chapter reviews key advances in the field of neuropathogenesis and studies that have highlighted how molecular diversity within the HIV genome may impact HIV-associated neurologic disease. We also discuss the possible functional implications of genetic variation within the viral promoter and possibly other regions of the viral genome, especially in the cells of monocyte–macrophage lineage, which are arguably key cellular players in HIV-associated CNS disease. PMID:23809924
Oh, Keun; Kim, Jang-Hee; Choi, Jin-Wook; Kang, Jae-Kyu
Pituitary apoplexy is a rare but life-threatening disorder. Clinical presentation of this condition includes severe headaches, impaired consciousness, fever, visual disturbance, and variable ocular paresis. The clinical presentation of meningeal irritation is very rare. Nonetheless, if present and associated with fever, pituitary apoplexy may be misdiagnosed as a meningitis. We experienced a case of pituitary apoplexy masquerading as a meningitis. A 42-year-old man presented with meningitis associated symptoms and initial imaging studies did not show evidence of intra-lesional hemorrhage in the pituitary mass. However, a follow-up imaging after neurological deterioration revealed pituitary apoplexy. Hereby, we report our case with a review of literatures. PMID:24904903
Altrocchi, Paul H.; Eckman, Paul B.
The clinical syndrome of meningeal carcinomatosis includes headache, dementia, radiculopathy, and cranial nerve palsies. Blindness may be the first, or most prominent, symptom. When blindness occurs in adult life, meningeal carcinomatosis should be included in the differential diagnosis, even in the absence of other symptoms and in the absence of known malignancy. Although all pathophysiological mechanisms of the blindness in meningeal carcinomatosis have not yet been elucidated, optic nerve involvement by meningeal tumour-cuffing, by chronic papilloedema, and by direct tumour infiltration represent the likeliest causes. In the neuropathological analysis of such cases, the importance of analysing the intra-orbital portion of the optic nerves, in addition to the portions of the optic nerve and chiasm usually examined at routine necropsy, is emphasized. A case is described to illustrate this point, with the only pathological abnormality in the optic nerves being found within 6 mm of the retina. Images PMID:4708455
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(1) Meningitis: two groups of cases. (2) A method of washing out the subarachnoid space in cases of septic meningitis secondary to infection of the ear. (3) Discussion on the value of maintaining a positive pressure of the cerebrospinal fluid when operating on a septic region communicating with the subarachnoid space. (4) Leaking cerebrospinal fluid from the region of the ear: operative treatment. PMID:19986899
Downs, Jennifer A.
Background. Limited information exists on the etiologies, clinical characteristics, and outcomes of meningitis among HIV-infected patients in Africa. We conducted a study to determine the etiology, clinical characteristics, and outcomes of meningitis among HIV-infected adults. Methods. A prospective cross-sectional hospital based study was conducted among HIV-infected patients aged ≥18 years admitted to the medical wards with symptoms and signs of meningitis. Sociodemographic and clinical information were collected using a standardized data collection tool. Lumbar puncture was performed to all patients; cerebrospinal fluid samples were sent for analysis. Results. Among 60 HIV-infected adults clinically diagnosed to have meningitis, 55 had CSF profiles consistent with meningitis. Of these, 14 (25.5%) had a laboratory-confirmed etiology while 41 (74.5%) had no isolate identified. Cryptococcus neoformans was the commonest cause of meningitis occurring in 11 (18.3%) of patients followed by Mycobacterium tuberculosis (6.7%). The in-hospital mortality was 20/55 (36.4%). Independent predictors of mortality were low baseline CD4 count and turbid CSF appearance. Conclusion. Cryptococcal meningitis is the most prevalent laboratory-confirmed etiological agent among adult HIV-infected patients with suspected meningitis admitted to medical wards in Western Tanzania. Mortality rate in this population remains unacceptably high. Improving diagnostic capacity and early treatment may help to decrease the mortality rate. PMID:27651801
Nalintya, Elizabeth; Kiggundu, Reuben; Meya, David
Over the last decade, an upsurge in both the frequency and severity of fungal infections due to the HIV/AIDS epidemic and the use of immunosuppressive therapy has occurred. Even diagnostic methods like culture and microscopy, which have low sensitivity and longer turn-around-times are not widely available, leading to delays in timely antifungal therapy and detrimental patient outcomes. The evolution of cryptococcal antigen (CrAg) testing to develop inexpensive and more sensitive methods to detect cryptococcal antigen is significant. These newer tests employ immunoassays as part of point-of-care platforms, which do not require complex laboratory infrastructure and they have the potential to detect early disease and reduce time to diagnosis of cryptococcal infection. Advocacy for widely available and efficacious life-saving antifungal treatment should be the only remaining challenge.
Leto, D.; Chagla, Z.
Disseminated cryptococcal infection carries a high risk of morbidity and mortality. Typical patients include HIV individuals with advanced immunosuppression or solid organ or hematopoietic transplant recipients. We report a case of disseminated cryptococcal disease in a 72-year-old male who was immunocompromised with chronic lymphocytic leukemia and ongoing chemotherapy. The patient presented with a subacute history of constitutional symptoms and headache after he received five cycles of FCR chemotherapy (fludarabine/cyclophosphamide/rituximab). Diagnosis of disseminated cryptococcal disease was made based on fungemia in peripheral blood cultures with subsequent involvement of the brain, lungs, and eyes. Treatment was started with liposomal amphotericin, flucytosine, and fluconazole as induction. He was discharged after 4 weeks of hospitalization on high dose fluconazole for consolidation for 2 months, followed by maintenance therapy. PMID:27957359
Haddow, Lewis J; Colebunders, Robert; Meintjes, Graeme; Lawn, Stephen D; Elliott, Julian H; Manabe, Yukari C; Bohjanen, Paul R; Sungkanuparph, Somnuek; Easterbrook, Philippa J; French, Martyn A; Boulware, David R
Cryptococcal immune reconstitution inflammatory syndrome (IRIS) may present as a clinical worsening or new presentation of cryptococcal disease after initiation of antiretroviral therapy (ART), and is thought to be caused by recovery of cryptococcus-specific immune responses. We have reviewed reports of cryptococcal IRIS and have developed a consensus case definition specifically for paradoxical crytopcoccal IRIS in patients with HIV-1 and known cryptococcal disease before ART, and a separate definition for incident cryptococcosis developed during ART (termed ART-associated cryptococcosis), for which a proportion of cases are likely to be unmasking cryptococcal IRIS. These structured case definitions are intended to aid design of future clinical, epidemiological, and immunopathological studies of cryptococcal IRIS, to standardise diagnostic criteria, and to facilitate comparisons between studies. As for definitions of tuberculosis-associated IRIS, definitions for cryptococcal IRIS should be regarded as preliminary until further insights into the immunopathology of IRIS permit their refinement.
Zhai, Bing; Wu, Cheng; Wang, Linqi; Sachs, Matthew S; Lin, Xiaorong
Therapeutic treatment for systemic mycoses is severely hampered by the extremely limited number of antifungals. The difficulty of treatment of fungal infections in the central nervous system is further compounded by the poor central nervous system (CNS) penetration of most antifungals due to the blood-brain barrier. Only a few fungistatic azole drugs, such as fluconazole, show reasonable CNS penetration. Here we demonstrate that sertraline (Zoloft), the most frequently prescribed antidepressant, displays potent antifungal activity against Cryptococcus neoformans, the major causative agent of fungal meningitis. In in vitro assays, this neurotropic drug is fungicidal to all natural Cryptococcus isolates tested at clinically relevant concentrations. Furthermore, sertraline interacts synergistically or additively with fluconazole against Cryptococcus. Importantly, consistent with our in vitro observations, sertraline used alone reduces the brain fungal burden at an efficacy comparable to that of fluconazole in a murine model of systemic cryptococcosis. It works synergistically with fluconazole in reducing the fungal burden in brain, kidney, and spleen. In contrast to its potency against Cryptococcus, sertraline is less effective against strains of Candida species and its interactions with fluconazole against Candida strains are often antagonistic. Therefore, our data suggest the unique application of sertraline against cryptococcosis. To understand the antifungal mechanisms of sertraline, we screened a whole-genome deletion collection of Saccharomyces cerevisiae for altered sertraline susceptibility. Gene ontology analyses of selected mutations suggest that sertraline perturbs translation. In vitro translation assays using fungal cell extracts show that sertraline inhibits protein synthesis. Taken together, our findings indicate the potential of adopting this antidepressant in treating cryptococcal meningitis.
Zhai, Bing; Wu, Cheng; Wang, Linqi
Therapeutic treatment for systemic mycoses is severely hampered by the extremely limited number of antifungals. The difficulty of treatment of fungal infections in the central nervous system is further compounded by the poor central nervous system (CNS) penetration of most antifungals due to the blood-brain barrier. Only a few fungistatic azole drugs, such as fluconazole, show reasonable CNS penetration. Here we demonstrate that sertraline (Zoloft), the most frequently prescribed antidepressant, displays potent antifungal activity against Cryptococcus neoformans, the major causative agent of fungal meningitis. In in vitro assays, this neurotropic drug is fungicidal to all natural Cryptococcus isolates tested at clinically relevant concentrations. Furthermore, sertraline interacts synergistically or additively with fluconazole against Cryptococcus. Importantly, consistent with our in vitro observations, sertraline used alone reduces the brain fungal burden at an efficacy comparable to that of fluconazole in a murine model of systemic cryptococcosis. It works synergistically with fluconazole in reducing the fungal burden in brain, kidney, and spleen. In contrast to its potency against Cryptococcus, sertraline is less effective against strains of Candida species and its interactions with fluconazole against Candida strains are often antagonistic. Therefore, our data suggest the unique application of sertraline against cryptococcosis. To understand the antifungal mechanisms of sertraline, we screened a whole-genome deletion collection of Saccharomyces cerevisiae for altered sertraline susceptibility. Gene ontology analyses of selected mutations suggest that sertraline perturbs translation. In vitro translation assays using fungal cell extracts show that sertraline inhibits protein synthesis. Taken together, our findings indicate the potential of adopting this antidepressant in treating cryptococcal meningitis. PMID:22508310
Ganiem, A Rizal; Parwati, Ida; Wisaksana, Rudi; van der Zanden, Adri; van de Beek, Diederik; Sturm, Patrick; van der Ven, Andre; Alisjahbana, Bachti; Brouwer, Anne-Marie; Kurniani, Nani; de Gans, Jan; van Crevel, Reinout
Indonesia has a concentrated but rapidly growing HIV epidemic. We examined the effect of HIV on causative organisms, clinical features and prognosis of adult meningitis. A prospective cohort study. All adult patients at a referral hospital who underwent cerebrospinal fluid examination for suspected meningitis were examined for HIV and included in a prospective cohort study. Microbiological testing was done for common bacterial pathogens, mycobacteria and fungi. Patients were followed for at least 6 months, and logistic regression models were used to identify risk factors for mortality. Among 185 patients who mostly presented with subacute meningitis, 60% were male and the median age was 30 years. HIV infection was present in 25% of the patients; almost two-thirds were newly confirmed, and all presented with severe immunosuppression (median CD4 cell count 13/microl, range 2-98). One-third of HIV-infected patients had cryptococcal meningitis whereas two-thirds suffered from tuberculosis. After 1 month, 41% of patients had died. HIV infection was strongly associated with 1-month mortality (adjusted odds ratio 12.15; 95% confidence interval 3.04-15.72) and death during extended follow-up (hazard ratio 2.48; 95% confidence interval 1.97-5.74). Although HIV is still uncommon in the general population in Indonesia, its prevalence among adult meningitis cases already seems high. Mycobacterium tuberculosis and Cryptococcus neoformans are the main causes of meningitis in this setting, and mortality is very high, especially in HIV-infected patients. Our data suggest that adult meningitis cases in Indonesia should be screened routinely for HIV infection. Further studies are needed to address the high mortality.
Bamba, Sanata; Lortholary, Olivier; Sawadogo, Adrien; Millogo, Athanase; Guiguemdé, Robert T; Bretagne, Stéphane
Cryptococcosis remains a major opportunistic infection in AIDS in sub-Saharan Africa, but few data exist from its western part. We report data from Bobo Dioulasso University Hospital, Bobo-Dioulasso, Burkina Faso, with a steady decline from 14 to two cases per year from 2002 to 2010 which contrasts with the increase (from 147 to 3940) of patients on antiretroviral therapy (ART). Better ART availability decreases the incidence of cryptococcosis in Burkina Faso.
Palta, Manisha; Riedel, Richard F.; Vredenburgh, James J.; Cummings, Thomas J.; Green, Scott; Chang, Zheng; Kirkpatrick, John P.
Primary meningeal rhabdomyosarcoma is a rare primary brain malignancy, with scant case reports. While most reports of primary intracranial rhabdomyosarcoma occur in pediatric patients, a handful of cases in adult patients have been reported in the medical literature. We report the case of a 44-year-old male who developed primary meningeal rhabdomyosarcoma. After developing episodes of right lower extremity weakness, word finding difficulty, and headaches, a brain magnetic resonance imaging (MRI) demonstrated a vertex lesion with radiographic appearance of a meningeal-derived tumor. Subtotal surgical resection was performed due to sagittal sinus invasion and initial pathology was interpreted as an anaplastic meningioma. Re-review of pathology demonstrated rhabdomyosarcoma negative for alveolar translocation t(2;13). Staging studies revealed no evidence of disseminated disease. He was treated with stereotactic radiotherapy with concurrent temozolamide to be followed by vincristine, actinomycin-D, and cyclophosphamide (VAC) systemic therapy. PMID:21772793
Gates-Hollingsworth, Marcellene A; Kozel, Thomas R
To meet the needs of a global community, an immunoassay for cryptococcal antigen (CrAg) must have high sensitivity for CrAg of all major serotypes. A new immunoassay for CrAg in lateral flow format was evaluated and found to have a high sensitivity for detection of serotypes A, B, C, and D.
Zheng, H; Chen, Q; Xie, Z; Wang, D; Li, M; Zhang, X; Man, Y; Lao, J; Chen, N; Zhou, L
Cryptococcal meningoencephalitis (CM) may present as an acute, subacute, or chronic infection. It manifests as a chronic process in over 75 % of cases, but, sometimes, it presents with a more acute onset, mostly in HIV-associated patients. Until now, there has been no study performed on the clinical features of HIV-negative CM patients with acute/subacute onset. We collected 106 HIV-negative patients diagnosed with CM in our hospital during a 15-year period, analyzed their epidemiological and clinical features, as well as the outcomes, and explored the independent prognosis factors and the factors related to the survival time among them. We found that impaired consciousness (23.4 % vs. 3.4 %, p = 0.017) was more common in CM patients with acute/subacute onset, while decreased cerebrospinal fluid (CSF) glucose (51.9 % vs. 75.9 %, p = 0.026) was less common. The ratio of CSF glucose/blood glucose [odds ratio (OR) 0.04, 95 % confidence interval (CI) 0.004-0.262, p = 0.02], impaired consciousness (OR 5.09, 95 % CI 1.477-17.522, p = 0.01), and hospitalization length (OR 0.98, 95 % CI 0.977-0.999, p = 0.04) were indicated to be not only independent prognosis factors in HIV-negative CM patients with acute/subacute onset, but also factors significantly related to the survival time. The results of our study demonstrated that the contact history and potential history risk factors would not affect the onset process of HIV-negative CM patients, and the mortality, hospitalization length, and survival time has not been related to the onset process. However, the ratio of CSF glucose/blood glucose, consciousness level, and hospitalization length of the HIV-negative CM patients with acute/subacute onset should be of greater focus in the clinical work.
Ostroy, P R
During 1977 the state of Washington maintained a surveillance system for reporting cases of bacterial meningitis. Hemophilus influenzae meningitis was the most common etiologic agent causing bacterial meningitis. A high incidence rate for H. influenzae meningitis was found among American Indians less than five years ago. A focus of ampicillin-resistant H. influenzae meningitis was found in Pierce County among military dependents or persons who had family members or relatives working or attending school with Fort Lewis Army Base personnel. Although relationships between the individual cases were not detected, the surveillance system continues to seek some association.
Ostroy, Paul R.
During 1977 the state of Washington maintained a surveillance system for reporting cases of bacterial meningitis. Hemophilus influenzae meningitis was the most common etiologic agent causing bacterial meningitis. A high incidence rate for H. influenzae meningitis was found among American Indians less than five years ago. A focus of ampicillin-resistant H. influenzae meningitis was found in Pierce County among military dependents or persons who had family members or relatives working or attending school with Fort Lewis Army Base personnel. Although relationships between the individual cases were not detected, the surveillance system continues to seek some association. PMID:506227
Lindl, Kathryn A.; Marks, David R.; Kolson, Dennis L.
Human immunodeficiency virus type 1 (HIV) infection presently affects more that 40 million people worldwide, and is associated with central nervous system (CNS) disruption in at least 30% of infected individuals. The use of highly active antiretroviral therapy has lessened the incidence, but not the prevalence of mild impairment of higher cognitive and cortical functions (HIV-associated neurocognitive disorders) as well as substantially reduced a more severe form dementia (HIV-associated dementia). Furthermore, improving neurological outcomes will require novel, adjunctive therapies that are targeted towards mechanisms of HIV-induced neurodegeneration. Identifying such molecular and pharmacological targets requires an understanding of the events preceding irreversible neuronal damage in the CNS, such as actions of neurotoxins (HIV proteins and cellular factors), disruption of ion channel properties, synaptic damage, and loss of adult neurogenesis. By considering the specific mechanisms and consequences of HIV neuropathogenesis, unified approaches for neuroprotection will likely emerge using a tailored, combined, and non-invasive approach. PMID:20396973
Lin, Wei-Che; Chen, Pei-Chin; Wang, Hung-Chen; Tsai, Nai-Wen; Chou, Kun-Hsien; Chen, Hsiu-Ling; Su, Yu-Jih; Lin, Ching-Po; Li, Shau-Hsuan; Chang, Wen-Neng; Lu, Cheng-Hsien
Tuberculous meningitis (TBM) and cryptococcal meningitis (CM) are two of the most common types of chronic meningitis. This study aimed to assess whether chronic neuro-psychological sequelae are associated with micro-structure white matter (WM) damage in HIV-negative chronic meningitis. Nineteen HIV-negative TBM patients, 13 HIV-negative CM patients, and 32 sex- and age-matched healthy volunteers were evaluated and compared. The clinical relevance of WM integrity was studied using voxel-based diffusion tensor imaging (DTI) magnetic resonance imaging. All of the participants underwent complete medical and neurologic examinations, and neuro-psychological testing. Differences in DTI indices correlated with the presence of neuro-psychological rating scores and cerebrospinal fluid (CSF) analysis during the initial hospitalization. Patients with CM had more severe cognitive deficits than healthy subjects, especially in TBM. There were changes in WM integrity in several limbic regions, including the para-hippocampal gyrus and cingulate gyrus, and in the WM close to the globus pallidus. A decline in WM integrity close to the globus pallidus and anterior cingulate gyrus was associated with worse CSF analysis profiles. Poorer DTI parameters directly correlated with worse cognitive performance on follow-up. These correlations suggest that WM alterations may be involved in the psychopathology and pathophysiology of co-morbidities. Abnormalities in the limbic system and globus pallidus, with their close relationship to the CSF space, may be specific biomarkers for disease evaluation.
Kim, Dong-Min; Chung, Jong-Hoon; Yun, Na-Ra; Kim, Seok Won; Lee, Jun-Young; Han, Mi Ah; Lee, Yong-Bok
Orientia tsutsugamushi induces vasculitis leading to symptoms of systemic organ invasion including meningitis and meningoencephalitis. We conducted a retrospective case-control study of scrub typhus patients to investigate the clinical and laboratory features of patients with scrub typhus meningitis or meningoencephalitis, and the therapeutic outcomes, and to determine the predictor factors. Cases were 22 patients with scrub typhus meningitis or meningoencephalitis, and controls were 303 patients without meningitis or meningoencephalitis. Multivariate analysis showed that the presence of pneumonitis was associated with the occurrence of scrub typhus meningitis and meningoencephalitis (odds ratio [OR] 8.9; P < 0.001; confidence interval [CI] 2.9-27.2). Although appropriate antimicrobials such as doxycycline agents were administered at an early stage, meningitis or meningoencephalitis still occurred in some cases. Physicians should be aware that meningitis or meningoencephalitis may develop during appropriate drug therapy such as doxycycline. Close observation and great care are essential for patients with risk factors, particularly pneumonitis.
Lauer, B A; Fisher, C E
Neisseria lactamica was recovered from the blood and cerebrospinal fluid of a 7-month-old girl with acute purulent meningitis. The isolate was identified initially as N meningitidis. However, additional biochemical testing at the Center for Disease Control showed that the organism fermented lactose and produced beta-D-galactosidase, thereby confirming its identity as N lactamica.
Lannigan, R; MacDonald, M A; Marrie, T J; Haldane, E V
The level of lactic acid in cerebrospinal fluid has been suggested as a useful diagnostic parameter to differentiate between bacterial and viral meningitis, especially in patients partially treated before admission to hospital. A concentration of greater than or equal to 35 mg/dl, determined by either gas-liquid chromatography or an enzymatic method, has been considered in several studies to provide definite evidence of meningitis of bacterial origin, whereas a lower level indicates no bacterial involvement. Over the past 18 months, we have analyzed by the enzymatic method the lactate level in 493 spinal fluids submitted from 434 adult patients with various conditions involving the central nervous system. Fifty fluids had a lactate level of greater than 35 mg/dl, of which 19 were cases of infective meningitis of varying etiology. The 435 specimens with lactate levels within the range considered normal included three cases of infective meningitis, of which two were cryptococcal and one was bacterial. In this adult study, the lactate level in the cerebrospinal fluid did not provide unequivocal evidence of bacterial infection and did not provide assistance to any greater degree than the standard parameters of leukocyte count, protein, and glucose contents in the differential diagnosis of bacterial meningitis from that of any other etiology. PMID:7372796
Leal, Fabio E.; Premeaux, Thomas A.; Abdel-Mohsen, Mohamed; Ndhlovu, Lishomwa C.
Now in its fourth decade, the burden of HIV disease still persists, despite significant milestone achievements in HIV prevention, diagnosis, treatment, care, and support. Even with long-term use of currently available antiretroviral therapies (ARTs), eradication of HIV remains elusive and now poses a unique set of challenges for the HIV-infected individual. The occurrence of HIV-associated non-AIDS-related comorbidities outside the scope of AIDS-defining illnesses, in particular non-AIDS-defining cancers, is much greater than the age-matched uninfected population. The underlying mechanism is now recognized in part to be related to the immune dysregulated and inflammatory status characteristic of HIV infection that persists despite ART. Natural killer (NK) cells are multifunctional effector immune cells that play a critical role in shaping the innate immune responses to viral infections and cancer. NK cells can modulate the adaptive immune response via their role in dendritic cell (DC) maturation, removal of immature tolerogenic DCs, and their ability to produce immunoregulatory cytokines. NK cells are therefore poised as attractive therapeutic targets that can be harnessed to control or clear both HIV and HIV-associated malignancies. To date, features of the tumor microenvironment and the evolution of NK-cell function among individuals with HIV-related malignancies remain unclear and may be distinct from malignancies observed in uninfected persons. This review intends to uncouple anti-HIV and antitumor NK-cell features that can be manipulated to halt the evolution of HIV disease and HIV-associated malignancies and serve as potential preventative and curative immunotherapeutic options. PMID:28377768
Bonnel, Renan A; Villalba, Maria L; Karwoski, Claudia B; Beitz, Julie
Rofecoxib is a nonsteroidal anti-inflammatory drug that is reported to act by selectively inhibiting cyclooxygenase-2. A review and analysis of reports sent to the Spontaneous Reporting System of the Food and Drug Administration, Rockville, Md, suggest that aseptic meningitis is associated with rofecoxib use. To our knowledge, there have been no published reports of aseptic meningitis occurring in association with rofecoxib use to date. We report 5 serious cases of aseptic meningitis associated with rofecoxib use.
Roth, Patrick; Weller, Michael
Leptomeningeal dissemination of tumor cells, also referred to as neoplastic meningitis, is most frequently seen in patients with late-stage cancer and mostly associated with a poor prognosis. Basically, neoplastic meningitis may affect all patients with a malignant tumor but is most common in patients affected by lung cancer, breast carcinoma, melanoma or hematologic neoplasms such as lymphoma and leukemia. Controlled clinical trials are largely lacking which results in various non-standardized treatment regimens. The presence of solid tumor manifestations in the CNS as well as the extracranial tumor load defines the most appropriate treatment approach. Radiation therapy, systemic chemotherapy and intrathecal treatment must be considered. For each patient, the individual situation needs to be carefully evaluated to determine the potential benefit as well as putative side effects associated with any therapy. A moderate survival benefit and particularly relief from pain and neurological deficits are the main treatment goals. Here, we summarize the management of patients with neoplastic meningitis and review the available treatment options.
Rosenstiel, Paul; Gharavi, Ali; D'Agati, Vivette; Klotman, Paul
HIV-associated nephropathy (HIVAN) is a major cause of HIV-related morbidity and mortality. Transgenic and infectious models of HIVAN faithfully recapitulate the human disease and are important tools in advancing our understanding of disease pathogenesis, genetic susceptibility, and therapeutic intervention beyond the inhibition of viral replication. This review discusses the available transgenic murine models and infectious models of HIVAN in mice, rats, nonhuman primates, and felines. Particular emphasis is given to cell type-specific HIV expression as well as partial HIV genome expression used to map HIV-1 Nef and Vpr as pathologic determinants.
Vázquez-Santiago, Fabián J.; Noel, Richard J.; Porter, James T.; Rivera-Amill, Vanessa
HIV-1 infection can lead to neurocognitive impairment collectively known as HIV-Associated Neurocognitive Disorders (HAND). Although combined antiretroviral treatment (cART) has significantly ameliorated HIV’s morbidity and mortality, persistent neuroinflammation and neurocognitive dysfunction continue. This review focuses on the current clinical and molecular evidence of the viral and host factors that influence glutamate-mediated neurotoxicity and neuropathogenesis as an important underlying mechanism during the course of HAND development. In addition, discusses potential pharmacological strategies targeting the glutamatergic system that may help prevent and improve neurological outcomes in HIV-1 infected subjects. PMID:24867611
Rockwood, Neesha; Wilkinson, Robert John
HIV-associated tuberculosis can present as extremes, ranging from acute life-threatening disseminated disease to occult asymptomatic infection. Both ends of this spectrum have distinct pathological correlates and require specific diagnostic and treatment approaches. Novel therapeutics, targeting both pathogen and host, are needed to augment pathogen clearance. In latent tuberculosis infection, enhancement of immune activation could be desirable. Antiretroviral therapy augments the beneficial effects of antitubercular therapy. However, in the context of high bacillary burden, antiretroviral therapy can also result in pathology (tuberculosis immune reconstitution inflammatory syndrome). In the immune reconstituting patient, modulation of immune activation controls tissue destruction. Interventions should also be appropriate and sustainable within the programmatic setting.
Chen, Sharon C A
Cryptococcus neoformans is an important fungal pathogen in both immunocompromised and immunocompetent hosts. The mean annual incidence during 1994-1997 was 6.6 cases per million people per year in Australia, and 2.2 cases per million people per year in New Zealand. C. neoformans var. neoformans caused 85% of 312 episodes (98% of episodes in immunocompromised hosts) and C. neoformans var. gattii caused 15% (44% in immunocompetent hosts). The AIDS-specific incidence declined significantly over the 3 years. Mortality from cryptococcosis remains substantial. In trials involving small numbers of AIDS patients, liposomal amphotericin B (AmBisome) was found to be active against C. neoformans, with mycological response rates of 67-85%; however, maintenance therapy with an oral antifungal agent is required indefinitely. In a randomized study of patients with cryptococcal meningitis, AmBisome (4 mg/kg/day) produced mycological eradication in 73% of patients compared with 38% with conventional amphotericin. AmBisome resulted in significantly earlier sterilization of cerebrospinal fluid than conventional amphotericin (7-14 days versus 21 days) and was less nephrotoxic. The benefit of this reduced toxicity is denied to many patients because of an enormous cost barrier. In a survey of the practices of clinical mycologists in Australia, 11 experts responded to a questionnaire survey regarding the use of available lipid preparations. Their indications for use as initial therapy were mucormycosis (7/10), renal failure (7/10), Fusarium infection (2/10) and aspergillosis (2/10). Cryptococcosis, candidosis and febrile neutropenia were rarely regarded as an indication; failed therapy with conventional amphotericin was an indication to use AmBisome for 8/11 respondents. The majority believed that AmBisome was equivalent to conventional amphotericin, with amphotericin B lipid complex and AmBisome equivalent to each other in terms of efficacy. The main barrier to replacement of
Tsoukas, Michael A; Farr, Olivia M; Mantzoros, Christos S
Leptin is a hormone secreted by adipocytes that regulates energy metabolism via peripheral action on glucose synthesis and utilization as well as through central regulation of food intake. Patients with decreased amounts of fat in their adipose tissue (lipoatrophy) will have low leptin levels, and hypoleptinemic states have been associated with a variety of metabolic dysfunctions. Pronounced complications of insulin resistance, dyslipidemia and fatty liver are observed in patients suffering from congenital or acquired generalized lipodystrophy while somewhat less pronounced abnormalities are associated with human immunodeficiency virus (HIV) and the use of highly active antiretroviral therapy, the so-called HIV-associated lipodystrophy. Previous uncontrolled open-label studies have demonstrated that physiological doses of leptin repletion have corrected many of the metabolic derangements observed in subjects with rare fat maldistribution syndromes such as generalized lipodystrophy. In the much more commonly encountered HIV-associated lipodystrophy, leptin replacement has been shown to decrease central fat mass and to improve insulin sensitivity, dyslipidemia, and glucose levels. The United States Food and Drug Administration has recently granted approval for recombinant leptin therapy for congenital and acquired generalized lipodystrophy, however large, well-designed, placebo-controlled studies are needed to assess long-term efficacy, safety and adverse effects of leptin replacement. In this review, we present the role of leptin in the metabolic complications of congenital and acquired lipodystrophy and discuss current and emerging clinical therapeutic uses of leptin in humans with lipodystrophy. Copyright © 2015 Elsevier Inc. All rights reserved.
Chan, Jasper F W; Teng, Jade L L; Li, Iris W S; Wong, Sally C Y; Leung, Sally S M; Ho, Po-On; To, Kelvin K W; Lau, Susanna K P; Woo, Patrick C Y; Yuen, Kwok-Yung
We report a fatal case of Schizophyllum commune empyema thoracis with cross-reactive cryptococcal antigenemia. In vitro testing confirmed the ability of the fungus to cause a positive cryptococcal antigen latex agglutination system (CALAS) test result. Such a result may lead to delay in diagnosis and treatment, as most strains of S. commune are resistant to fluconazole.
Chan, Jasper F. W.; Teng, Jade L. L.; Li, Iris W. S.; Wong, Sally C. Y.; Leung, Sally S. M.; Ho, Po-On; To, Kelvin K. W.; Lau, Susanna K. P.; Woo, Patrick C. Y.
We report a fatal case of Schizophyllum commune empyema thoracis with cross-reactive cryptococcal antigenemia. In vitro testing confirmed the ability of the fungus to cause a positive cryptococcal antigen latex agglutination system (CALAS) test result. Such a result may lead to delay in diagnosis and treatment, as most strains of S. commune are resistant to fluconazole. PMID:24478514
Durski, Kara N.; Kuntz, Karen M.; Yasukawa, Kosuke; Virnig, Beth A.; Meya, David B.; Boulware, David R.
Background Checklists can standardize patient care, reduce errors, and improve health outcomes. For meningitis in resource-limited settings, with high patient loads and limited financial resources, CNS diagnostic algorithms may be useful to guide diagnosis and treatment. However, the cost-effectiveness of such algorithms is unknown. Methods We used decision analysis methodology to evaluate the costs, diagnostic yield, and cost-effectiveness of diagnostic strategies for adults with suspected meningitis in resource limited settings with moderate/high HIV prevalence. We considered three strategies: 1) comprehensive “shotgun” approach of utilizing all routine tests; 2) “stepwise” strategy with tests performed in a specific order with additional TB diagnostics; 3) “minimalist” strategy of sequential ordering of high-yield tests only. Each strategy resulted in one of four meningitis diagnoses: bacterial (4%), cryptococcal (59%), TB (8%), or other (aseptic) meningitis (29%). In model development, we utilized prevalence data from two Ugandan sites and published data on test performance. We validated the strategies with data from Malawi, South Africa, and Zimbabwe. Results The current comprehensive testing strategy resulted in 93.3% correct meningitis diagnoses costing $32.00/patient. A stepwise strategy had 93.8% correct diagnoses costing an average of $9.72/patient, and a minimalist strategy had 91.1% correct diagnoses costing an average of $6.17/patient. The incremental cost effectiveness ratio was $133 per additional correct diagnosis for the stepwise over minimalist strategy. Conclusions Through strategically choosing the order and type of testing coupled with disease prevalence rates, algorithms can deliver more care more efficiently. The algorithms presented herein are generalizable to East Africa and Southern Africa. PMID:23466647
Durski, Kara N; Kuntz, Karen M; Yasukawa, Kosuke; Virnig, Beth A; Meya, David B; Boulware, David R
Checklists can standardize patient care, reduce errors, and improve health outcomes. For meningitis in resource-limited settings, with high patient loads and limited financial resources, central nervous system diagnostic algorithms may be useful to guide diagnosis and treatment. However, the cost effectiveness of such algorithms is unknown. We used decision analysis methodology to evaluate the costs, diagnostic yield, and cost effectiveness of diagnostic strategies for adults with suspected meningitis in resource-limited settings with moderate/high HIV prevalence. We considered 3 strategies: (1) comprehensive "shotgun" approach of utilizing all routine tests; (2) "stepwise" strategy with tests performed in a specific order with additional tuberculosis (TB) diagnostics; (3) "minimalist" strategy of sequential ordering of high-yield tests only. Each strategy resulted in 1 of 4 meningitis diagnoses: bacterial (4%), cryptococcal (59%), TB (8%), or other (aseptic) meningitis (29%). In model development, we utilized prevalence data from 2 Ugandan sites and published data on test performance. We validated the strategies with data from Malawi, South Africa, and Zimbabwe. The current comprehensive testing strategy resulted in 93.3% correct meningitis diagnoses costing $32.00 per patient. A stepwise strategy had 93.8% correct diagnoses costing an average of $9.72 per patient, and a minimalist strategy had 91.1% correct diagnoses costing an average of $6.17 per patient. The incremental cost-effectiveness ratio was $133 per additional correct diagnosis for the stepwise over minimalist strategy. Through strategically choosing the order and type of testing coupled with disease prevalence rates, algorithms can deliver more care more efficiently. The algorithms presented herein are generalizable to East Africa and Southern Africa.
Himmelreich, Uwe; Malik, Richard; Kühn, Till; Daniel, Heide-Marie; Somorjai, Ray L.; Dolenko, Brion; Sorrell, Tania C.
Bacterial meningitis is an acute disease with high mortality that is reduced by early treatment. Identification of the causative microorganism by culture is sensitive but slow. Large volumes of cerebrospinal fluid (CSF) are required to maximise sensitivity and establish a provisional diagnosis. We have utilised nuclear magnetic resonance (NMR) spectroscopy to rapidly characterise the biochemical profile of CSF from normal rats and animals with pneumococcal or cryptococcal meningitis. Use of a miniaturised capillary NMR system overcame limitations caused by small CSF volumes and low metabolite concentrations. The analysis of the complex NMR spectroscopic data by a supervised statistical classification strategy included major, minor and unidentified metabolites. Reproducible spectral profiles were generated within less than three minutes, and revealed differences in the relative amounts of glucose, lactate, citrate, amino acid residues, acetate and polyols in the three groups. Contributions from microbial metabolism and inflammatory cells were evident. The computerised statistical classification strategy is based on both major metabolites and minor, partially unidentified metabolites. This data analysis proved highly specific for diagnosis (100% specificity in the final validation set), provided those with visible blood contamination were excluded from analysis; 6–8% of samples were classified as indeterminate. This proof of principle study suggests that a rapid etiologic diagnosis of meningitis is possible without prior culture. The method can be fully automated and avoids delays due to processing and selective identification of specific pathogens that are inherent in DNA-based techniques. PMID:19390697
Dohtsu, Yasumasa; Ishimatsu, Yuji; Takatani, Hiroshi; Minami, Kazunori; Inoue, Keiji; Kohara, Norihiro; Yanagihara, Katsunori; Higashiyama, Yasuhito; Miyazaki, Yoshitsugu; Hirakata, Yoichi; Kohno, Shigeru
Clinical studies of sixteen cases with pulmonary cryptococcosis, during the past six years between 1998 and 2004, were peformed mainly with respect to serum cryptococcal antigen titer. Serum cryptococcal antigen was positive in twelve of 16 cases, the other three cases were diagnosed by VATS, the other one by positive culture of cryptococcus in BALF. In these twelve cases, the serum cryptococcal antigen titer was continuously tested after treatment. The serum cryptococcal antigen titer decreased from half to 6 months after treatment. And the cryptococcal Ag changed to negative in six of the 12 cases by antifungal agents from 5 to 19 months. But four cases whose pneumonia was severe tended to have a high titer level of cryptococcal antigen and were positive for a long period. In the Chest CT of four pulmonary cryptococcosis case with negative cryptococcal antigen, all of the maximum nodule size was less than or equal to 15mm in diameter.
Purohit, Vishnudutt; Rapaka, Rao; Frankenheim, Jerry; Avila, Albert; Sorensen, Roger; Rutter, Joni
The National Institute on Drug Abuse organized a symposium on drugs of abuse, dopamine, and HIV-associated neurocognitive disorders (HAND)/HIV-associated dementia (HAD) in Rockville, Maryland, October 4, 2011. The purpose of this symposium was to evaluate the potential role of dopamine in the potentiation of HAND/HAD by drugs of abuse. A summary of the symposium has been presented in this report.
Gorantla, Santhi; Poluektova, Larisa; Gendelman, Howard E.
Human immunodeficiency virus (HIV)-associated neurocognitive disorders (HAND) reflect the spectrum of neural impairments seen during chronic viral infection. Current research efforts focus on improving antiretroviral and adjunctive therapies, defining disease onset and progression, facilitating drug delivery, and halting neurodegeneration and viral resistance. As HIV is species-specific, generating disease in small animal models has proved challenging. After two decades of research, rodent HAND models now include those containing a human immune system. Antiviral responses, neuroinflammation and immunocyte blood-brain barrier (BBB) trafficking follow HIV infection in these rodent models. Here, we review these and other rodent models of HAND and discuss their unmet potential in reflecting human pathobiology and in facilitating disease monitoring and therapeutic discoveries. PMID:22305769
Brew, Bruce J; Chan, Phillip
The introduction of combined antiretroviral therapy (cART) has dramatically reduced the risk of central nervous system opportunistic infection and severe dementia secondary to HIV infection in the last two decades. However, a milder form of HIV-associated neurocognitive disorder (HAND) remains prevalent in the cART era and has a significant impact on patients' quality of life. In this review, we outline updated research findings on investigating and monitoring cognitive impairment in HAND patients. The outcomes of recent research on the pathogenesis of HAND and how it overlaps with neurodegenerative diseases are discussed. Lastly, there is a brief discussion of the results of clinical trials using a brain-penetrating cART regimen.
De Niro, Jennifer Edith; Silkiss, Rona Z
HIV-associated lipoatrophy has been closely linked to the use of the thymidine nucleoside reverse-transcriptase inhibitors stavudine and zidovudine. The lipoatrophy can have severe psychological effects and is associated with increased risk of metabolic disorders and cardiovascular disease. The authors present a case of a 45-year-old HIV-positive man who presented with severe bilateral enophthalmos (recession of the eyes) and lagophthamos (inability to fully close the eyes) from orbital fat atrophy. He had taken zidovudine for 8 years and stavudine for 13 years. Cessation of the causative drugs usually does not result in noticeable improvement of the lipoatrophy. Placement of bilateral orbital floor implants decreased our patient's orbital volume and substantially improved his eyelid function and cosmetic appearance.
da Silva, D R; Gluz, I C; Kurz, J; Thomé, G G; Zancan, R; Bringhenti, R N; Schaefer, P G; Dos Santos, M; Barros, E J G; Veronese, F V
HIV infection has a broad spectrum of renal manifestations. This study examined the clinical and histological manifestations of HIV-associated renal disease, and predictors of renal outcomes. Sixty-one (64% male, mean age 45 years) HIV patients were retrospectively evaluated. Clinical presentation and renal histopathology were assessed, as well as CD4 T-cell count and viral load. The predictive value of histological lesion, baseline CD4 cell count and viral load for end-stage renal disease (ESRD) or death were determined using the Cox regression model. The outcomes of chronic kidney disease (CKD) and ESRD or death were evaluated by baseline CD4 cell count. The percent distribution at initial clinical presentation was non-nephrotic proteinuria (54%), acute kidney injury (28%), nephrotic syndrome (23%), and chronic kidney disease (22%). Focal segmental glomerulosclerosis (28%), mainly the collapsing form (HIVAN), acute interstitial nephritis (AIN) (26%), and immune complex-mediated glomerulonephritis (ICGN) (25%) were the predominant renal histology. Baseline CD4 cell count ≥ 200 cells/mm3 was a protective factor against CKD (hazard ratio=0.997; 95%CI=0.994-0.999; P=0.012). At last follow-up, 64% of patients with baseline CD4 ≥ 200 cells/mm3 had eGFR >60 mL·min-1·(1.73 m2)-1 compared to the other 35% of patients who presented with CD4 <200 cells/mm3 (log rank=9.043, P=0.003). In conclusion, the main histological lesion of HIV-associated renal disease was HIVAN, followed by AIN and ICGN. These findings reinforce the need to biopsy HIV patients with kidney impairment and/or proteinuria. Baseline CD4 cell count ≥ 200 cells/mm3 was associated with better renal function after 2 years of follow-up.
da Silva, D.R.; Gluz, I.C.; Kurz, J.; Thomé, G.G.; Zancan, R.; Bringhenti, R.N.; Schaefer, P.G.; dos Santos, M.; Barros, E.J.G.; Veronese, F.V.
HIV infection has a broad spectrum of renal manifestations. This study examined the clinical and histological manifestations of HIV-associated renal disease, and predictors of renal outcomes. Sixty-one (64% male, mean age 45 years) HIV patients were retrospectively evaluated. Clinical presentation and renal histopathology were assessed, as well as CD4 T-cell count and viral load. The predictive value of histological lesion, baseline CD4 cell count and viral load for end-stage renal disease (ESRD) or death were determined using the Cox regression model. The outcomes of chronic kidney disease (CKD) and ESRD or death were evaluated by baseline CD4 cell count. The percent distribution at initial clinical presentation was non-nephrotic proteinuria (54%), acute kidney injury (28%), nephrotic syndrome (23%), and chronic kidney disease (22%). Focal segmental glomerulosclerosis (28%), mainly the collapsing form (HIVAN), acute interstitial nephritis (AIN) (26%), and immune complex-mediated glomerulonephritis (ICGN) (25%) were the predominant renal histology. Baseline CD4 cell count ≥200 cells/mm3 was a protective factor against CKD (hazard ratio=0.997; 95%CI=0.994-0.999; P=0.012). At last follow-up, 64% of patients with baseline CD4 ≥200 cells/mm3 had eGFR >60 mL·min-1·(1.73 m2)-1 compared to the other 35% of patients who presented with CD4 <200 cells/mm3 (log rank=9.043, P=0.003). In conclusion, the main histological lesion of HIV-associated renal disease was HIVAN, followed by AIN and ICGN. These findings reinforce the need to biopsy HIV patients with kidney impairment and/or proteinuria. Baseline CD4 cell count ≥200 cells/mm3 was associated with better renal function after 2 years of follow-up. PMID:27007656
Kandanearatchi, Apsara; Brew, Bruce J
This brief review will first consider HIV associated neurocognitive disorder followed by the current understanding of its neuropathogenesis. Against this background the role of the kynurenine pathway will be detailed. Evidence both direct and indirect will be discussed for involvement of the kynurenine pathway at each step in the neuropathogenesis of HIV associated neurocognitive disorder.
van de Beek, Diederik; Brouwer, Matthijs; Hasbun, Rodrigo; Koedel, Uwe; Whitney, Cynthia G; Wijdicks, Eelco
Meningitis is an inflammation of the meninges and subarachnoid space that can also involve the brain cortex and parenchyma. It can be acquired spontaneously in the community - community-acquired bacterial meningitis - or in the hospital as a complication of invasive procedures or head trauma (nosocomial bacterial meningitis). Despite advances in treatment and vaccinations, community-acquired bacterial meningitis remains one of the most important infectious diseases worldwide. Streptococcus pneumoniae and Neisseria meningitidis are the most common causative bacteria and are associated with high mortality and morbidity; vaccines targeting these organisms, which have designs similar to the successful vaccine that targets Haemophilus influenzae type b meningitis, are now being used in many routine vaccination programmes. Experimental and genetic association studies have increased our knowledge about the pathogenesis of bacterial meningitis. Early antibiotic treatment improves the outcome, but the growing emergence of drug resistance as well as shifts in the distribution of serotypes and groups are fuelling further development of new vaccines and treatment strategies. Corticosteroids were found to be beneficial in high-income countries depending on the bacterial species. Further improvements in the outcome are likely to come from dampening the host inflammatory response and implementing preventive measures, especially the development of new vaccines.
van Samkar, Anusha; Brouwer, Matthijs C.; van der Ende, Arie; van de Beek, Diederik
Abstract The zoonotic pathogen Campylobacter fetus is a rare cause of bacterial meningitis. Little is known about the clinical characteristics, predisposing factors and outcome of C fetus meningitis in adults. We report cases of C fetus meningitis in a nationwide cohort study of adult bacterial meningitis patients in the Netherlands and performed a review of the literature. Two patients with C fetus meningitis were identified from January 2006 through May 2015. The calculated annual incidence was 0.02 per million adults. Combined with the literature, we identified 22 patients with a median age of 48 years. An immunocompromised state was present in 16 patients (73%), mostly due to alcoholism (41%) and diabetes mellitus (27%). The source of infection was identified in 13 out of 19 patients (68%), consisting of regular contact with domestic animals in 5 and working on a farm in 4. Recurrent fever and illness was reported in 4 patients (18%), requiring prolonged antibiotic treatment. Two patients died (9%) and 3 survivors (15%) had neurological sequelae. C fetus is a rare cause of bacterial meningitis and is associated with an immunocompromised state. Based on the apparent slow clinical response seen in this limited number of cases, the authors of this study recommend a prolonged course of antimicrobial therapy when C fetus is identified as a causative agent of bacterial meningitis. Cases appeared to do best with carbapenem therapy. PMID:26937916
Kim, Dong-Min; Chung, Jong-Hoon; Yun, Na-Ra; Kim, Seok Won; Lee, Jun-Young; Han, Mi Ah; Lee, Yong-Bok
Orientia tsutsugamushi induces vasculitis leading to symptoms of systemic organ invasion including meningitis and meningoencephalitis. We conducted a retrospective case-control study of scrub typhus patients to investigate the clinical and laboratory features of patients with scrub typhus meningitis or meningoencephalitis, and the therapeutic outcomes, and to determine the predictor factors. Cases were 22 patients with scrub typhus meningitis or meningoencephalitis, and controls were 303 patients without meningitis or meningoencephalitis. Multivariate analysis showed that the presence of pneumonitis was associated with the occurrence of scrub typhus meningitis and meningoencephalitis (odds ratio [OR] 8.9; P < 0.001; confidence interval [CI] 2.9–27.2). Although appropriate antimicrobials such as doxycycline agents were administered at an early stage, meningitis or meningoencephalitis still occurred in some cases. Physicians should be aware that meningitis or meningoencephalitis may develop during appropriate drug therapy such as doxycycline. Close observation and great care are essential for patients with risk factors, particularly pneumonitis. PMID:24166036
Garg, Ravindra K; Jain, Amita; Malhotra, Hardeep S; Agrawal, Avinash; Garg, Rajiv
Drug-resistant tuberculosis, including drug-resistant tuberculous meningitis, is an emerging health problem in many countries. An association with Beijing strains and drug resistance-related mutations, such as mutations in katG and rpoB genes, has been found. The pathology, clinical features and neuroimaging characteristics of drug-resistant tuberculous meningitis are similar to drug-responsive tuberculous meningitis. Detection of mycobacteria in cerebrospinal fluid (CSF) by conventional methods (smear examination or culture) is often difficult. Nucleic acid amplification assays are better methods owing to their rapidity and high sensitivity. The Xpert MTB/RIF assay (Cepheid, CA, USA) is a fully-automated test that has also been found to be effective for CSF samples. Treatment of multidrug-resistant tuberculous meningitis depends on the drug susceptibility pattern of the isolate and/or the previous treatment history of the patient. Second-line drugs with good penetration of the CSF should be preferred. Isoniazid monoresistant disease requires addition of another drug with better CSF penetration. Drug-resistant tuberculous meningitis is associated with a high mortality. HIV infected patients with drug-resistant tuberculous meningitis have severe clinical manifestations with exceptionally high mortality. Prevention of tuberculosis is the key to reduce drug-resistant tuberculous meningitis.
Binnicker, M J; Jespersen, D J; Bestrom, J E; Rollins, L O
We compared the performance of four assays for the detection of cryptococcal antigen in serum samples (n = 634) and cerebrospinal fluid (CSF) samples (n = 51). Compared to latex agglutination, the sensitivity and specificity of the Premier enzyme immunoassay (EIA), Alpha CrAg EIA, and CrAg lateral flow assay (LFA) were 55.6 and 100%, 100 and 99.7%, and 100 and 99.8%, respectively, from serum samples. There was 100% agreement among the four tests for CSF samples, with 18 samples testing positive by each of the assays.
Ferraro, Richard A; Ivanidze, Jana; Margolskee, Elizabeth; Tsang, Hamilton; Sconomiglio, Theresa; Jhanwar, Yuliya S
We report a case of cryptococcal sinusitis, a rare presentation of Cryptococcus neoformans infection in a patient with multiple myeloma. The objective of this case report is to highlight the utility of structural and functional imaging modalities in the differential diagnosis of sinonasal soft tissue masses in the immunocompromised patient population. PET-CT was the first imaging modality in this patient, who presented for routine follow-up staging of multiple myeloma, and was asymptomatic at the time of his presentation. PET-CT findings prompted further evaluation with MRI, to aid in the differential diagnosis with respect to a neoplastic versus infectious etiology. Ultimately, surgical excision with histopathology was required to provide definitive diagnosis. Final histopathology displayed yeast-organism staining consistent with Cryptococcus neoformans/gatti. The patient subsequently underwent treatment for this infection, along continued treatment for multiple myeloma. To our knowledge this is the first known case of cryptococcal sinusitis in a patient with neoplastic disease. Imaging represents an important tool to differentiate fungal infection from neoplasm in the immunocompromised patient population. As the population of immunocompromised patients continues to grow, the relevance of this diagnosis as well as the use of alternative imaging modalities is becoming more important in clinical practice.
Tarlov, I. M.
Perineurial cysts may be responsible for clinical symptoms and a cure effected by their removal. They do not fill on initial myelography but may fill with Pantopaque some time, days or weeks, after Pantopaque has been instilled into the subarachnoid space. Perineurial cysts arise at the site of the posterior root ganglion. The cyst wall is composed of neural tissue. When initial myelography fails to reveal an adequate cause for the patient's symptoms and signs referable to the caudal nerve roots, then about a millilitre of Pantopaque should be left in the canal for delayed myelography which may later reveal a sacral perineurial cyst or, occasionally, a meningeal cyst. Meningeal diverticula occur proximal to the posterior root ganglia and usually fill on initial myelography. They are in free communication with the subarachnoid space and are rarely in my experience responsible for clinical symptoms. Meningeal diverticula and meningeal cysts appear to represent a continuum. Pantopaque left in the subarachnoid space may convert a meningeal diverticulum into an expanding symptomatic meningeal cyst, as in the case described. Many cases described as perineurial cysts represent abnormally long arachnoidal prolongations over nerve roots or meningeal diverticula. In general, neither of the latter is of pathological significance. Perineurial, like meningeal cysts and diverticula, may be asymptomatic. They should be operated upon only if they produce progressive or disabling symptoms or signs clearly attributable to them. When myelography must be done, and this should be done only as a preliminary to a probable necessary operation, then patient effort should be made to remove the Pantopaque. Images PMID:5531903
Shrikanth, Vandana; Salazar, Lucrecia; Khoury, Nabil; Wootton, Susan; Hasbun, Rodrigo
Hypoglycorrhachia (cerebrospinal fluid (CSF) glucose <45 mg/dl) has been identified as a prognostic factor in patients with meningitis. The differential diagnosis of hypoglycorrhachia and its clinical significance was analyzed in the present study. This was a retrospective study of 620 adult patients with community-acquired meningitis (CSF white blood cell count >5 × 10(6) cells/l and absence of a CSF shunt or recent neurosurgical procedure (<1 month)) at eight Memorial Hermann hospitals in Houston, Texas, from January 2005 to December 2010. An adverse clinical outcome was defined as a Glasgow outcome scale score of ≤ 4. Out of 620 patients with meningitis, 116 (19%) had hypoglycorrhachia. Etiologies of hypoglycorrhachia were idiopathic (n=40), bacterial (n=27), cryptococcal (n=26), viral (n=15), and tuberculous (n=4). Patients with hypoglycorrhachia were more likely to be immunosuppressed, have a history of intravenous drug use, and present with a vesicular or petechial rash, nausea or vomiting, nuchal rigidity, sinusitis/otitis, abnormal mental status, and focal neurological deficits compared to those patients without hypoglycorrhachia (p<0.05). Additionally, patients in the hypoglycorrhachia group had significantly higher rates of positive CSF and blood cultures, urgent treatable conditions, and abnormal cranial imaging (p<0.05). Furthermore, patients with hypoglycorrhachia had more adverse clinical outcomes (26/116 (22.4%) vs. 45/504 (8.9%); p<0.001). Hypoglycorrhachia has significant clinical and prognostic value in the evaluation of adult patients with community-acquired meningitis. Copyright © 2015 The Authors. Published by Elsevier Ltd.. All rights reserved.
Ogasawara, Noriko; Takano, Ken-Ichi; Kobayashi, Hajime; Kikuchi, Keisuke; Matsumiya, Hiroshi; Yoshioka, Iwao; Himi, Tetsuo
We present two cases of an HIV-associated parotid gland cyst. One case was a 36-year-old HIV infected woman. She was diagnosed with HIV infection and presented with slowly enlarged parotid gland cysts together with elevation of HIV viral RNA copies/mL in her serum. She was performed parotid gland biopsy under the general anesthesia. The histopathologic analysis revealed negative HIV p24-antigen in her parotid gland tissue. The other case was a 43-year-old man found his parotid gland swelling shortly after highly active antiretroviral therapy (HAART). He was diagnosed with HIV infection 2 years previously. He had started HAART several days before. He showed exceeding elevation of IgE in his serum. We treated him with medication using anti-histamic drugs for his cyst. A computed tomography scan revealed a complete response of his parotid gland cyst 4 weeks after the medication. His serum IgE level was decreased to half of the level before the medication. These findings suggested that the parotid gland swelling associated with HIV was due to various factors including immune reconstitution inflammatory syndrome (IRIS). In case such a parotid gland swelling, we could avoid invasive treatments.
Seider, Talia R; Gongvatana, Assawin; Woods, Adam J; Chen, Huaihou; Porges, Eric C; Cummings, Tiffany; Correia, Stephen; Tashima, Karen; Cohen, Ronald A
Both HIV disease and advanced age have been associated with alterations to cerebral white matter, as measured with white matter hyperintensities (WMH) on fluid-attenuated inversion recovery (FLAIR) magnetic resonance imaging (MRI), and more recently with diffusion tensor imaging (DTI). This study investigates the combined effects of age and HIV serostatus on WMH and DTI measures, as well as the relationships between these white matter measures, in 88 HIV seropositive (HIV+) and 49 seronegative (HIV-) individuals aged 23-79 years. A whole-brain volumetric measure of WMH was quantified from FLAIR images using a semi-automated process, while fractional anisotropy (FA) was calculated for 15 regions of a whole-brain white matter skeleton generated using tract-based spatial statistics (TBSS). An age by HIV interaction was found indicating a significant association between WMH and older age in HIV+ participants only. Similarly, significant age by HIV interactions were found indicating stronger associations between older age and decreased FA in the posterior limbs of the internal capsules, cerebral peduncles, and anterior corona radiata in HIV+ vs. HIV- participants. The interactive effects of HIV and age were stronger with respect to whole-brain WMH than for any of the FA measures. Among HIV+ participants, greater WMH and lower anterior corona radiata FA were associated with active hepatitis C virus infection, a history of AIDS, and higher current CD4 cell count. Results indicate that age exacerbates HIV-associated abnormalities of whole-brain WMH and fronto-subcortical white matter integrity.
Kumar, Dileep; Salhan, Divya; Magoon, Sandeep; Torri, Deepti D.; Sayeneni, Swapna; Sagar, Ankita; Bandhlish, Anshu; Malhotra, Ashwani; Chander, Praveen N.; Singhal, Pravin C.
In the present study, we hypothesized that HIV-1–induced occult HIV-associated nephropathy (HIVAN) would become apparent in the presence of adverse host factors. To test our hypothesis, Vpr mice (which display doxycycline-dependent Vpr expression in podocytes) with two, three, and four copies of the angiotensinogen (Agt) gene (Vpr-Agt-2, Vpr-Agt-3, and Vpr-Agt-4) were administered doxycycline for 3 weeks (to develop clinically occult HIVAN) followed by doxycycline-free water during the next 3 weeks. Subsequently, renal biomarkers were measured, and kidneys were harvested for renal histology. Vpr-Agt-2 developed neither proteinuria nor elevated blood pressure, and displayed minimal glomerular and tubular lesions only, without any microcyst formation. Vpr-Agt-3 showed mild glomerular and tubular lesions and microcyst formation, whereas Vpr-Agt-4 showed moderate proteinuria, hypertension, glomerular sclerosis, tubular dilation, microcysts, and expression of epithelial mesenchymal transition markers. Vpr-Agt-4 not only displayed enhanced renal tissue expression of Agt, renin, and angiotensin-converting enzyme, but also had higher renal tissue concentrations of angiotensin II. Moreover, renal cells in Vpr-Agt-4 showed enhanced expression of transforming growth factor-β, connective tissue growth factor, and vascular endothelial growth factor. These findings indicate that adverse host factors, such as the activation of the renin-angiotensin system, promote the progression of occult HIVAN to apparent HIVAN. PMID:21871425
Minassian, Arpi; Henry, Brook L; Woods, Steven Paul; Vaida, Florin; Grant, Igor; Geyer, Mark A; Perry, William
Sensorimotor inhibition, or the ability to filter out excessive or irrelevant information, theoretically supports a variety of higher-level cognitive functions. Impaired inhibition may be associated with increased impulsive and risky behavior in everyday life. Individuals infected with HIV frequently show impairment on tests of neurocognitive function, but sensorimotor inhibition in this population has not been studied and may be a contributor to the profile of HIV-associated neurocognitive disorders (HAND). Thirty-seven HIV-infected individuals (15 with HAND) and 48 non-infected comparison subjects were assessed for prepulse inhibition (PPI), an eyeblink startle paradigm measuring sensorimotor gating. Although HIV status alone was not associated with PPI deficits, HIV-positive participants meeting criteria for HAND showed impaired PPI compared to cognitively intact HIV-positive subjects. In HIV-positive subjects, PPI was correlated with working memory but was not associated with antiretroviral therapy or illness factors. In conclusion, sensorimotor disinhibition in HIV accompanies deficits in higher-order cognitive functions, although the causal direction of this relationship requires investigation. Subsequent research on the role of sensorimotor gating on decision-making and risk behaviors in HIV may be indicated.
Minassian, Arpi; Henry, Brook L.; Woods, Steven Paul; Vaida, Florin; Grant, Igor; Geyer, Mark A.; Perry, William
Sensorimotor inhibition, or the ability to filter out excessive or irrelevant information, theoretically supports a variety of higher-level cognitive functions. Impaired inhibition may be associated with increased impulsive and risky behavior in everyday life. Individuals infected with HIV frequently show impairment on tests of neurocognitive function, but sensorimotor inhibition in this population has not been studied and may be a contributor to the profile of HIV-associated Neurocognitive Disorders (HAND). 37 HIV-infected individuals (15 with HAND) and 48 non-infected comparison subjects were assessed for prepulse inhibition (PPI), an eyeblink startle paradigm measuring sensorimotor gating. Although HIV status alone was not associated with PPI deficits, HIV-positive participants meeting criteria for HAND showed impaired PPI compared to cognitively intact HIV-positive subjects. In HIV-positive subjects, PPI was correlated with working memory but was not associated with antiretroviral therapy or illness factors. In conclusion, sensorimotor disinhibition in HIV accompanies deficits in higher-order cognitive functions, though the causal direction of this relationship requires investigation. Subsequent research on the role of sensorimotor gating on decision-making and risk behaviors in HIV may be indicated. PMID:23552464
Prevedel, Lisa; Morocho, Camilla; Bennett, Michael V L; Eugenin, Eliseo A
Chronic HIV infection due to effective antiretroviral treatment has resulted in a broad range of clinical complications, including accelerated heart disease. Individuals with HIV infection have a 1.5 to 2 times higher incidence of cardiovascular diseases than their uninfected counterparts; however, the underlying mechanisms are poorly understood. To explore the link between HIV infection and cardiovascular diseases, we used postmortem human heart tissues obtained from HIV-infected and control uninfected individuals to examine connexin 43 (Cx43) expression and distribution and HIV-associated inflammation. Here, we demonstrate that Cx43 is dysregulated in the hearts of HIV-infected individuals. In all HIV heart samples analyzed, there were areas where Cx43 was overexpressed and found along the lateral membrane of the cardiomyocyte and in the intercalated disks. Areas of HIV tissue with anomalous Cx43 expression and localization also showed calcium overload, sarcofilamental atrophy, and accumulation of collagen. All these changes were independent of viral replication, CD4 counts, inflammation, and type of antiretroviral treatment. Overall, we propose that HIV infection increases Cx43 expression in heart, resulting in tissue damage that likely contributes to the high rates of cardiovascular disease in HIV-infected individuals. Copyright © 2017 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.
Loonam, Cathríona Rosemary; Mullen, Anne
HIV-associated lipodystrophy syndrome (HALS), comprising metabolic and morphological alterations, is a known side effect of highly active antiretroviral therapy (HAART). Evidence for the role of nutrition in the management of the systemic parameters of HALS is currently limited. In the present paper we review the current knowledge base surrounding HALS, focusing particularly on the role of nutrition in mitigating the systemic parameters of the syndrome. Reported prevalence of HALS was found to vary from 9 to 83 % due to lack of a standardised definition, as well as variations in assessment methods and in the study population used. HALS is associated with both morphological (lipoatrophy, lipohypertrophy) and metabolic (dyslipidaemia, glucose intolerance, diabetes, hypertension, endothelial dysfunction and atherosclerosis) alterations, which may occur singly or in combination, and are associated with an increased risk of CVD. HAART-induced adipocyte inflammation, oxidative stress and macrophage infiltration, as well as altered adipocyte function and mitochondrial toxicity, have been shown to be central to the development of HALS. The adipocyte, therefore, represents a plausible target for treatment. Pharmacological and surgical treatment interventions have shown effect. However, their use is associated with numerous adverse effects and complications. Targeted lifestyle interventions may provide a useful alternative for managing HALS owing to their safety and tolerability. A Mediterranean-style diet has been found to be effective in improving the systemic parameters of HALS. Furthermore, the effects of n-3 PUFA supplementation are encouraging and future randomised controlled trials investigating the beneficial effects of n-3 PUFA in HALS are justified.
Macharia, W M; Mbaabu, C; Wachira, L; Muhudhia, S O M; Moniz, G
Angio-oedema may be hereditary or acquired and is characterised by episodes of potentially life threatening localised tissue oedema and swelling resulting from deficiency of compliment pathway C1 esterase inhibitor. Acquired angio-oedema is about ten times less frequent than the hereditary type and has been associated with immune-deficiency disorders, malignancies and exposure to specific medications and food substances. We present a case of seven year old, human immune-deficiency virus positive girl, who developed gross swelling of the tongue and neck while on treatment for pneumococcal meningitis with ceftriaxone. Difficulties in arriving at a definitive diagnosis of angio-oedema in a resource poor country are discussed and alternative diagnostic options proposed.
Ramkillawan, Y; Dawood, H; Ferreira, N
Cryptococcus neoformans is a ubiquitous organism that often causes opportunistic infections in immune-compromised patients. The pulmonary and central nervous systems are most commonly affected. Osseous involvement is infrequent and is usually associated with disseminated systemic infection. Isolated cryptococcal osteomyelitis is exceedingly rare. We report the case of a 56-year-old immunocompetent man who presented with isolated cryptococcal osteomyelitis of the humerus.
Ito, H; Hasegawa, T; Kawano, H; Shoin, K; Yamamoto, S; Matsubara, F
A 44-year-old farmer complained blurred vision and disturbance of recent memory. During his driving car traffic accident happened due to his right homonymous hemianopsia. On the 1st admission, neurological examination revealed choked disc(1 D.), hemianopsia, memory disturbance, dyscalculia, dyslexia and dysgraphia. The angiograms showed feeding arteries from left middle cerebral artery and posterior cerebral artery. Tumor vessels looked like cork-screw in the arterial phase and homogeneous tumor shadow was depicted in late venous phase. Contrast enhancement CT scan revealed a nodular homogeneous high dense lesion on the occipital region. Hemorrhage during every craniotomy was too much to remove and at last metastasized to left II rib and right VIII rib and right radius. Their histological examination reveals numerous endothelial-lined vascular channels and atypia of tumor cells with mitoses. Silver impregnation demonstrates networks of reticulum fibers surrounding the capillaries and tumor cells. Hemangiopericytoma in meninges forms entity and our case reports the WHO classification. Total removal should have to be done once for all by means of LASER (light amplification by stimulated emission of radiation).
Yoneda, T; Itami, Y; Hirayama, A; Saka, T; Yoshida, K; Fujimoto, K
A 50-year-old man, who had received an ABO-incompatible living related preemptive renal transplantation 1 year before, presented with painful lesions on both lower extremities and fever. At first, bacterial cellulitis was suspected and antibiotic therapy was initiated, but it was not effective. The serum cryptococcal antigen titer was 1:4,098, and pathologic examination of debrided tissue and wound pus culture revealed cryptococcal necrotizing fasciitis. Liposomal amphotericin B and fluconazole were started, and repeated debridement and skin grafting were performed. Because his graft function deteriorated because of antibody-mediated rejection and polyoma viral nephropathy, hemodialysis was induced on day 9 of hospitalization. During the treatment, he suffered repeated urinary tract infections, which were treated with antibiotics, and cytomegalovirus retinopathy, which was treated with ganciclovir. His cryptococcal necrotizing fasciitis was successfully cured by the combination of antimicrobial treatment and surgical procedures. He could walk with a cane and was discharged on day 298 of hospitalization. Cryptococcal necrotizing fasciitis in renal transplant recipients is so rare that only 14 cases have been reported. The mortality is not very high, but the prognosis of the patient is complicated by worsening of the cryptococcal infection of the central nervous system (CNS). Early detection and treatment to prevent spreading to other sites, especially the CNS or disseminated disease, is very important in cases of cryptococcal necrotizing fasciitis.
Dietemann, J L; Correia Bernardo, R; Bogorin, A; Abu Eid, M; Koob, M; Nogueira, Th; Vargas, M I; Fakhoury, W; Zöllner, G
The authors describe normal imaging of the meninges and meningeal spaces and MR (magnetic resonance) imaging findings in tumoral and nontumoral diseases. Dural or/and pial enhancement may be related to tumoral, infectious or granulomatous diseases.
Gray, L D; Fedorko, D P
Bacterial meningitis is relatively common, can progress rapidly, and can result in death or permanent debilitation. This infection justifiably elicits strong emotional reactions and, hopefully, immediate medical intervention. This review is a brief presentation of the pathogenesis of bacterial meningitis and a review of current knowledge, literature, and recommendations on the subject of laboratory diagnosis of bacterial meningitis. Those who work in clinical microbiology laboratories should be familiar with the tests used in detecting bacteria and bacterial antigens in cerebrospinal fluid (CSF) and should always have the utmost appreciation for the fact that results of such tests must always be reported immediately. Academic and practical aspects of the laboratory diagnosis of bacterial meningitis presented in this review include the following: anatomy of the meninges; pathogenesis; changes in the composition of CSF; etiological agents; processing CSF; microscopic examination of CSF; culturing CSF; methods of detecting bacterial antigens and bacterial components in CSF (counter-immunoelectrophoresis, coagglutination, latex agglutination, enzyme-linked immunosorbent assay, Limulus amebocyte lysate assay, and gas-liquid chromatography); use of the polymerase chain reaction; and practical considerations for testing CSF for bacterial antigens. PMID:1576585
Kalyesubula, Robert; Wearne, Nicola; Semitala, Fred C; Bowa, Kasonde
With the recent massive scale-up of access to antiretroviral therapy (ART) in resource-limited countries, HIV has become a chronic disease with new challenges. There is mounting evidence of an increased burden of renal and genitourinary diseases among HIV-infected persons caused by direct HIV viral effects and/or indirectly through the development of opportunistic infections, ART medication-related toxicities, and other noncommunicable diseases (NCDs). We review the epidemiology of HIV-associated renal and urogenital diseases, including interactions with kidney-related NCDs such as hypertension, diabetes mellitus, and cardiovascular disease. We also examine the current evidence regarding the impact of HIV infection on the development of urogenital diseases. Highly advisable in sub-Saharan Africa are the establishment of renal disease registries, reviews of existing clinical practice including cost-effectiveness studies, and the adoption and use of HIV-related NCD management, with training for different cadres of health providers. Epidemiological research priorities include prospective studies to evaluate the true prevalence and spectrum of HIV-related renal disease and their progression. Simple diagnostics tools should be evaluated, including urinary dipsticks and point-of-care urea and creatinine tests to screen for kidney injury in primary care settings. Study of urological manifestations of HIV can help determine the extent of disease and outcomes. As patients live longer on ART, the burden of renal and genitourological complications of HIV and of ART can be expected to increase with a commensurate urgency in both discovery and evidence-based improvements in clinical management.
Hodgson, Shane; Griffin, Timothy J; Reilly, Cavan; Harvey, Stephen; Witthuhn, Bruce A; Sandri, Brian J; Wendt, Chris H
Introduction Chronic obstructive pulmonary disease (COPD) is a significant cause of morbidity in persons living with HIV (PLWH) and HIV appears to uniquely cause COPD, independent of smoking. The mechanisms by which HIV leads to COPD are not clear. The objective of this study was to identify metabolomic biomarkers and potential mechanistic pathways of HIV-associated COPD (HIV-COPD). Methods We performed case–control metabolite profiling via mass spectrometry in plasma from 38 individuals with HIV-COPD (cases), comparing to matched controls with/without HIV and with/without COPD. Untargeted metabolites of interest were identified with liquid chromatography with mass spectrometry (LC-MS/mass spectrometry (MS)), and targeted metabolomics for tryptophan (Trp) and kynurenine (Kyn) were measured by selective reaction monitoring (SRM) with LC-MS/MS. We used mixed-effects models to compare metabolite concentrations in cases compared with controls while controlling for relevant biological variables. Results We identified 1689 analytes associated with HIV-COPD at a false discovery rate (FDR) of 10%. In PLWH, we identified 263 analytes (10% FDR) between those with and without COPD. LC MS/MS identified Trp and 17 lipids, including sphingolipids and diacylglycerol. After adjusting for relevant covariates, the Kyn/Trp ratio measured by SRM was significantly higher in PLWH (p=0.022), but was not associated with COPD status (p=0.95). Conclusions There is a unique metabolite profile in HIV-COPD that includes sphingolipids. Trp metabolism is increased in HIV, but does not appear to independently contribute to HIV-COPD. Trial registration numbers NCT01810289, NCT01797367, NCT00608764. PMID:28409005
Rivera, S; Sattler, F R; Boyd, H; Auffenberg, T; Nakao, S; Moldawer, L L
The relationship between cytokines and HIV-related weight loss has not been well established. Unlike most cytokines that are secreted in a paracrine manner, IL-6, sTNFR-II, and IL-1ra are readily detected in the systemic circulation and serve as markers of the inflammatory response. Twenty-four-hour urine concentrations of these proteins are believed to provide an integrative assessment of their systemic levels over the preceding hours. We sought to determine whether spot measurements of IL-6, sTNFR-II, and IL-1ra could be related to subsequent 24 h concentrations and prior weight loss. Eighteen subjects with severe wasting (average BMI=18+/-3 kg/m2with 19+/-13 kg of weight loss) and six HIV-negative healthy subjects were tested. Compared to values in controls, 24-h urinary concentrations of the three proteins adjusted for creatinine excreted were elevated in 44%, 89%, and 72% of patients, respectively. Twenty-four-hour concentrations were highly correlated with the spot concentrations (r=0.80, 0.87, 0.84, respectively, P<0.001). IL-1ra concentrations (24 h and spot) were correlated with weight loss in the previous 6 months, lifetime rate of weight loss and the 6 month rate of weight loss (spot: r=0.66, 0.73, 0.68, respectively, P< or =0.001). These data suggest that spot urinary collections can be used to estimate 24 h excretion rates. This strategy may be useful in assessing the inflammatory response in HIV-associated wasting.
Ikumi, Kazuhiro; Yokoi, Katsunori; Ando, Tetsuo
The patient is a 72-year-old Japanese woman. Seven years prior to admission, multiple nodules in her left lung were found. Bronchoscopic biopsy of the nodules did not provide a confirmative diagnosis, and probable diagnosis of cryptococcosis was made. Follow-up CT scan of the chest revealed reduction in size of the lung nodules. She was admitted to our hospital due to progressive cognitive impairment and difficulty in walking that lasted for 5 months. On admission, athetotic involuntary movement was observed in her lower extremities, predominantly in the right side. Blood and cerebrospinal fluid culture of the patient were positive for Cryptococcus neoformans. Antifungal drugs resolved the cognitive impairment, the difficulty in walking, and the involuntary movement. We assessed the cognitive impairment and observed the clinical improvement of the patient, with the use of neuropsychological examinations. To our knowledge, there has been only a few reported case of cryptococcal meningoencephalitis presenting with treatable cognitive impairment and involuntary movement.
Nielsen, Judith N.; Charlier, Caroline; Baltes, Nicholas J.; Chrétien, Fabrice; Heitman, Joseph; Dromer, Françoise; Nielsen, Kirsten
Cryptococcus neoformans is a common life-threatening human fungal pathogen. The size of cryptococcal cells is typically 5 to 10 µm. Cell enlargement was observed in vivo, producing cells up to 100 µm. These morphological changes in cell size affected pathogenicity via reducing phagocytosis by host mononuclear cells, increasing resistance to oxidative and nitrosative stress, and correlated with reduced penetration of the central nervous system. Cell enlargement was stimulated by coinfection with strains of opposite mating type, and ste3aΔ pheromone receptor mutant strains had reduced cell enlargement. Finally, analysis of DNA content in this novel cell type revealed that these enlarged cells were polyploid, uninucleate, and produced daughter cells in vivo. These results describe a novel mechanism by which C. neoformans evades host phagocytosis to allow survival of a subset of the population at early stages of infection. Thus, morphological changes play unique and specialized roles during infection. PMID:20585559
Meningococcal Disease (Bacterial Meningitis) Vaccine In every pregnancy, a woman starts out with a 3-5% chance of having a baby with a ... advice from your health care provider. What is meningitis? Meningitis is an infection of the lining around ...
Pond, Eric DR; El-Bailey, Sameh; Webster, Duncan
Pasteurella multocida is a rare cause of bacterial meningitis. A 56-year-old man with several pets developed a profoundly decreased level of consciousness following left tympanomastoidectomy. Lumbar puncture produced cerebrospinal fluid with the typical findings of meningitis (low glucose, high protein, high leukocytes). Cultures from the cerebrospinal fluid and a swab of the left ear revealed Gram-negative coccobacillus identified as P multocida. The organism was sensitive to ceftriaxone, ampicillin and penicillin, and a 14-day course of intravenous penicillin was used as definitive treatment, resulting in full recovery. Although rare, P multocida should be considered as a potential cause of meningitis in patients with animal exposure, particularly in the setting of recent cranial surgery. PMID:26236360
Pond, Eric Dr; El-Bailey, Sameh; Webster, Duncan
Pasteurella multocida is a rare cause of bacterial meningitis. A 56-year-old man with several pets developed a profoundly decreased level of consciousness following left tympanomastoidectomy. Lumbar puncture produced cerebrospinal fluid with the typical findings of meningitis (low glucose, high protein, high leukocytes). Cultures from the cerebrospinal fluid and a swab of the left ear revealed Gram-negative coccobacillus identified as P multocida. The organism was sensitive to ceftriaxone, ampicillin and penicillin, and a 14-day course of intravenous penicillin was used as definitive treatment, resulting in full recovery. Although rare, P multocida should be considered as a potential cause of meningitis in patients with animal exposure, particularly in the setting of recent cranial surgery.
Lamers, Susanna L.; Gray, Rebecca R.; Salemi, Marco; Huysentruyt, Leanne C.; McGrath, Michael
Brain infection by the human immunodeficiency virus type 1 (HIV-1) has been investigated in many reports with a variety of conclusions concerning the time of entry and degree of viral compartmentalization. To address these diverse findings, we sequenced HIV-1 gp120 clones from a wide range of brain, peripheral and meningeal tissues from five patients who died from several HIV-1 associated disease pathologies. High-resolution phylogenetic analysis confirmed previous studies that showed a significant degree of compartmentalization in brain and peripheral tissue subpopulations. Some intermixing between the HIV-1 subpopulations was evident, especially in patients that died from pathologies other than HIV-associated dementia. Interestingly, the major tissue harboring virus from both the brain and peripheral tissues was the meninges. These results show that 1) HIV-1 is clearly capable of migrating out of the brain, 2) the meninges are the most likely primary transport tissues, and 3) infected brain macrophages comprise an important HIV reservoir during highly active antiretroviral therapy. PMID:21055482
Mulder, C J; Zanen, H C
Bacteriological and clinical data on 68 children with neonatal group B streptococcal meningitis were analysed as part of a wider study of bacterial meningitis undertaken between 1976 and 1982. Twenty five per cent of patients died and there was no difference in the mortality rate between early and late onset disease. Sixteen per cent of the infants weighed less than 2500 g at birth but in 50% no predisposing aetiological factor was found. Streptococcus agalactiae type III was isolated in 57% of the patients. PMID:6375583
Luthe, Sarah Kyuragi; Sato, Ryota; Maeda, Tetsuro; Takahashi, Kuniko
Listeria monocytogenes is a well-known cause of meningitis in immunocompromised patients. This organism has a growing significance for community-acquired meningitis, which should have ampicillin added to the usual regimen. We describe a case of L. monocytogenes meningitis preceded by cholangitis. This case suggests gastrointestinal symptoms preceding meningitis may be a clue of listeriosis. It is important for physicians to consider L. monocytogenes as a cause of bacterial meningitis in patients with altered mental status preceded by gastrointestinal symptoms, especially in the immunocompromised population.
Decloedt, Eric H.; Freeman, Carla; Howells, Fleur; Casson-Crook, Martine; Lesosky, Maia; Koutsilieri, Eleni; Lovestone, Simon; Maartens, Gary; Joska, John A.
Abstract Background: HIV-associated neurocognitive disorder (HAND) remains highly prevalent despite effective anti-retroviral therapy (ART). A number of adjunctive pharmacotherapies for HAND have been studied with disappointing results, but preliminary data suggest that lithium may provide clinical benefit. In addition, the low cost of lithium would facilitate access in low- and middle-income countries which carry the greatest burden of HIV. Methods: Our objective was to evaluate the 24-week efficacy and safety of lithium in patients with moderate to severe HAND. Our primary efficacy endpoint was the change in Global Deficit Score (GDS) from baseline to 24 weeks, whereas our secondary endpoint was the change in proton magnetic resonance spectroscopy (1H-MRS) brain metabolite concentrations. We conducted a 24-week randomized placebo-controlled trial of lithium as adjunctive pharmacotherapy. We enrolled participants with moderate to severe HAND, on ART for at least 6 months, with suppressed viral loads and attending public sector primary care clinics in Cape Town, South Africa. We randomized 66 participants to lithium (n = 32) or placebo (n = 34). Lithium or placebo was dosed 12-hourly and titrated to achieve the maintenance target plasma concentration of 0.6 to 1.0 mmol/L. Sham lithium concentrations were generated for participants receiving placebo. Results: Totally 61 participants completed the study (lithium arm = 30; placebo arm = 31). Participants at enrolment had a mean age of 40 years and a median CD4+ T-cell count of 500 cells/μL. The median change in GDS between baseline and week 24 for the lithium and placebo arms were –0.57 (95% confidence interval [CI] –0.77, –0.32) and –0.56 (–0.69, –0.34) respectively, with a mean difference of –0.054 (95% CI –0.26, 0.15); P = 0.716. The improvement remained similar when analyzed according to age, severity of impairment, CD4+ count, time on ART, and ART regimen. Standard 1H
Holzinger, Emily R.; Hulgan, Todd; Ellis, Ronald J.; Samuels, David C.; Ritchie, Marylyn D.; Haas, David W.; Kallianpur, Asha R.; Bloss, Cinnamon S.; Clifford, David B.; Collier, Ann C.; Gelman, Benjamin B.; Marra, Christina M.; McArthur, Justin C.; McCutchan, J. Allen; Morgello, Susan; Simpson, David M.; Franklin, Donald R.; Rosario, Debralee; Selph, Doug; Letendre, Scott; Grant, Igor
HIV-associated sensory neuropathy remains an important complication of combination antiretroviral therapy (CART) and HIV infection. Mitochondrial DNA haplogroups and single nucleotide polymorphisms (SNPs) have previously been associated with symptomatic neuropathy in clinical trial participants. We examined associations between mitochondrial DNA variation and HIV-associated sensory neuropathy in CHARTER. CHARTER is a U.S. based longitudinal observational study of HIV-infected adults who underwent a structured interview and standardized examination. HIV-associated sensory neuropathy was determined by trained examiners as ≥1 sign (diminished vibratory and sharp-dull discrimination or ankle reflexes) bilaterally. Mitochondrial DNA sequencing was performed and haplogroups were assigned by published algorithms. Multivariable logistic regression of associations between mitochondrial DNA SNPs, haplogroups and HIV-associated sensory neuropathy were performed. In analyses of associations of each mitochondrial DNA SNP with HIV-associated sensory neuropathy, the two most significant SNPs were at positions A12810G (odds ratio [95% confidence interval] = 0.27 [0.11-0.65]; p = 0.004) and T489C (odds ratio [95% confidence interval] = 0.41 [0.21-0.80]; p = 0.009). These synonymous changes are known to define African haplogroup L1c and European haplogroup J, respectively. Both haplogroups are associated with decreased prevalence of HIV-associated sensory neuropathy compared with all other haplogroups (odds ratio [95% confidence interval] = 0.29 [0.12-0.71]; p = 0.007 and odds ratio [95% confidence interval] = 0.42 [0.18-1.0]; p = 0.05, respectively). In conclusion, in this cohort of mostly combination antiretroviral therapy-treated subjects, two common mitochondrial DNA SNPs and their corresponding haplogroups were associated with a markedly decreased prevalence of HIV-associated sensory neuropathy. PMID:23073667
Holzinger, Emily R; Hulgan, Todd; Ellis, Ronald J; Samuels, David C; Ritchie, Marylyn D; Haas, David W; Kallianpur, Asha R; Bloss, Cinnamon S; Clifford, David B; Collier, Ann C; Gelman, Benjamin B; Marra, Christina M; McArthur, Justin C; McCutchan, J Allen; Morgello, Susan; Simpson, David M; Franklin, Donald R; Rosario, Debralee; Selph, Doug; Letendre, Scott; Grant, Igor
HIV-associated sensory neuropathy remains an important complication of combination antiretroviral therapy and HIV infection. Mitochondrial DNA haplogroups and single nucleotide polymorphisms (SNPs) have previously been associated with symptomatic neuropathy in clinical trial participants. We examined associations between mitochondrial DNA variation and HIV-associated sensory neuropathy in CNS HIV Antiretroviral Therapy Effects Research (CHARTER). CHARTER is a USA-based longitudinal observational study of HIV-infected adults who underwent a structured interview and standardized examination. HIV-associated sensory neuropathy was determined by trained examiners as ≥1 sign (diminished vibratory and sharp-dull discrimination or ankle reflexes) bilaterally. Mitochondrial DNA sequencing was performed and haplogroups were assigned by published algorithms. Multivariable logistic regression of associations between mitochondrial DNA SNPs, haplogroups, and HIV-associated sensory neuropathy were performed. In analyses of associations of each mitochondrial DNA SNP with HIV-associated sensory neuropathy, the two most significant SNPs were at positions A12810G [odds ratio (95 % confidence interval) = 0.27 (0.11-0.65); p = 0.004] and T489C [odds ratio (95 % confidence interval) = 0.41 (0.21-0.80); p = 0.009]. These synonymous changes are known to define African haplogroup L1c and European haplogroup J, respectively. Both haplogroups were associated with decreased prevalence of HIV-associated sensory neuropathy compared with all other haplogroups [odds ratio (95 % confidence interval) = 0.29 (0.12-0.71); p = 0.007 and odds ratio (95 % confidence interval) = 0.42 (0.18-1.0); p = 0.05, respectively]. In conclusion, in this cohort of mostly combination antiretroviral therapy-treated subjects, two common mitochondrial DNA SNPs and their corresponding haplogroups were associated with a markedly decreased prevalence of HIV-associated sensory neuropathy.
Marí, José María Navarro; Ruiz, Mercedes Pérez; Anza, Diego Vicente
Lymphocytic meningitis, mainly those with an acute and benign course, are caused by viruses. In our area, the most commonly involved agents are enteroviruses, herpes simplex, varicella zoster and Toscana viruses. Nucleic acids amplification techniques (NAAT) are the methods of choice to diagnose viral meningitis from cerebrospinal fluid (CSF) samples. They are more rapid and sensitive, and indeed, they are not influenced by the viability of the virus in the clinical specimen as traditional methods are. The development of commercial equipments, the degree of automation, and the use of real-time polymerase chain reaction (PCR) systems are the most important premises to choose the molecular method in each laboratory. Recently, commercial kits of real-time PCR are available for the detection of enteroviruses and herpesviruses, which are the most frequently viruses involved in meningitis. Although NAAT from the clinical sample have replaced cell culture for diagnostic purposes, the combination of both methods remain useful. When the detection of the causal agent from the CSF sample is not possible, other specimens (pharyngeal exudates, stools) or serological methods can be used. Serology is the reference method for meningitis caused by West Nile virus and lymphocytic choriomeningitis virus, which are less frequently detected in our area.
Rosso, Marisa; Rojas, Pilar; Garcia, Elisa; Marquez, Javier; Losada, Antonio; Muñoz, Miguel
Kluyvera is described infrequently in association with clinically significant infections in humans. It can produce a wide range of clinically significant manifestations. We describe a newborn with ventriculoperitoneal shunt, who was successfully treated for Kluyvera meningitis. We believe that this is the first case of Kluyvera central nervous system infection reported in a child.
Miller, Michael A; Menowsky, Michael; Leeson, Kimberly; Leeson, Ben
We report a case of a 22-year-old man who presented to the emergency department (ED) with altered mental status and was diagnosed with eosinophilic meningitis due to Angiostrongylus cantonensis (AC) acquired in the United States after exposure to snails.
Wilson, Deborah A; Sholtis, Mary; Parshall, Sharon; Hall, Gerri S; Procop, Gary W
A total of 52 residual CSF and serum specimens, which were originally negative with the Cryptococcal Antigen Latex Agglutination System (CALAS), were shown to become falsely positive after placement in BBL Port-A-Cul anaerobic transport vials. This transport device, although excellent for specimen transportation for subsequent culture, should not be used if cryptococcal antigen testing is needed.
Wilson, Deborah A.; Sholtis, Mary; Parshall, Sharon; Hall, Gerri S.; Procop, Gary W.
A total of 52 residual CSF and serum specimens, which were originally negative with the Cryptococcal Antigen Latex Agglutination System (CALAS), were shown to become falsely positive after placement in BBL Port-A-Cul anaerobic transport vials. This transport device, although excellent for specimen transportation for subsequent culture, should not be used if cryptococcal antigen testing is needed. PMID:21159939
Proia, Laurie A.; Demarais, Patricia L.
Cryptococcus is a unique environmental fungus that can cause disease most often in immunocompromised individuals with defective cell-mediated immunity. Chronic lymphocytic leukemia (CLL) is not known to be a risk factor for cryptococcal disease although cases have been described mainly in patients treated with agents that suppress cell-mediated immunity. Ibrutinib is a new biologic agent used for treatment of CLL, mantle cell lymphoma, and Waldenstrom's macroglobulinemia. It acts by inhibiting Bruton's tyrosine kinase, a kinase downstream of the B-cell receptor critical for B-cell survival and proliferation. Ibrutinib use has not been associated previously with cryptococcal disease. However, recent evidence suggested that treatments aimed at blocking the function of Bruton's tyrosine kinase could pose a higher risk for cryptococcal infection in a mice model. Here, we report the first case of disseminated cryptococcal disease in a patient with CLL treated with ibrutinib. When evaluating possible infection in CLL patients receiving ibrutinib, cryptococcal disease, which could be life threatening if overlooked, could be considered. PMID:27703818
Wyatt, Christina M.; Klotman, Paul E.; D’Agati, Vivette D.
The classic kidney disease of Human Immunodeficiency Virus (HIV) infection, HIV-associated nephropathy, is characterized by progressive acute renal failure, often accompanied by proteinuria and ultrasound findings of enlarged, echogenic kidneys. Definitive diagnosis requires kidney biopsy, which demonstrates collapsing focal segmental glomerulosclerosis with associated microcystic tubular dilatation and interstitial inflammation. Podocyte proliferation is a hallmark of HIV-associated nephropathy, although this classic pathology is observed less frequently in antiretroviral-treated patients. The pathogenesis of HIV-associated nephropathy involves direct HIV infection of renal epithelial cells, and the widespread introduction of combination antiretroviral therapy has had a significant impact on the natural history and epidemiology of this unique disease. These observations have established antiretroviral therapy as the cornerstone of treatment for HIV-associated nephropathy, in the absence of prospective clinical trials. Adjunctive therapy for HIV-associated nephropathy includes ACE inhibitors or angiotensin receptor blockers, as well as corticosteroids in selected patients with significant interstitial inflammation or rapid progression. PMID:19013322
Parkhomenko, Iu G; Ziuzia, Iu R
If a patient dies from HIV-associated disease, after the heading "Underlying disease" the postmortem diagnosis should contain the heading "Secondary diseases" wherein HIV-associated infection is given with the form, site, extent, and activity of the process being indicated. While comparing clinical and postmortem diagnoses in HIV infection, the discrepancy should be specified in view of a secondary disease. If there are a few HIV-associated infections, they all are indicated in the heading "Secondary diseases", one of them, the complications of which are of crucial importance in tanatogenesis, is better chosen to be encoded in the medical death certificate. In some situations, HIV infection can be mixed, competitive, background, or concomitant regardless of its stage.
Human immunodeficiency virus (HIV)-associated lipodystrophy refers to fat accumulation, also known as lipohypertrophy, and fat wasting, also known as lipoatrophy. Both conditions can be very disturbing to patients and have been associated with metabolic disturbances such as insulin resistance and hyperlipidemias. The prevalence of HIV-associated lipodystrophy ranges from 6% to 69% in the medical literature. Although no clear associations have been made between specific drugs and HIV lipohypertrophy, stavudine and zidovudine have been implicated in the development of HIV lipoatrophy. The case of Mr B, a 39-year-old man with HIV-associated lipodystrophy whose facial changes are a cause of significant distress, highlights the need for clinicians to be attuned to the psychological impact that lipodystrophy can have on patients, especially because it may serve as a disincentive to adherence to antiretroviral drug regimens, resulting in an increased risk of developing viral resistance.
Siddiqui, Tahseen J; Zamani, Tanveer; Parada, Jorge P
The prostate gland is a rare site of primary infection due to Cryptococcus neoformans; however, it may serve as a site of its sequestration after an occult or treated disseminated infection. Serum prostate specific antigen may correlate with the severity of prostatic inflammation, but its role as a diagnostic and prognostic marker is unclear. We report the first case of primary cryptococcal prostatitis in a renal transplant recipient. The diagnosis was established based on asymmetrically enlarged prostate gland, markedly elevated serum PSA levels, cryptococcal fungemia, an ultrasound-guided prostatic biopsy that demonstrated cryptococcal fungal elements and growth of C. neoformans on culture. The patient was successfully treated with a prolonged course of fluconazole and remained disease-free for more than 28 months of follow-up. In addition, we present a review of the published literature since 1946 and discuss possible correlation with PSA levels.
Ndimbie, O K; Dekker, A; Martinez, A J; Dixon, B
We report a case of a patient with acquired immune deficiency syndrome who was successfully treated for cryptococcal meningoencephalitis with amphotericin B and 5-flucytosine. He died from other sequelae of acquired immune deficiency syndrome two years later. An autopsy revealed prominent cryptococcal prostatitis. Cryptococci were neither found in the central nervous system nor in other anatomic sites. The autopsy files yielded seven other cases of men with a history of cryptococcal meningoencephalitis. The possibility that the prostate sequesters Cryptococcus neoformans thereby contributing to systemic relapse is explored. The qualify as a sequestration, cyptococci must be cultured from the prostate, or from a midstream voided specimen after prostatic massage, and the prostate must be the only focus of infection.
Li, Zheng; Liang, Jinqian; Shen, Jianxiong; Qiu, Guixing; Weng, Xisheng
Cryptococcus neoformans causes opportunistic infections in immunocompromised patients, with vertebral osteomyelitis being a very rare involvement.This study is to present a case of thoracolumbar scoliosis occurring in the setting of cryptococcal osteomyelitis.Pharmacological intervention with anticryptococcal medicine and medical management of immune hemolytic anemia were administered. After initial acute stabilization, she underwent spinal debridement and fusion on October 29, 2008. She eventually recovered fully from this episode with no subsequent mechanical instability or neurological deficits on subsequent clinic follow-ups.To the best of our knowledge, there have been no reports describing the onset of spinal cryptococcal osteomyelitis along with immune hemolytic anemia. We suggest a comprehensive algorithm for the diagnosis of vertebral cryptococcal osteomyelitis.
Kasembeli, Alex N.; Duarte, Raquel; Ramsay, Michèle; Mosiane, Pulane; Dickens, Caroline; Dix-Peek, Thérèse; Limou, Sophie; Sezgin, Efe; Nelson, George W.; Fogo, Agnes B.; Goetsch, Stewart; Kopp, Jeffrey B.
APOL1 variants are associated with HIV-associated nephropathy and FSGS in African Americans. The prevalence of these variants in African populations with CKD in HIV-1 infection has not been investigated. We determined the role of APOL1 variants in 120 patients with HIV-associated nephropathy and CKD and 108 controls from a South-African black population. Patients with CKD were selected on the basis of histology. Genotypes were successfully determined for APOL1 G1 and G2 variants and 42 single nucleotide polymorphisms, including 18 ancestry informative markers, for 116 patients with CKD (96.7%; 38 patients with HIV-associated nephropathy, 39 patients with HIV-positive CKD, and 39 patients with HIV-negative CKD), and 108 controls (100%). Overall, 79% of patients with HIV-associated nephropathy and 2% of population controls carried two risk alleles. In a recessive model, individuals carrying any combination of two APOL1 risk alleles had 89-fold higher odds (95% confidence interval, 18 to 912; P<0.001) of developing HIV-associated nephropathy compared with HIV-positive controls. Population allele frequencies were 7.3% for G1 and 11.1% for G2. APOL1 risk alleles were not significantly associated with other forms of CKD. These results indicate HIV-positive, antiretroviral therapy–naïve South-African blacks with two APOL1 risk alleles are at very high risk for developing HIV-associated nephropathy. Further studies are required to determine the effect of APOL1 risk variants on kidney diseases in other regions of sub-Saharan Africa. PMID:25788523
Prasad, Kameshwar; Singh, Mamta B; Ryan, Hannah
Background Tuberculous meningitis is a serious form of tuberculosis (TB) that affects the meninges that cover a person's brain and spinal cord. It is associated with high death rates and with disability in people who survive. Corticosteroids have been used as an adjunct to antituberculous drugs to treat people with tuberculous meningitis, but their role has been controversial. Objectives To evaluate the effects of corticosteroids as an adjunct to antituberculous treatment on death and severe disability in people with tuberculous meningitis. Search methods We searched the Cochrane Infectious Diseases Group Specialized Register up to the 18 March 2016; CENTRAL; MEDLINE; EMBASE; LILACS; and Current Controlled Trials. We also contacted researchers and organizations working in the field, and checked reference lists. Selection criteria Randomized controlled trials that compared corticosteroid plus antituberculous treatment with antituberculous treatment alone in people with clinically diagnosed tuberculous meningitis and included death or disability as outcome measures. Data collection and analysis We independently assessed search results and methodological quality, and extracted data from the included trials. We analysed the data using risk ratios (RR) with 95% confidence intervals (CIs) and used a fixed-effect model. We performed an intention-to-treat analysis, where we included all participants randomized to treatment in the denominator. This analysis assumes that all participants who were lost to follow-up have good outcomes. We carried out a sensitivity analysis to explore the impact of the missing data. Main results Nine trials that included 1337 participants (with 469 deaths) met the inclusion criteria. At follow-up from three to 18 months, steroids reduce deaths by almost one quarter (RR 0.75, 95% CI 0.65 to 0.87; nine trials, 1337 participants, high quality evidence). Disabling neurological deficit is not common in survivors, and steroids may have little or no
Liaw, Y S; Yang, P C; Yu, C J; Chang, D B; Wang, H J; Lee, L N; Kuo, S H; Luh, K T
Pulmonary cryptococcosis causes significant morbidity and mortality in immunocompromised patients. Definitive diagnosis of pulmonary cryptococcosis is usually difficult. The use of direct determination of cryptococcal antigen in transthoracic needle aspirate to diagnose pulmonary cryptococcosis was investigated. Over a 2-year period, we studied a total of 41 patients with respiratory symptoms and pulmonary infiltrates of unknown etiology who were suspected of having pulmonary cryptococcosis. Twenty-two patients were immunocompetent patients and 19 patients were immunocompromised. A diagnosis of pulmonary cryptococcosis was based on cytological examination, culture for Cryptococcus neoformans, histopathologic examination, and clinical response to antifungal therapy. All patients underwent chest ultrasound and ultrasound-guided percutaneous transthoracic needle aspiration to obtain specimens for cryptococcal antigen determination. The presence of cryptococcal antigen was determined by the latex agglutination system (CALAS; Meridian Diagnostics, Cincinnati, Ohio). An antigen titer equal to or greater than 1:8 was considered positive. The specimens were also sent for cytological examination, fungal culture, and/or histopathologic examination. A final diagnosis of pulmonary cryptococcosis was made in eight patients. Direct determinations of cryptococcal antigen in lung aspirate were positive in all eight patients with pulmonary cryptococcosis (100% sensitivity, 97% specificity, a positive predictive value of 89%, and negative value of 100%), and there was only one false-positive in noncryptococcosis patients. The diagnostic accuracy was 97.5%. Serum cryptococcal antigen was positive in only three patients with pulmonary cryptococcosis (sensitivity, 37.5%). This study showed that direct measurement of cryptococcal antigen in lung aspirate can be a rapid and useful test for diagnosis of pulmonary cryptococcosis.
Liaw, Y S; Yang, P C; Yu, C J; Chang, D B; Wang, H J; Lee, L N; Kuo, S H; Luh, K T
Pulmonary cryptococcosis causes significant morbidity and mortality in immunocompromised patients. Definitive diagnosis of pulmonary cryptococcosis is usually difficult. The use of direct determination of cryptococcal antigen in transthoracic needle aspirate to diagnose pulmonary cryptococcosis was investigated. Over a 2-year period, we studied a total of 41 patients with respiratory symptoms and pulmonary infiltrates of unknown etiology who were suspected of having pulmonary cryptococcosis. Twenty-two patients were immunocompetent patients and 19 patients were immunocompromised. A diagnosis of pulmonary cryptococcosis was based on cytological examination, culture for Cryptococcus neoformans, histopathologic examination, and clinical response to antifungal therapy. All patients underwent chest ultrasound and ultrasound-guided percutaneous transthoracic needle aspiration to obtain specimens for cryptococcal antigen determination. The presence of cryptococcal antigen was determined by the latex agglutination system (CALAS; Meridian Diagnostics, Cincinnati, Ohio). An antigen titer equal to or greater than 1:8 was considered positive. The specimens were also sent for cytological examination, fungal culture, and/or histopathologic examination. A final diagnosis of pulmonary cryptococcosis was made in eight patients. Direct determinations of cryptococcal antigen in lung aspirate were positive in all eight patients with pulmonary cryptococcosis (100% sensitivity, 97% specificity, a positive predictive value of 89%, and negative value of 100%), and there was only one false-positive in noncryptococcosis patients. The diagnostic accuracy was 97.5%. Serum cryptococcal antigen was positive in only three patients with pulmonary cryptococcosis (sensitivity, 37.5%). This study showed that direct measurement of cryptococcal antigen in lung aspirate can be a rapid and useful test for diagnosis of pulmonary cryptococcosis. PMID:7650192
Imai, Kazuo; Misawa, Kazuhisa; Matsumura, Takahiro; Fujikura, Yuji; Mikita, Kei; Tokoro, Masaharu; Maeda, Takuya; Kawana, Akihiko
We herein describe a case of progressive human immunodeficiency virus (HIV)-associated cholangiopathy despite normalization of laboratory parameters, which had indicated liver dysfunction, after the initiation of combined anti-retroviral therapy (cART). HIV-associated cholangiopathy remains important as a differential diagnosis of bile duct disorders, although it is considered to be a rare disease in the era of cART. Magnetic resonance cholangiopancreatography could thus be a powerful tool for the diagnosis and follow-up of this disease. PMID:27725553
Humphreys, R. P.
A variety of associated lesions may require the neurosurgeon's assistance in the management of bacterial meningitis. As treatment of this infection of the central nervous system proceeds, the surgeon will have to decide about the concurrent or subsequent operative treatment of congenital dysraphic states, paraneural infections, compound fractures or penetrating wounds of thecranium or spine, or infected bypass shunts for cerebrospinal fluid (CSF). In patients with intractable meningitic infections the surgeon may have to insert a ventricular drainage-irrigation system to permit adequate perfusion of the CSF pathways with antibiotic. Hydrocephalus or subdural effusions complicating meningitis may bring the patient to the surgeon long after the infection has been cured. This paper examines these problems and outlines the current principles of management. Images FIG. 1 FIG. 2 PMID:1098760
Elenga, N; Sicard, S; Cuadro-Alvarez, E; Long, L; Njuieyon, F; Martin, E; Kom-Tchameni, R; Balcaen, J; Moreau, B; Boukhari, R
Controlling vaccine-preventable infectious diseases is a public health priority in French Guiana but there is currently no epidemiological data on pediatric bacterial meningitis in this overseas department. Our aim was to describe data related to pediatric bacterial meningitis in French Guiana and compare it with that of metropolitan France. We conducted a multicenter retrospective study from 2000 to 2010 to describe the clinical picture, biological data, epidemiology, and outcome of pediatric bacterial meningitis case patients in French Guiana. The median age of bacterial meningitis patients was 6months [0-15] and the sex ratio 1.06. We observed a total of 60 bacterial meningitis case patients. Most presented with pneumococcal meningitis (24 patients; 40%); 11 with Haemophilus influenzae type b meningitis (23%), five with group B streptococcal meningitis (8.5%), and five others (8.5%) with staphylococcal meningitis (three patients presented with coagulase-negative staphylococci and two with Staphylococcus aureus). Only one patient presented with group B meningococcal meningitis, an 18-month-old infant. We recorded 14 deaths (overall case fatality: 23%); eight were due to Streptococcus pneumoniae (case fatality: 33%). The overall sequelae rate was 28%. It was 32% for patients presenting with pneumococcal meningitis. We observed that 38% of children who had never been vaccinated were infected by a vaccine-preventable bacterium. We observed many differences in the distribution of the bacteria and in the patients' prognosis when comparing the French Guiana data with that of metropolitan France. Improving vaccination coverage would decrease the incidence of H. influenzae meningitis. Copyright © 2015 Elsevier Masson SAS. All rights reserved.
Husain, Entesar H; Al-Shawaf, Faisal; Bahbahani, Esmaeel; El-Nabi, Mamdooh Hasab; Al-Fotooh, Kamal Abo; Shafiq, Magdi Hilmi; Al-Ateeqi, Nahid; Abo Talib, Mohamed Atef
Haemophilus influenzae type b (Hib) conjugate vaccine was introduced as part of childhood routine immunization in Kuwait in 1996. The aim of this study is to describe the epidemiological, microbiological, and clinical features of meningitis among children in Kuwait from 2001 to 2003. A multicenter retrospective review of clinical records of otherwise healthy children hospitalized with a diagnosis of meningitis. A total of 172 children had a diagnosis of meningitis and had lumbar puncture during the study period. The median age was 8 months. The majority (67%) of the patients were less than 5 yeas of age. Eighty-six (50%) of the patients had aseptic meningitis and 19 (11%) had partially treated meningitis. The remaining 67 (39%) were diagnosed with bacterial meningitis. The underlying organisms were: Neisseria meningitidis (49%), group B streptococci (18%), Streptococcus pneumoniae (18%), Mycobacterium tuberculosis (6%), Gram-negative organisms (6%), and Haemophilus species (1.5%). Twelve percent required admission to the intensive care unit. At the time of discharge from the hospital, 9% had neurological sequelae, the majority of which were in patients who had S. pneumoniae meningitis. Two patients died during the study period. N. meningitidis is the leading bacterial agent of bacterial meningitis in Kuwait. S. pneumoniae is responsible for the majority of neurological sequelae of bacterial meningitis in infants and young children. The results of this study can be used in future public health planning in the context of the newly available vaccines.
Maurya, Pradeep Kumar; Singh, Ajai Kumar; Sharma, Lalit; Kulshreshtha, Dinkar; Thacker, Anup Kumar
Ophthalmological complications are common and disabling in patients with tuberculous meningitis. We aimed to study the visual pathway abnormalities in patients with tuberculous meningitis. Forty-three patients with tuberculous meningitis were subjected to visual evoked responses (VER) and neuroophthalmologic assessment. Neuroophthalmologic assessment revealed abnormalities in 22 (51.3%) patients. VER were found to be abnormal in 27 (62.8%) patients. The VER abnormalities included prolonged P100 latencies with relatively normal amplitude and significant interocular latency differences. Visual pathways abnormalities are common in patients with tuberculous meningitis and are often subclinical. Pathophysiologic explanations for electrophysiological abnormalities on VER in these patients are incompletely understood and needs further exploration.
Nakamura, Takashi; Okumura, Hiroyuki; Tachibana, Naoko; Hamano, Toshiaki
We report a 65-year-old man who had repetitive seizures 6 months after receiving etanercept, methotrexate, and prednisolone for rheumatoid arthritis. Mononuclear cells were mildly increased in the cerebrospinal fluid (CSF). Brain magnetic resonance imaging (MRI) showed high intensity along sulci of the frontal and parietal lobes. Brain biopsy revealed lymphocyte and plasma cell infiltration in the meninges, confirming the diagnosis of rheumatoid meningitis. After steroid pulse therapy, seizures resolved and clinical findings improved. When etanercept was replaced by tocilizumab, rheumatoid meningitis did not recur. Although TNF-α inhibitors can control joint symptoms of rheumatoid arthritis, they may induce rheumatoid meningitis. PMID:28286682
Yang, Ence; Wang, Linqi; Cai, James J.; Lin, Xiaorong
In the fungal pathogen Cryptococcus neoformans, the switch from yeast to hypha is an important morphological process preceding the meiotic events during sexual development. Morphotype is also known to be associated with cryptococcal virulence potential. Previous studies identified the regulator Znf2 as a key decision maker for hypha formation and as an anti-virulence factor. By a forward genetic screen, we discovered that a long non-coding RNA (lncRNA) RZE1 functions upstream of ZNF2 in regulating yeast-to-hypha transition. We demonstrate that RZE1 functions primarily in cis and less effectively in trans. Interestingly, RZE1’s function is restricted to its native nucleus. Accordingly, RZE1 does not appear to directly affect Znf2 translation or the subcellular localization of Znf2 protein. Transcriptome analysis indicates that the loss of RZE1 reduces the transcript level of ZNF2 and Znf2’s prominent downstream targets. In addition, microscopic examination using single molecule fluorescent in situ hybridization (smFISH) indicates that the loss of RZE1 increases the ratio of ZNF2 transcripts in the nucleus versus those in the cytoplasm. Taken together, this lncRNA controls Cryptococcus yeast-to-hypha transition through regulating the key morphogenesis regulator Znf2. This is the first functional characterization of a lncRNA in a human fungal pathogen. Given the potential large number of lncRNAs in the genomes of Cryptococcus and other fungal pathogens, the findings implicate lncRNAs as an additional layer of genetic regulation during fungal development that may well contribute to the complexity in these “simple” eukaryotes. PMID:26588844
Zainal, A I; Wong, S L; Pan, K L; Wong, O L; Tzar, M N
Fungal osteomyelitis is a rare opportunistic infection. It exhibits some clinical and radiological similarities to several other bone pathologies. A diagnostic delay may result in significant increase in morbidity. We report a case of a 37-year-old man with underlying hypogammaglobulinaemia presented with isolated cryptococcal osteomyelitis of the femur.
Jitmuang, Anupop; Panackal, Anil A; Williamson, Peter R; Bennett, John E; Dekker, John P; Zelazny, Adrian M
The cryptococcal antigen lateral flow assay (CrAg LFA) was evaluated for the diagnosis of cryptococcosis in HIV-negative patients. The sensitivity was excellent, suggesting that this assay can replace conventional testing based on latex agglutination (LA). CrAg LFA and LA titers were correlated but were not directly comparable, with implications for conversion between assays.
Najvar, Laura K.; Bocanegra, Rosie; Kirkpatrick, William R.; Sorrell, Tania C.; Patterson, Thomas F.
Miltefosine is an alkyl phosphocholine with good oral bioavailability and in vitro activity against Cryptococcus species that has gained interest as an additional agent for cryptococcal infections. Our objective was to further evaluate the in vivo efficacy of miltefosine in experimental in vivo models of cryptococcal meningoencephalitis and disseminated cryptococcosis. Mice were infected intracranially or intravenously with either C. neoformans USC1597 or H99. Miltefosine treatment (1.8 to 45 mg/kg of body weight orally once daily) began at either 1 h or 1 day postinoculation. Fluconazole (10 mg/kg orally twice daily) or amphotericin B deoxycholate (3 mg/kg intraperitoneally once daily) served as positive controls. In our standard models, miltefosine did not result in significant improvements in survival or reductions in fungal burden against either C. neoformans isolate. There was a trend toward improved survival with miltefosine at 7.2 mg/kg against disseminated cryptococcosis with the H99 strain but only at a low infecting inoculum. In contrast, both fluconazole and amphotericin B significantly improved survival in mice with cryptococcal meningoencephalitis and disseminated cryptococcosis due to USC1597. Amphotericin B also improved survival against both cryptococcal infections caused by H99. Combination therapy with miltefosine demonstrated neither synergy nor antagonism in both models. These results demonstrate limited efficacy of miltefosine and suggest caution with the potential use of this agent for the treatment of C. neoformans infections. PMID:23165465
Jitmuang, Anupop; Panackal, Anil A.; Williamson, Peter R.; Bennett, John E.; Dekker, John P.
The cryptococcal antigen lateral flow assay (CrAg LFA) was evaluated for the diagnosis of cryptococcosis in HIV-negative patients. The sensitivity was excellent, suggesting that this assay can replace conventional testing based on latex agglutination (LA). CrAg LFA and LA titers were correlated but were not directly comparable, with implications for conversion between assays. PMID:26607986
Singh, Nina; Alexander, Barbara D.; Lortholary, Olivier; Dromer, Françoise; Gupta, Krishan L.; John, George T.; del Busto, Ramon; Klintmalm, Goran B.; Somani, Jyoti; Lyon, G. Marshall; Pursell, Kenneth; Stosor, Valentina; Muňoz, Patricia; Limaye, Ajit P.; Kalil, Andre C.; Pruett, Timothy L.; Garcia-Diaz, Julia; Humar, Atul; Houston, Sally; House, Andrew A.; Wray, Dannah; Orloff, Susan; Dowdy, Lorraine A.; Fisher, Robert A.; Heitman, Joseph; Wagener, Marilyn M.; Husain, Shahid
Background Role of serum cryptococcal antigen in the diagnosis and determinants of antigen positivity in solid organ transplant (SOT) recipients with pulmonary cryptococcosis has not been fully defined. Methods Study population included SOT recipients with pulmonary cryptococcosis in a prospective, multicenter study conducted between 1999 and 2006. Results Cryptococcal antigen was positive in 83% (40/48) of the patients with pulmonary cryptococcosis. Patients with concomitant extrapulmonary disease were more likely to have a positive antigen (p=0.018), and antigen titers were higher in those with extrapulmonary disease (p=0.003) or fungemia (p=0.045). Patients with single nodules were less likely to have a positive antigen than those with all other radiographic presentations (p=0.053). Among patients with isolated pulmonary cryptococcosis, lung transplant recipients were less likely to have positive cryptococcal antigen than other types of SOT recipients (p=0.003). In all, 38% of the patients were asymptomatic or had pulmonary cryptococcosis detected as an incidental finding. Nodular densities or mass lesions were more likely to present as asymptomatic or incidentally detected pulmonary cryptococcosis than pleural effusions and infiltrates (p=0.008). Conclusions A positive serum cryptococcal antigen in SOT recipients with pulmonary cryptococcosis appears to reflect extrapulmonary or more advanced radiographic disease. PMID:18171241
Letendre, Jo-Annie; Boysen, Søren
The successful management of cranial vena cava syndrome with suspected secondary chylothorax due to mediastinal cryptococcal granuloma in a 4-year-old male domestic shorthair cat is described. Treatment included long-term antifungal medication, short-term corticosteroids, intermittent thoracocentesis, rutin, octreotide, and enalapril. PMID:25829555
Lucas, Marjolein J; Brouwer, Matthijs C; van der Ende, Arie; van de Beek, Diederik
Endocarditis may precede or complicate bacterial meningitis, but the incidence and impact of endocarditis in bacterial meningitis are unknown. We assessed the incidence and clinical characteristics of patients with meningitis and endocarditis from a nationwide cohort study of adults with community-acquired bacterial meningitis in the Netherlands from 2006 to 2012. Endocarditis was identified in 24 of 1025 episodes (2%) of bacterial meningitis. Cultures yielded Streptococcus pneumoniae in 13 patients, Staphylococcus aureus in 8 patients, and Streptococcus agalactiae, Streptococcus pyogenes, and Streptococcus salivarius in 1 patient each. Clues leading to the diagnosis of endocarditis were cardiac murmurs, persistent or recurrent fever, a history of heart valve disease, and S aureus as the causative pathogen of bacterial meningitis. Treatment consisted of prolonged antibiotic therapy in all patients and surgical valve replacement in 10 patients (42%). Two patients were treated with oral anticoagulants, and both developed life-threatening intracerebral hemorrhage. Systemic (70%) and neurological (54%) complications occurred frequently, leading to a high proportion of patients with unfavorable outcome (63%). Seven of 24 patients (29%) with meningitis and endocarditis died. Endocarditis is an uncommon coexisting condition in bacterial meningitis but is associated with a high rate of unfavorable outcome.
Pai, Poulomi J; Blackburn, Brian G; Kazacos, Kevin R; Warrier, Rajasekharan P; Bégué, Rodolfo E
Infection by Baylisascaris procyonis is an uncommon but devastating cause of eosinophilic meningitis. We report the first case-patient, to our knowledge, who recovered from B. procyonis eosinophilic meningitis without any recognizable neurologic deficits. The spectrum of illness for this organism may be wider than previously recognized.
Snyder, R D; Stovring, J; Cushing, A H; Davis, L E; Hardy, T L
Forty-nine children with complicated bacterial meningitis were studied. Thirteen had abnormalities on computed tomography compatible with the diagnosis of brain infarction; one had a brain biopsy with the histological appearance of infarction. Factors exist in childhood bacterial meningitis which are associated with the development of brain infraction.
Charlier, Caroline; Dromer, Françoise; Lévêque, Christophe; Chartier, Loïc; Cordoliani, Yves-Sébastien; Fontanet, Arnaud; Launay, Odile; Lortholary, Olivier
Cryptococcal meningoencephalitis has an overall global mortality rate of 20% in AIDS patients despite antifungals. There is a need for additional means of precise assessment of disease severity. We thus studied the radiological brain images available from 62 HIV-positive patients with cryptococcocal meningoencephalitis to analyse the brain lesions associated with cryptococcosis in relationship with disease severity, and the respective diagnostic contribution of magnetic resonance (MR) versus computed tomography (CT). In this retrospective multicenter analysis, two neuroradiologists blindly reviewed the brain imaging. Prospectively acquired clinical and mycological data were available at baseline and during follow-up. Baseline images were abnormal on 92% of the MR scans contrasting with 53% of the CT scans. MR/CT cryptococcosis-related lesions included mass(es) (21%/9%), dilated perivascular spaces (46%/5%) and pseudocysts (8%/4%). The presence compared to absence of cryptococcosis-related lesions was significantly associated with high serum (78% vs. 42%, p = 0.008) and CSF (81% vs. 50%, p = 0.024) antigen titers, independently of neurological abnormalities. MR detected significantly more cryptococcosis-related lesions than CT for 17 patients who had had both investigations (76% vs. 24%, p = 0.005). In conclusion, MR appears more effective than CT for the evaluation of AIDS-associated cerebral cryptococcosis. Furthermore, brain imaging is an effective tool to assess the initial disease severity in this setting. Given this, we suggest that investigation for cryptococcosis-related lesions is merited, even in the absence of neurological abnormality, if a high fungal burden is suspected on the basis of high serum and/or CSF antigen titers. PMID:18414656
Ondounda, Magloire; Ilozue, Chinenye; Magne, Caroline
Cerebro-meningeal pathology is common in human immunodeficiency virus (HIV) infection and the aetiology is often difficult to ascertain with certainty. To describe the major suspected and identified causes of meningeal or encephalitic syndromes in HIV infection in Libreville, Gabon. A descriptive study using clinical records of patients hospitalised in the Department of Medicine in the Military Hospital of Libreville (Gabon) between January 2006 and May 2010. Clinical features were evaluated using multivariable logistic regression to evaluate association with the outcome of a clinical improvement or death. The most frequent neurological symptoms were reduced level of consciousness (54.3%), headache (55.2%), motor deficit (38.7%), and convulsions (36.2%). Cerebral toxoplasmosis represented 64.7% of diagnoses, followed by cryptococcal neuromeningitis in 12.9% of cases. Tuberculoma was diagnosed in 4 cases and lymphoma in 2 cases. In 9.5% of cases, no aetiology was determined. Toxoplasmosis treatment led to clinical improvement in 69.3% of cases with suspected cerebral toxoplasmosis. Overall mortality was 39.7%. The diagnosis of neurological conditions in HIV positive patients is difficult, particularly in a low-resource setting. A trial of treatment for toxoplasmosis should be initiated first line with all signs of neurological pathology in a patient infected with HIV.
Paradowska-Stankiewicz, Iwona; Piotrowska, Anna
The aim of this study was to assess the epidemiology of meningitis and/or encephalitis in Poland in 2014. In the last three years in Poland, about 3000 cases of meningitis and/or encephalitis of viral or bacterial etiology were recorded annually. Assessment of the epidemiological situation of meningitis and/or encephalitis in Poland in 2014, was based on the results of the analysis of epidemiological reports sent to the NIZP-PZH by the Regional Sanitary-Epidemiological Stations published in the annual bulletin “Infectious diseases and poisonings in Poland in 2014” and “Preventive immunizations in Poland in 2014”. In 2014 in Poland 3488 cases of bacterial meningitis and/or encephalitis were recorded. Almost 61.3% of these were viral infections. In 2014, in comparison to 2013, a 1.1% increase in the number of cases of meningitis and/or encephalitis was observed and 91% with viral etiology.
Paradowska-Stankiewicz, Iwona; Piotrowska, Anna
The aim of this study was to assess the epidemiology of meningitis and/or encephalitis in Poland in 2013. In the last three years in Poland, about 3000 cases of meningitis and/or encephalitis of viral or bacterial etiology were recorded annually. Assessment of the epidemiological situation of meningitis and/or encephalitis in Poland in 2013, was based on the results of the analysis of epidemiological reports sent to the NIZP-PZH by the Regional Sanitary-Epidemiological Stations published in the annual bulletin "Infectious diseases and poisonings in Poland in 2013" and "Preventive immunizations in Poland in 2013". In 2013 in Poland 3,116 cases of bacterial meningitis and/or encephalitis were recorded. Almost 50% of these were viral infections. The epidemiological situation of meningitis and/or encephalitis in Poland in 2013 compared to 2012 did not change significantly.
Osterholzer, John J; Chen, Gwo-Hsiao; Olszewski, Michal A; Zhang, Yan-Mei; Curtis, Jeffrey L; Huffnagle, Gary B; Toews, Galen B
Clearance of pulmonary infection with the fungal pathogen Cryptococcus neoformans is associated with the accumulation and activation of lung macrophages. However, the phenotype of these macrophages and the mechanisms contributing to their accumulation are not well-defined. In this study, we used an established murine model of cryptococcal lung infection and flow cytometric analysis to identify alveolar macrophages (AMs) and the recently described exudate macrophages (ExMs). Exudate macrophages are distinguished from AMs by their strong expression of CD11b and major histocompatibility complex class II and modest expression of costimulatory molecules. Exudate macrophages substantially outnumber AMs during the effector phase of the immune response; and accumulation of ExMs, but not AMs, was chemokine receptor 2 (CCR2) dependent and attributable to the recruitment and subsequent differentiation of Ly-6C(high) monocytes originating from the bone marrow and possibly the spleen. Peak ExM accumulation in wild-type (CCR2(+/+)) mice coincided with maximal lung expression of mRNA for inducible nitric oxide synthase and correlated with the known onset of cryptococcal clearance in this strain of mice. Exudate macrophages purified from infected lungs displayed a classically activated effector phenotype characterized by cryptococcal-enhanced production of inducible nitric oxide synthase and tumor necrosis factor α. Cryptococcal killing by bone marrow-derived ExMs was CCR2 independent and superior to that of AMs. We conclude that clearance of cryptococcal lung infection requires the CCR2-mediated massive accumulation of fungicidal ExMs derived from circulating Ly-6C(high) monocytes.
Haddow, Lewis J; Colebunders, Robert; Meintjes, Graeme; Lawn, Stephen D; Elliott, Julian H; Manabe, Yukari C; Bohjanen, Paul R; Sungkanuparph, Somnuek; Easterbrook, Philippa J; French, Martyn A; Boulware, David R
Cryptococcal immune reconstitution inflammatory syndrome (C-IRIS) may present as a clinical deterioration or new presentation of cryptococcal disease following initiation of antiretroviral therapy (ART) and is believed to be caused by recovery of cryptococcus-specific immune responses. We have reviewed the existing literature on C-IRIS to inform the development of a consensus case definition specific for paradoxical cryptococcal IRIS in patients with known cryptococcal disease prior to ART, and a second definition for incident cases of cryptococcosis developing during ART (here termed ART-associated cryptococcosis), a proportion of which are likely to be “unmasking” C-IRIS. These structured case definitions are intended for use in future clinical, epidemiologic and immunopathologic studies of C-IRIS, harmonizing diagnostic criteria, and facilitating comparisons between studies. As with tuberculosis-associated IRIS, these proposed definitions should be regarded as preliminary until further insights into the immunopathology of IRIS permit their refinement. PMID:21029993
Magaki, Shino; Chang, Edward; Hammond, Robert R; Yang, Isaac; Mackenzie, Ian R A; Chou, Benedict T; Choi, Soo I; Jen, Joanna C; Pope, Whitney B; Bell, David A; Vinters, Harry V
Central nervous system (CNS) involvement by rheumatoid arthritis (RA) in the form of rheumatoid meningitis (RM) is rare and most commonly occurs in the setting of longstanding severe RA. Due to a wide range of clinical presentations and nonspecific laboratory findings, it presents a diagnostic challenge often requiring brain biopsy. Only a few histopathologically confirmed cases have been described in the literature. Our aim is to describe two cases of RM and review the literature. The first case is of a previously healthy 37-year-old man who presented with severe headaches and focal neurologic deficits. Magnetic resonance imaging demonstrated abnormal leptomeningeal enhancement in the left frontal and parietal sulci. The second case is of a 62-year-old woman with a history of mild chronic joint pain who presented with confusion, personality changes and seizures. Both patients ultimately underwent brain biopsy which demonstrated RM on pathologic examination. Administration of corticosteroids resulted in significant clinical improvement in both cases. To our knowledge, our unusual case of RM in the young man is the fifth reported case of rheumatoid meningitis in a patient with no prior history of RA. Such an atypical presentation makes diagnosis even more difficult and highlights the need for awareness of this entity in the diagnostic consideration of a patient presenting with unexplained neurologic symptoms. Our literature review underscores the clinical and pathologic heterogeneity of CNS involvement in RA. © 2015 Japanese Society of Neuropathology.
The University Corporation for Atmospheric Research (UCAR), in conjunction with a team of health and weather organizations, has launched a project to provide weather forecasts to medical officials in Africa to help reduce outbreaks of meningitis. The forecasts will enable local health care providers to target vaccination programs more effectively. In 2009, meteorologists with the National Center for Atmospheric Research, which is managed by UCAR, will begin issuing 14-day forecasts of atmospheric conditions in Ghana. Later, UCAR plans to work closely with health experts from several African countries to design and test a decision support system to provide health officials with useful meteorological information. ``By targeting forecasts in regions where meningitis is a threat, we may be able to help vulnerable populations. Ultimately, we hope to build on this project and provide information to public health programs battling weather-related diseases in other parts of the world,'' said Rajul Pandya, director of UCAR's Community Building Program. Funding for the project comes from a $900,000 grant from Google.org, the philanthropic arm of the Internet search company.
Rockers, Peter C.; Bonawitz, Rachael; Sriruttan, Charlotte; Glencross, Deborah K.; Cassim, Naseem; Coetzee, Lindi M.; Greene, Gregory S.; Chiller, Tom M.; Vallabhaneni, Snigdha; Long, Lawrence; van Rensburg, Craig; Govender, Nelesh P.
countries with substantial numbers of people with untreated, advanced HIV disease such as South Africa, CrAg screening before initiation of ART has the potential to reduce cryptococcal meningitis and save lives. Reflex screening compared to provider-initiated screening saves more lives and is likely to be cost saving or have low additional costs per additional year of life saved. PMID:27390864
Larson, Bruce A; Rockers, Peter C; Bonawitz, Rachael; Sriruttan, Charlotte; Glencross, Deborah K; Cassim, Naseem; Coetzee, Lindi M; Greene, Gregory S; Chiller, Tom M; Vallabhaneni, Snigdha; Long, Lawrence; van Rensburg, Craig; Govender, Nelesh P
people with untreated, advanced HIV disease such as South Africa, CrAg screening before initiation of ART has the potential to reduce cryptococcal meningitis and save lives. Reflex screening compared to provider-initiated screening saves more lives and is likely to be cost saving or have low additional costs per additional year of life saved.
Namani, Sadie A; Koci, Remzie A; Qehaja-Buçaj, Emine; Ajazaj-Berisha, Lindita; Mehmeti, Murat
The purpose of this study was to present the epidemiologic features of bacterial meningitis in the developing country of Kosovo. Data were collected from active surveillance of bacterial meningitis cases treated at the University Clinical Center of Kosovo in the years 2000 (first post-war year) and 2010. Meningitis cases in 2000 compared with 2010 showed a 35.5% decline in incidence (from 4.8 to 3.1 cases per 100,000 population) and a decrease in the case fatality rate from 10% to 5%. In children, there was a lower mortality rate (5% versus 2%) and a lower incidence of neurological complications (13% versus 16%) as compared to adults (32% versus 10% and 16% versus 35%, respectively). Neisseria meningitidis was the most common pathogen of bacterial meningitis in both study periods. Bacterial meningitis was most prevalent in the pediatric population, and showed an increase in the median age, from three years in 2000 to seven years in 2010. A steady number of bacterial meningitis cases in adults throughout last decade (around 20 cases per year) was recorded. During the last decade, gradual changes have been observed in the epidemiology of bacterial meningitis that are unrelated to the introduction of new vaccines, but are partly due to the improvement of living conditions.
Forgacs, P; Geyer, C A; Freidberg, S R
We reviewed the records of 70 consecutive adult patients with meningitis after a neurosurgical procedure, to determine the characteristics that might help to distinguish a sterile postoperative chemical meningitis from bacterial infection. The spinal fluid profiles in bacterial and chemical meningitis are similar. The exceptions are that a spinal fluid white blood cell count > 7500/microL (7500 x 10(6)/L) and a glucose level of < 10 mg/dL were not found in any case of chemical meningitis. The clinical setting and clinical manifestations were distinct enough that no antibiotic was administered after lumbar puncture to 30 (43%) of the 70 patients with postoperative meningitis. Chemical meningitis was infrequent after surgery involving the spine and sinuses. Patients with chemical meningitis did not have purulent wound drainage or significant wound erythema or tenderness, coma, new focal neurological findings, or onset of a new seizure disorder. They rarely had temperatures > 39.4 degrees C or cerebrospinal fluid rhinorrhea or otorrhea.
Codjoe, Samuel Nii Ardey; Nabie, Vivian Adams
Cerebrospinal meningitis (CSM) is one of the infectious diseases likely to be affected by climate change. Although there are a few studies on the climate change-CSM nexus, none has considered perceptions of community members. However, understanding public perception in relation to a phenomenon is very significant for the design of effective communication and mitigation strategies as well as coping and adaptation strategies. This paper uses focus group discussions (FGDs) to fill this knowledge lacuna. Results show that although a few elderly participants ascribed fatal causes (disobedience to gods, ancestors, and evil spirits) to CSM infections during FGDs, majority of participants rightly linked CSM infections to dry, very hot and dusty conditions experienced during the dry season. Finally, community members use a suite of adaptation options to curb future CSM epidemics. PMID:25003550
Ances, Beau M.; Clifford, David B.
HIV-associated neurocognitive disorders (HAND) are the most common preventable and treatable cause of dementia. While the incidence of the most severe form of HAND, HIV-associated dementia, has decreased since the introduction of combination antiretroviral therapy (cART), the prevalence of less severe forms of HAND has continued to rise. HAND leads to a subcortical dementia consisting of a triad of cognitive, behavior, and motor dysfunction. No single laboratory test can establish HAND, but ancillary studies including neuropsychological testing, neuroimaging studies, and cerebrospinal fluid (CSF) analysis are useful for supporting or refuting the diagnosis. More recent evidence has suggested that higher central nervous system–penetrating cART may lead to greater suppression of CSF HIV viral loads and improved cognition. Because viral control generally has been successful without eliminating cognitive dysfunction, further clinical studies that assess adjunctive neuroprotective drugs are likely to be required. PMID:18957181
Beatrous, Surget V; Grisoli, Stratton B; Riahi, Ryan R; Cohen, Philip R
Kaposi sarcoma (KS) is a malignancy of viral etiology whose course ranges from cutaneous limited lesions to fulminant disease with multi-organ involvement. Four clinical variants of the disease exist: classic, endemic, iatrogenic, and epidemic. Iatrogenic and epidemic variants of Kaposi sarcoma develop in the setting of immune suppression. Transplant recipients who develop iatrogenic KS typically demonstrate improvement of lesions following de-escalation of immunosuppressive therapy. Similarly, HIV-infected patients who begin highly active antiretroviral therapy (HAART) experience immune reconstitution, which can induce KS regression. We describe two patients with varying clinical outcomes of cutaneous-limited HIV-associated KS after immune reconstitution with HAART. We propose that immune reconstitution with HAART, followed by clinical and radiographic surveillance for disease progression, may be an appropriate initial management strategy for limited cutaneous HIV-associated KS. In patients with more extensive disease at presentation or failure of HAART alone, antineoplastic therapy should be instituted.
Nakazato, Ai; Tominaga, Daisuke; Tasato, Daisuke; Miyagi, Kyoko; Nakamura, Hideta; Haranaga, Shusaku; Higa, Futoshi; Tateyama, Masao; Fujita, Jiro
HIV-associated neurocognitive disorders (HAND) are one of major comorbidities in patients with HIV-1 infection. There are currently no standardized tests for screening HAND in such patients. The sensitivity of the cognitive function tests routinely used in clinical practice, such as the Mini-Mental State Examination and the Revised Hasegawa's Dementia Scale, is inadequate to rule out HAND, even in patients with clear abnormal behavior. We report a 41-year-old man with HIV-associated dementia, the most severe form of HAND, in whom the simplified methods did not show abnormal results, and a comprehensive battery of neuropsychological tests which covering several cognitive domains was needed to detect cognitive impairment.
Baldwin, Kelly; Whiting, Chris
Chronic meningitis can be a diagnostic dilemma for even the most experienced clinician. Many times, the differential diagnosis is broad and encompasses autoimmune, neoplastic, and infectious etiologies. This review will focus on a general approach to chronic meningitis to simplify the diagnostic challenges many clinicians face. The article will also review the most common etiologies of chronic meningitis in some detail including clinical presentation, diagnostic testing, treatment, and outcomes. By using a case-based approach, we will focus on the key elements of clinical presentation and laboratory analysis that will yield the most rapid and accurate diagnosis in these complicated cases.
Harries, Anthony D; Zachariah, Rony; Corbett, Elizabeth L; Lawn, Stephen D; Santos-Filho, Ezio T; Chimzizi, Rhehab; Harrington, Mark; Maher, Dermot; Williams, Brian G; De Cock, Kevin M
Despite policies, strategies, and guidelines, the epidemic of HIV-associated tuberculosis continues to rage, particularly in southern Africa. We focus our attention on the regions with the greatest burden of disease, especially sub-Saharan Africa, and concentrate on prevention of tuberculosis in people with HIV infection, a challenge that has been greatly neglected. We argue for a much more aggressive approach to early diagnosis and treatment of HIV infection in affected communities, and propose urgent assessment of frequent testing for HIV and early start of antiretroviral treatment (ART). This approach should result in short-term and long-term declines in tuberculosis incidence through individual immune reconstitution and reduced HIV transmission. Implementation of the 3Is policy (intensified tuberculosis case finding, infection control, and isoniazid preventive therapy) for prevention of HIV-associated tuberculosis, combined with earlier start of ART, will reduce the burden of tuberculosis in people with HIV infection and provide a safe clinical environment for delivery of ART. Some progress is being made in provision of HIV care to HIV-infected patients with tuberculosis, but too few receive co-trimoxazole prophylaxis and ART. We make practical recommendations about how to improve this situation. Early HIV diagnosis and treatment, the 3Is, and a comprehensive package of HIV care, in association with directly observed therapy, short-course (DOTS) for tuberculosis, form the basis of prevention and control of HIV-associated tuberculosis. This call to action recommends that both HIV and tuberculosis programmes exhort implementation of strategies that are known to be effective, and test innovative strategies that could work. The continuing HIV-associated tuberculosis epidemic needs bold but responsible action, without which the future will simply mirror the past.
Lawn, S. D.; Harries, A. D.; Williams, B. G.; Chaisson, R. E.; Losina, E.; De Cock, K. M.; Wood, R.
SUMMARY The human immunodeficiency virus (HIV) associated tuberculosis (TB) epidemic remains an enormous challenge to TB control in countries with a high prevalence of HIV. In their 1999 article entitled ‘Will DOTS do it?’, De Cock and Chaisson questioned whether the World Health Organization’s DOTS Strategy could control this epidemic. Data over the past 10 years have clearly shown that DOTS is insufficient as a single TB control intervention in such settings because it does not address the fundamental epidemiological interactions between TB and HIV. Immunodeficiency is a principal river of this epidemic, and the solution must therefore include immune recovery using antiretroviral therapy (ART). Thus, in the era of global ART scale-up, we now ask the question, ‘Will ART do it?’ ART reduces the risk of TB by 67% (95%CI 61–73), halves TB recurrence rates, reduces mortality risk by 64–95% in cohorts and prolongs survival in patients with HIV-associated drug-resistant TB. However, the cumulative lifetime risk of TB in HIV infected individuals is a function of time spent at various CD4-defined levels of risk, both before and during ART. Current initiation of ART at low CD4 cell counts (by which time much HIV-associated TB has already occurred) and low effective coverage greatly undermine the potential impact of ART at a population level. Thus, while ART has proven a critical intervention for case management of HIV-associated TB, much of its preventive potential for TB control is currently being squandered. Much earlier ART initiation with high coverage is required if ART is to substantially influence the incidence of TB. PMID:21756508
Heaton, R.K.; Clifford, D.B.; Franklin, D.R.; Woods, S.P.; Ake, C.; Vaida, F.; Ellis, R.J.; Letendre, S.L.; Marcotte, T.D.; Atkinson, J.H.; Rivera-Mindt, M.; Vigil, O.R.; Taylor, M.J.; Collier, A.C.; Marra, C.M.; Gelman, B.B.; McArthur, J.C.; Morgello, S.; Simpson, D.M.; McCutchan, J.A.; Abramson, I.; Gamst, A.; Fennema-Notestine, C.; Jernigan, T.L.; Wong, J.; Grant, I.
Objectives: This is a cross-sectional, observational study to determine the frequency and associated features of HIV-associated neurocognitive disorders (HAND) in a large, diverse sample of infected individuals in the era of combination antiretroviral therapy (CART). Methods: A total of 1,555 HIV-infected adults were recruited from 6 university clinics across the United States, with minimal exclusions. We used standardized neuromedical, psychiatric, and neuropsychological (NP) examinations, and recently published criteria for diagnosing HAND and classifying 3 levels of comorbidity (minimal to severe non-HIV risks for NP impairment). Results: Fifty-two percent of the total sample had NP impairment, with higher rates in groups with greater comorbidity burden (40%, 59%, and 83%). Prevalence estimates for specific HAND diagnoses (excluding severely confounded cases) were 33% for asymptomatic neurocognitive impairment, 12% for mild neurocognitive disorder, and only 2% for HIV-associated dementia (HAD). Among participants with minimal comorbidities (n = 843), history of low nadir CD4 was a strong predictor of impairment, and the lowest impairment rate on CART occurred in the subset with suppressed plasma viral loads and nadir CD4 ≥200 cells/mm3 (30% vs 47% in remaining subgroups). Conclusions: The most severe HAND diagnosis (HAD) was rare, but milder forms of impairment remained common, even among those receiving CART who had minimal comorbidities. Future studies should clarify whether early disease events (e.g., profound CD4 decline) may trigger chronic CNS changes, and whether early CART prevents or reverses these changes. GLOSSARY ANI = asymptomatic neurocognitive impairment; CART = combination antiretroviral therapy; CHARTER = CNS HIV Antiretroviral Therapy Effects Research; CIDI = Composite International Diagnostic Interview; CLIA = Clinical Laboratory Improvement Amendments; CPE = CNS penetration effectiveness; HAD = HIV-associated dementia; HAND = HIV-associated
Ambler, Kimberley L. S.; Vickars, Linda M.; Leger, Chantal S.; Foltz, Lynda M.; Montaner, Julio S. G.; Harris, Marianne; Dias Lima, Viviane; Leitch, Heather A.
The characteristics of HIV-associated ITP were documented prior to the HAART era, and the optimal treatment beyond HAART is unknown. We performed a review of patients with HIV-associated ITP and at least one platelet count <20 × 109/L since January 1996. Of 5290 patients in the BC Centre for Excellence in HIV/AIDS database, 31 (0.6%) had an ITP diagnosis and platelet count <20 × 109/L. Initial ITP treatment included IVIG, n = 12; steroids, n = 10; anti-RhD, n = 8; HAART, n = 3. Sixteen patients achieved response and nine patients achieved complete response according to the International Working Group criteria. Median time to response was 14 days. Platelet response was not significantly associated with treatment received, but complete response was lower in patients with a history of injection drug use. Complications of ITP treatment occurred in two patients and there were four unrelated deaths. At a median followup of 48 months, 22 patients (71%) required secondary ITP treatment. This is to our knowledge the largest series of severe HIV-associated ITP reported in the HAART era. Although most patients achieved a safe platelet count with primary ITP treatment, nearly all required retreatment for ITP recurrence. New approaches to the treatment of severe ITP in this population are needed. PMID:22693513
Raviglione, M. C.; Narain, J. P.; Kochi, A.
This article reviews the clinical aspects and diagnosis of HIV-associated tuberculosis in developing countries, and summarizes WHO's recommendations for treatment. According to WHO estimates (early 1992) over 4 million persons worldwide have been infected with HIV and tuberculosis; 95% of them are in the developing countries. Clinical features of HIV-associated pulmonary tuberculosis in adults are frequently atypical, particularly in the late stage of HIV infection, with non-cavitary disease, lower lobe infiltrates, hilar lymphadenopathy and pleural effusion. More typical post-primary tuberculosis with upper lobe infiltrates and cavitations is seen in the earlier stages of HIV infection. Extrapulmonary tuberculosis is reported more frequently, despite the difficulties in diagnosing it. WHO's recent guidelines recommend 6-month short-course chemotherapy with isoniazid, rifampicin, pyrazinamide and ethambutol for patients with HIV-associated tuberculosis. The older 12-month regimen without rifampicin is much less effective. Streptomycin should not be used, because of the risk of transmitting blood-borne pathogens through contaminated needles. Thioacetazone should be abandoned, because of severe adverse reactions observed among HIV-infected patients. The roles of preventive chemotherapy and BCG vaccination for prevention of tuberculosis are also briefly discussed. PMID:1394786
Orentreich, David; Leone, Anna-Sophia
Patients infected with the HIV may experience HIV-associated lipodystrophy, a symptom of which is facial lipoatrophy, a dramatic loss of subcutaneous facial tissue. This visible manifestation of HIV infection causes significant psychosocial pain for patients and has been associated with impaired compliance with medical regimens. To improve the appearance of facial lipoatrophy in a safe, long-lasting, expeditious, and relatively economical manner. An HIV-associated lipodystrophy patient with facial lipoatrophy underwent multiple sessions of soft-tissue augmentation therapy with liquid injectable silicone (LIS) using the microdroplet serial puncture technique. Administration of LIS by the microdroplet serial puncture technique produced satisfactory improvement of areas of facial atrophy. The treatment time is limited, the patient discomfort and morbidity are minimal, and results are long lasting. Patients report significant satisfaction with treatment. LIS administered by the microdroplet serial puncture technique is a safe and effective method for treating HIV-associated facial lipoatrophy and compares favorably with other methods of tissue augmentation.
Gopal, Satish; Liomba, N George; Montgomery, Nathan D; Moses, Agnes; Kaimila, Bongani; Nyasosela, Richard; Chikasema, Maria; Dhungel, Bal M; Kampani, Coxcilly; Sanders, Marcia K; Krysiak, Robert; Dittmer, Dirk P; Fedoriw, Yuri
Clinical reports of multicentric Castleman disease (MCD) from sub-Saharan Africa (SSA) are scarce despite high prevalence of HIV and Kaposi sarcoma-associated herpesvirus (KSHV). Our objective is to describe characteristics and survival for HIV-associated MCD patients in Malawi. To our knowledge, this is the first HIV-associated MCD case series from the region. We describe HIV-positive patients with MCD in Lilongwe, and compare them to HIV-associated lymph node Kaposi sarcoma (KS) and non-Hodgkin lymphoma (NHL) patients treated at our centre. All patients were enrolled into a prospective longitudinal cohort study at a national teaching hospital and cancer referral centre serving half of Malawi's 16 million people. We included adult patients≥18 years of age with HIV-associated MCD (n=6), lymph node KS (n=5) or NHL (n=31) enrolled between 1 June 2013 and 31 January 2015. MCD patients had a median age of 42.4 years (range 37.2-51.8). All had diffuse lymphadenopathy and five had hepatosplenomegaly. Concurrent KS was present for one MCD patient, and four had performance status ≥3. MCD patients had lower median haemoglobin (6.4 g/dL, range 3.6-9.3) than KS (11.0 g/dL, range 9.1-12.0, p=0.011) or NHL (11.2 g/dL, range 4.5-15.1, p=0.0007). Median serum albumin was also lower for MCD (2.1 g/dL, range 1.7-3.2) than KS (3.7 g/dL, range 3.2-3.9, p=0.013) or NHL (3.4 g/dL, range 1.8-4.8, p=0.003). All six MCD patients were on antiretroviral therapy (ART) with median CD4 count 208 cells/µL (range 108-1146), and all with HIV RNA <400 copies/mL. Most KS and NHL patients were also on ART, although ART duration was longer for MCD (56.4 months, range 18.2-105.3) than KS (14.2 months, range 6.8-21.9, p=0.039) or NHL (13.8 months, range 0.2-98.8, p=0.017). Survival was poorer for MCD patients than lymph node KS or NHL. HIV-associated MCD occurs in Malawi, is diagnosed late and is associated with high mortality. Improvements in awareness, diagnostic facilities, treatment and
Noor, Jawad; Yegneswaran, Balaji; Kodali, Hanish
Neurosurgical interventions are rarely associated with meningitis with a very low incidence rate ranging from 1.1% to 2.5%. Gram negative bacillary meningitis first described in the 1940’s, previously uncommon has been increasing in the recent past associated with advanced age, immunosuppression and neurosurgery. Enterobacter meningitis though relatively uncommon is recently increasing in incidence and treatment is frequently complicated due to resistance to antibiotics making this a challenging, difficult to treat infection that may be associated with adverse clinical outcomes. Here, we describe a case of a 27-year-old patient diagnosed with brain sarcoma at the age of four years, who presented with Enterobacter meningitis following a neurosurgical intervention for resection of a recurrent brain tumor (meningioma on pathology) and had a prolonged hospital stay with a difficult to treat infection. PMID:28208914
Prieto-González, Sergio; Escoda, Rosa; Coloma, Emmanuel; Grau, Josep M
A 58-year-old man presented to the hospital with fever and headache after amoxicillin intake. Physical examination, laboratory, and a cranial CT scan were unremarkable. Cerebrospinal fluid (CSF) testing revealed lymphocytic pleocytosis. After discontinuation of amoxicillin and symptomatic care, the patient quickly improved. Interestingly, he had had two prior episodes of aseptic meningitis that were probably also related to the administration of amoxicillin. Aseptic meningitis can be caused by multiple non-infectious conditions including drugs, malignancy, and autoimmune diseases. We report a case associated with amoxicillin that meets the criteria of drug-induced aseptic meningitis. Considering the wide utilization of amoxicillin, healthcare providers should be aware of it as a possible cause of drug-induced aseptic meningitis.
Richie, Megan B; Josephson, S Andrew
Meningitis is an inflammatory syndrome involving the meninges that classically manifests with headache and nuchal rigidity and is diagnosed by cerebrospinal fluid examination. In contrast, encephalitis refers to inflammation of the brain parenchyma itself and often results in focal neurologic deficits or seizures. In this article, the authors review the differential diagnosis of meningitis and encephalitis, with an emphasis on infectious etiologies. The recommended practical clinical approach focuses on early high-yield diagnostic testing and empiric antimicrobial administration, given the high morbidity associated with these diseases and the time-sensitive nature of treatment initiation. If the initial workup does not yield a diagnosis, further etiology-specific testing based upon risk factors and clinical characteristics should be pursued. Effective treatment is available for many causes of meningitis and encephalitis, and when possible should address both the primary disease process as well as potential complications.
Krysan, Damian J
Cryptococcosis is one of the most important fungal infections of humans. It primarily, but not exclusively, afflicts people with compromised immune function. Cryptococcosis is most commonly caused by Cryptococcus neoformans var. grubii with C. neoformans var. neoformans and C. gatti also contributing to the disease. Cryptococcosis is primarily manifested as meningoencephalitis although pneumonia occurs frequently as well. Globally, the burden of disease is highest among those living with HIV/AIDS and is one of the most common causes of death in this patient population. Cryptococcal meningitisis almost invariably fatal if untreated. The current gold standard therapy is amphotericin B combined with 5-flucytosine. Unfortunately, this therapy has significant toxicity and is not widely available in resource-limited regions. Fluconazole, which is associated with poorer outcomes, is frequently as an alternative. Here, I present the characteristics of an ideal anti-cryptococcal agent and review recent progress toward identifying both novel and repurposed drugs as potential new therapies.
Alviedo, Joseph N; Sood, Beena G; Aranda, Jacob V; Becker, Cristie
Pneumocephalus, intracranial air or gas collection, associated with neonatal meningitis is extremely rare. We report the first case in the United States and the second case in the world of intracranial gas accumulation in a neonate with Citrobacter koseri meningitis. The clinical presentation was acute with pneumocephalus demonstrated by cranial sonography and computed tomography. The clinical course was fatal despite the prompt administration of antibiotics.
Molesworth, Anna M.; Cuevas, Luis E.; Connor, Stephen J.; Morse, Andrew P.
Epidemics of meningococcal meningitis occur in areas with particular environmental characteristics. We present evidence that the relationship between the environment and the location of these epidemics is quantifiable and propose a model based on environmental variables to identify regions at risk for meningitis epidemics. These findings, which have substantial implications for directing surveillance activities and health policy, provide a basis for monitoring the impact of climate variability and environmental change on epidemic occurrence in Africa. PMID:14609465
Sbai, H; Smail, L; Hamdani, S; Essatara, Y; Harrandou, M; Khatouf, M; Kanjaa, N
Fahr's disease refers to a rare syndrome characterized by symmetrical and bilateral intracranial calcifications. The basal ganglia and dentate nucleus are the most common site of involvement and most cases present extrapyramidal symptoms. This disease is mostly associated with a phosphocalcic metabolism disorder, especially to hypoparathyroidism. The authors report a case of Fahr syndrome (FS) discovered when a young patient with hypocalcemia and bacterial meningitis had a cerebral CT scan disclosing intracerebral calcifications. She fully recovered after both meningitis and hypocalcemia were treated.
Shah, Ira; Kapdi, Muznah
Acinetobacter species have emerged as one of the most troublesome pathogens for healthcare institutions globally. In more recent times, nosocomial infections involving the central nervous system, skin and soft tissue, and bone have emerged as highly problematic. Acinetobacter species infection is common in intensive care units; however, Acinetobacter baumannii meningitis is rarely reported. Here, we report two cases of Acinetobacter baumannii meningitis which was multidrug resistance and ultimately required the carbapenem group of drugs for the treatment.
Plit, M L; Miller, G B; Berkowitz, F E; Gear, J H
Mollaret's meningitis or the benign recurrent meningitis syndrome is a rare disorder not previously described in Africa. The syndrome has a characteristic clinical presentation with spinal fluid pleocytosis, often with unusual 'epithelial' cells. With contemporary techniques no causative organism has been incriminated. The aetiology remains speculative, but we report on a patient found to have a cerebrospinal fluid leak, which may represent a factor in the pathogenesis of this disorder.
Liao, T-L; Chen, Y-M; Chen, D-Y
Increasing evidence indicates that the risk of cryptococcal infections is increased in patients with rheumatoid arthritis (RA). However, the association between cryptococcosis and immunosuppressive medications in RA patients is still uncertain and little is known about risk factors for cryptococcal disease among RA patients. We conducted a retrospective case-control study to investigate the epidemiology of RA patients with cryptococcosis in a medical centre during the period 2001-14. We estimated ORs with 95% CI for cryptococcosis according to co-morbidities and immunosuppressive medications by using backward stepwise logistic regression. Among 9132 newly diagnosed RA patients, 20 (0.22%) were newly diagnosed with cryptococcal infection after RA identification. All cryptococcosis cases had been receiving corticosteroid treatment for some time (3.9±3.3 years) before infection. After full adjustment, chronic kidney disease (adjusted OR (aOR) 2.72, 95% CI 1.04-7.08, p 0.041) was a significant risk factor for cryptococcosis in RA patients. Exposure to adalimumab (monoclonal anti-tumour necrosis factor (TNF) antibodies) (aOR 4.50, 95% CI 1.03-19.66, p 0.046) were significantly associated with increased risks of cryptococcosis. Time to cryptococcosis diagnosis among RA patients receiving anti-TNF biologicals was shorter than in patients not receiving anti-TNF biologicals (1.5±1.2 years versus 8.4±5.5 years, p<0.001). Among RA patients, the risk for development of cryptococcosis was higher among those who had chronic kidney disease and were receiving the monoclonal anti-TNF antibody adalimumab. Therefore, we suggest that cryptococcal infection should be suspected in RA patients with risk factors.
Thompson, Amy D; Cohn, Keri A; Shah, Samir S; Lyons, Todd; Welsh, Elizabeth J; Hines, Elizabeth M; Nigrovic, Lise E
The rate and type of treatment complications in children treated for Lyme meningitis have not been described. We performed a retrospective cohort study of children with Lyme meningitis who presented to 1 of 3 emergency departments located in Lyme disease endemic areas between 1997 and 2010. We defined a case of Lyme meningitis as a child with cerebrospinal fluid pleocytosis and either positive Lyme serology or an erythema migrans rash. We identified prescribed treatment and reasons for all return visits. Our primary outcome was the presence of any treatment complication within 30 days of diagnosis. We identified 157 patients with Lyme meningitis with a median age of 10 years (interquartile range: 7-13 years). Of the 149 children with Lyme meningitis and available follow-up records, 39 (26%) had 1 or more complications, and 21 (14%) required a change in prescribed antibiotic therapy. The median time for developing the first complication was 11 days (interquartile range: 9-14 days). Ten percent of the patients had an adverse drug reaction. Of the 144 children who had a peripherally inserted central catheter placed, 25 (17%) had at least 1 peripherally inserted central catheter-associated complication: 14 (10%) had a mechanical problem, 11 (8%) had an infectious complication and 1 (1%) had a venous thromboembolism. As current Lyme meningitis treatment regimens have substantial associated morbidity, future research should investigate the efficacy of alternate regimens.
Tunkel, A R; Scheld, W M
Bacterial meningitis remains a disease with associated unacceptable morbidity and mortality rates despite the availability of effective bactericidal antimicrobial therapy. Through the use of experimental animal models of infection, a great deal of information has been gleaned concerning the pathogenic and pathophysiologic mechanisms operable in bacterial meningitis. Most cases of bacterial meningitis begin with host acquisition of a new organism by nasopharyngeal colonization followed by systemic invasion and development of a high-grade bacteremia. Bacterial encapsulation contributes to this bacteremia by inhibiting neutrophil phagocytosis and resisting classic complement-mediated bactericidal activity. Central nervous system invasion then occurs, although the exact site of bacterial traversal into the central nervous system is unknown. By production and/or release of virulence factors into and stimulation of formation of inflammatory cytokines within the central nervous system, meningeal pathogens increase permeability of the blood-brain barrier, thus allowing protein and neutrophils to move into the subarachnoid space. There is then an intense subarachnoid space inflammatory response, which leads to many of the pathophysiologic consequences of bacterial meningitis, including cerebral edema and increased intracranial pressure. Attenuation of this inflammatory response with adjunctive dexamethasone therapy is associated with reduced concentrations of tumor necrosis factor in the cerebrospinal fluid, with diminished cerebrospinal fluid leukocytosis, and perhaps with improvement of morbidity, as demonstrated in recent clinical trials. Further information on the pathogenesis and pathophysiology of bacterial meningitis should lead to the development of more innovative treatment and/or preventive strategies for this disorder. Images PMID:8472245
Schwenkenbecher, Philipp; Stoll, Matthias; Conzen, Josef; Bolat, Seza; Vonberg, Ralf-Peter; Wurster, Ulrich; Trebst, Corinna
Cryptococcal meningoencephalitis represents a serious infection of the central nervous system, where reliable prognostic factors during the disease course are needed. Twenty-one patients diagnosed with cryptococcal meningoencephalitis in a German university hospital from 1999 to 2013 were analysed retrospectively. CSF parameters were analysed prior to therapy and during antifungal treatment and were compared between patients who survived or deceased. Fifteen patients clinically improved after antifungal therapy, while six patients died. No differences were observed between the outcome groups for the CSF parameters cell count, lactate, total protein, and CSF-serum albumin quotients (QAlb). Follow-up examinations of serum cryptococcal antigen titer and CSF cell count have shown that these parameters cannot be used to monitor the efficacy of antifungal therapy as well. In contrast, the course of QAlb during therapy was indicative for the outcome as a possible prognostic marker. In patients with clinical improvement QAlb values were falling under therapy, while rising QAlb values were found in patients with fatal outcome indicating a continuing dysfunction of the blood-CSF barrier. In conclusion, our results indicate that, among the various CSF parameters, the course of QAlb presents a promising marker that might be used to monitor the efficacy of antifungal therapy. PMID:25374433
Kim, Jinseung; Kim, Si Eun; Park, Bong Soo; Shin, Kyong Jin; Ha, Sam Yeol; Park, JinSe; Kim, Sung Eun
Background and Purpose We investigated the potential role of serum procalcitonin in differentiating tuberculosis meningitis from bacterial and viral meningitis, and in predicting the prognosis of tuberculosis meningitis. Methods This was a retrospective study of 26 patients with tuberculosis meningitis. In addition, 70 patients with bacterial meningitis and 49 patients with viral meningitis were included as the disease control groups for comparison. The serum procalcitonin level was measured in all patients at admission. Differences in demographic and laboratory data, including the procalcitonin level, were analyzed among the three groups. In addition, we analyzed the predictive factors for a prognosis of tuberculosis meningitis using the Glasgow Coma Scale (GCS) at discharge, and the correlation between the level of procalcitonin and the GCS score at discharge. Results Multiple logistic regression analysis showed that a low level of procalcitonin (≤1.27 ng/mL) independently distinguished tuberculosis meningitis from bacterial meningitis. The sensitivity and specificity for distinguishing tuberculosis meningitis from bacterial meningitis were 96.2% and 62.9%, respectively. However, the level of procalcitonin in patients with tuberculosis meningitis did not differ significantly from that in patients with viral meningitis. In patients with tuberculosis meningitis, a high level of procalcitonin (>0.4 ng/mL) was a predictor of a poor prognosis, and the level of procalcitonin was negatively correlated with the GCS score at discharge (r=-0.437, p=0.026). Conclusions We found that serum procalcitonin is a useful marker for differentiating tuberculosis meningitis from bacterial meningitis and is also valuable for predicting the prognosis of tuberculosis meningitis. PMID:27165424
Eross, J; Silink, M; Dorman, D
A rapid, microenzymatic method was used to measure cerebrospinal fluid lactate levels in 205 children with suspected bacterial meningitis. Fifty children with normal CSF containing fewer than 0.005 X 10(9)/l WBC, no segmented neutrophils, glucose 3.4 +/- 0.8 mmol/l (61.2 +/- 14.4 mg/100 ml), and a protein of less than 0.30 g/l had CSF lactate levels below 2.0 mmol/l (18 mg/100 ml) (mean and standard deviation 1.3 +/- 0.3 mmol/l (11.8 +/- 2.7 mg/100 ml)). In 31 cases of proved viral meningitis as with 58 cases of clinically diagnosed viral meningitis, levels were below 3.8 mmol/l (34.5 mg/100 ml), being 2.3 +/- 0.6 mmol/l (20.9 +/- 5.4 mg/100 ml), and 2.1 +/- 0.7 mmol/l (19.1 +/- 6.4 mg/100 ml) respectively. Sixty-six cases of bacterial meningitis had CSF lactate levels ranging from 3.9 mmol/l (35.4 mg/100 ml) to greater than 10.0 mmol/l (90.0 mg/100 ml). Longitudinal studies in 7 children with bacterial meningitis showed that cerebrospinal fluid lactate levels differentiated bacterial from viral meningitis up to 4 days after starting treatment with antibiotics. Use of CSF lactate measurement for monitoring the efficacy of treatment is illustrated in a case of bacterial meningitis due to Pseudomonas aeruginosa. The origin of the cerebrospinal fluid lactate acidosis and the role of lactate in the pathophysiological cycle leading to intensification of brain tissue hypoxia and cellular damage is discussed with respect to the short-term prognosis and the long-term neurological sequelae. PMID:7294872
Perez Garcia-Pando, Carlos; Thomson, Madeleine C.; Stanton, Michelle C.; Diggle, Peter J.; Hopson, Thomas; Pandya, Rajul; Miller, Ron L.; Hugonnet, Stephane
Meningococcal meningitis is a climate sensitive infectious disease. The regional extent of the Meningitis Belt in Africa, where the majority of epidemics occur, was originally defined by Lapeysonnie in the 1960s. A combination of climatic and environmental conditions and biological and social factors have been associated to the spatial and temporal patterns of epidemics observed since the disease first emerged in West Africa over a century ago. However, there is still a lack of knowledge and data that would allow disentangling the relative effects of the diverse risk factors upon epidemics. The Meningitis Environmental Risk Information Technologies Initiative (MERIT), a collaborative research-to-practice consortium, seeks to inform national and regional prevention and control strategies across the African Meningitis Belt through the provision of new data and tools that better determine risk factors. In particular MERIT seeks to consolidate a body of knowledge that provides evidence of the contribution of climatic and environmental factors to seasonal and year-to-year variations in meningococcal meningitis incidence at both district and national scales. Here we review recent research and practice seeking to provide useful information for the epidemic response strategy of National Ministries of Health in the Meningitis Belt of Africa. In particular the research and derived tools described in this paper have focused at "getting science into policy and practice" by engaging with practitioner communities under the umbrella of MERIT to ensure the relevance of their work to operational decision-making. We limit our focus to that of reactive vaccination for meningococcal meningitis. Important but external to our discussion is the development and implementation of the new conjugate vaccine, which specifically targets meningococcus A
Yuan, Subo; Shi, Yuqiang; Chen, Jinghong; Zhou, Xiangfu; Li, Guangyu; Gelman, Benjamin B.; Lisinicchia, Joshua G.; Carlton, Susan M.; Ferguson, Monique R.; MD, Alai Tan.; Sarna, Sushil K.; Tang, Shao-Jun
Objective Chronic pain is a common neurological comorbidity of HIV-1 infection, but the etiological cause remains elusive. The objective of this study was to identify the HIV-1 causal factor that critically contributes to the pathogenesis of HIV-associated pain. Methods We first compared the levels of HIV-1 proteins in postmortem tissues of the spinal cord dorsal horn (SDH) from HIV-1/AIDS patients who developed chronic pain (‘pain-positive’ HIV-1 patients) and HIV-1 patients who did not develop chronic pain (‘pain-negative’ HIV-1 patients). Then, we used the HIV-1 protein that was specifically increased in the ‘pain-positive’ patients to generate mouse models. Finally, we performed comparative analyses on the pathological changes in the models and the HIV-1 patients. Results We found that HIV-1 gp120 was significantly higher in ‘pain-positive’ HIV-1 patients (vs. ‘pain-negative’ HIV-1 patients). This finding suggested that gp120 was a potential causal factor of the HIV-associated pain. To test this hypothesis, we used a mouse model generated by intrathecal injection (i.t.) of gp120 and compared the pathologies of the model and the ‘pain-positive’ human HIV-1 patients. The results showed that the mouse model and ‘pain-positive’ human HIV-1 patients developed extensive similarities in their pathological phenotypes, including pain behaviors, peripheral neuropathy, glial reactivation, synapse degeneration and aberrant activation of pain-related signaling pathways in the SDH. Interpretation Our findings suggest that gp120 may critically contribute to the pathogenesis of HIV-associated pain. PMID:24633867
Abrams, D I; Jay, C A; Shade, S B; Vizoso, H; Reda, H; Press, S; Kelly, M E; Rowbotham, M C; Petersen, K L
To determine the effect of smoked cannabis on the neuropathic pain of HIV-associated sensory neuropathy and an experimental pain model. Prospective randomized placebo-controlled trial conducted in the inpatient General Clinical Research Center between May 2003 and May 2005 involving adults with painful HIV-associated sensory neuropathy. Patients were randomly assigned to smoke either cannabis (3.56% tetrahydrocannabinol) or identical placebo cigarettes with the cannabinoids extracted three times daily for 5 days. Primary outcome measures included ratings of chronic pain and the percentage achieving >30% reduction in pain intensity. Acute analgesic and anti-hyperalgesic effects of smoked cannabis were assessed using a cutaneous heat stimulation procedure and the heat/capsaicin sensitization model. Fifty patients completed the entire trial. Smoked cannabis reduced daily pain by 34% (median reduction; IQR = -71, -16) vs 17% (IQR = -29, 8) with placebo (p = 0.03). Greater than 30% reduction in pain was reported by 52% in the cannabis group and by 24% in the placebo group (p = 0.04). The first cannabis cigarette reduced chronic pain by a median of 72% vs 15% with placebo (p < 0.001). Cannabis reduced experimentally induced hyperalgesia to both brush and von Frey hair stimuli (p < or = 0.05) but appeared to have little effect on the painfulness of noxious heat stimulation. No serious adverse events were reported. Smoked cannabis was well tolerated and effectively relieved chronic neuropathic pain from HIV-associated sensory neuropathy. The findings are comparable to oral drugs used for chronic neuropathic pain.
Naftalin, Claire; Nathan, Bavithra; Hamzah, Lisa; Post, Frank A
Acute renal failure and chronic kidney disease are more common in HIV-infected patients compared with the general population. Several studies have shown age to be a risk factor for HIV-associated kidney disease. The improved life expectancy of HIV-infected patients as a result of widespread use of antiretroviral therapy has resulted in progressive aging of HIV cohorts in the developed world, and an increased burden of cardiovascular and kidney disease. Consequently, HIV care increasingly needs to incorporate strategies to detect and manage these non-infectious co-morbidities.
Larriviere, Daniel G
The number of states legalizing medical marijuana is increasing. Medical marijuana is possibly effective therapy for HIV-associated sensory neuropathy. Despite legalization at the state level, however, the current and contradictory federal drug enforcement policy creates the risk that physicians who recommend medical marijuana to their patients will lose their ability to prescribe medications. The federal-state tension has legal and ethical implications for neurologists who receive a request for medical marijuana from their patients since neurologists must strive to both relieve suffering and obey relevant laws. Recommendation of medical marijuana by neurologists to their patients is ethically permissible but is not ethically mandatory.
Markus, H. S.; Allison, S. P.
Two cases of vertebral osteomyelitis presenting with secondary Staphylococcus aureus meningitis are described. In staphylococcal meningitis a search for a primary source should include the lower vertebral spine. PMID:2616438
Depreitere, Bart; Bruyninckx, Dominike; Güiza, Fabian
The literature on intracranial pressure (ICP) monitoring in meningitis is limited to case reports and a handful of descriptive series. The aim of this study is to investigate relationships among ICP, cerebral perfusion pressure (CPP), and outcome in meningitis and to identify whether ICP affected clinical decisions. Between 1999 and 2011, a total of 17 patients with meningitis underwent ICP monitoring at the University Hospitals Leuven. Charts were reviewed for clinical history, ICP/CPP data, imaging findings, and Glasgow Outcome Scale score. Univariate correlations were computed for outcome and ICP/CPP variables, computed tomography characteristics, and Corticosteroid Randomization After Significant Head Injury outcome model variables. Treatment decisions were assessed regarding whether or not they were based on ICP. At drain placement, Glasgow Coma Scale scores showed a median of 8 (range 3-12). Six of 17 patients had either one or two nonreactive pupils. Significant correlations with outcome were found for the highest documented ICP value (r = -0.70), the number of episodes when CPP <50 mmHg (r =-0.50), the lowest documented CPP value (r = 0.61), and pupil reactivity (r = 0.57). Treatment was influenced by ICP in all patients. The results support the notion that in meningitis high ICP and low CPP represent secondary insults. The poor condition of the patients illustrates that the level of suspicion for increased ICP in meningitis may not be high enough.
KIM, KWANG SIK
E. coli is the most common Gram-negative bacillary organism causing meningitis and E. coli meningitis continues to be an important cause of mortality and morbidity throughout the world. Our incomplete knowledge of its pathogenesis contributes to such mortality and morbidity. Recent reports of E. coli strains producing CTX-M-type or TEM-type extended-spectrum β-lactamases create a challenge. Studies using in vitro and in vivo models of the blood-brain barrier have shown that E. coli meningitis follows a high-degree of bacteremia and invasion of the blood-brain barrier. E. coli invasion of the blood-brain barrier, the essentials step in the development of E. coli meningitis, requires specific microbial and host factors as well as microbe- and host-specific signaling molecules. Blockade of such microbial and host factors contributing to E. coli invasion of the blood-brain barrier is shown to be efficient in preventing E. coli penetration into the brain. The basis for requiring a high-degree of bacteremia for E. coli penetration of the blood-brain barrier, however, remains unclear. Continued investigation on the microbial and host factors contributing to a high-degree of bacteremia and E. coli invasion of the blood-brain barrier is likely to identify new targets for prevention and therapy of E. coli meningitis. PMID:27223820
Takeshima, Shinichi; Yoshimoto, Takeshi; Shiga, Yuji; Kanaya, Yuhei; Neshige, Shuichiro; Himeno, Takahiro; Kono, Ryuhei; Takamatsu, Kazuhiro; Shimoe, Yutaka; Kuriyama, Masaru
We experienced 13 cases (29.8 ± 7.0 years) of mumps meningitis and 365 cases of adult aseptic meningitis during 11 years from 2004 to 2014. A small epidemic of mumps occurred for 3-4 years, and the incidence rate of adult mumps meningitis coincided with the epidemic without seasonal fluctuation. Parotitis was observed in 8 of the 13 mumps meningitis patients (61.5%) and orchitis in 2 of 7 male patients (28.6%). There were no differences in clinical manifestations, laboratory findings, and outcome between patients with adult mumps meningitis and those with echovirus 9 meningitis (9 patients), except for the low frequency of nausea/vomiting and a high percentage of mononuclear cells of the cerebrospinal fluid in those with mumps. Eight patients had contact with persons with mumps before the symptomatic stage of meningitis. Only one patient had received mumps vaccination in childhood. On the basis of the values of the anti-mumps IgM and IgG antibodies, we speculated primary infection and the re-infection of mumps in 6 and 2 patients, respectively. Moreover, second vaccine failure was suggested in the vaccinated patient.
Yoshino, Yusuke; Kitazawa, Takatoshi; Tatsuno, Keita; Ota, Yasuo; Koike, Kazuhiko
Cryptococcal infection is the 4th most common opportunistic infection in patients with acquired immune deficiency syndrome (AIDS). Although pleural effusion alone is an unusual presentation, we present a case of cryptococcal pleuritis in an AIDS patient which was initially difficult to discriminate from tuberculous pleuritis because of the high level of pleural adenosine deaminase (ADA). Cryptococcus neoformans was detected in the culture of the pleural effusion after the initiation of antituberculous treatment. High levels of ADA in the pleural fluid can be observed in patients with cryptococcal pleuritis, and longer incubation of pleural fluid should be performed in all patients who present with pleuritis associated with a high ADA level as the only significant finding.
McDaniel, Edward L; Ferguson, Tomas M; Kwon, Herbert P; Thompson, Jennifer C
Meningitis from herpes simplex virus (HSV) may have a clinical presentation similar to other forms of viral meningitis. However, subtle facets of the history and use of the polymerase chain reaction (PCR) can differentiate HSV from other etiologies. During an outbreak of meningitis from enterovirus, a 32-year-old woman presented to the hospital with clinical meningitis, a history of genital HSV infection, and two previous bouts of viral meningitis. Her signs and symptoms as well as lumbar puncture results were similar to patients meeting our case definition for patients with presumed enteroviral meningitis. The cerebral spinal fluid was positive for HSV by PCR, and she was ultimately diagnosed with recurrent meningitis from HSV. We compared her presentation with patients who met our case definition for enteroviral meningitis. A thorough history and use of PCR may assist in differentiating these clinically similar presentations.
Sukhwani, Kalpesh S; Bansal, Nitin; Soni, Mamta; Ramamurthy, Anand; Gopalakrishnan, Ram
Introduction Strongyloidiasis can cause hyperinfection or disseminated infection in an immunocompromised host, and is an important factor linked to enterococcal bacteremia and meningitis. Case reports We report two cases highlighting the importance of suspecting Strongyloides hyperinfection syndrome in patients with enterococcal meningitis. Conclusion Our cases highlight the importance of suspecting Strongyloides hyperinfection syndrome in cases of community acquired enterococcal bacteremia and meningitis. PMID:28331839
Lumsden, Rebecca H; Bloomfield, Gerald S
Antiretroviral therapy (ART) has transformed the clinical profile of human immunodeficiency virus (HIV) from an acute infection with a high mortality into a treatable, chronic disease. As a result, the clinical sequelae of HIV infection are changing as patients live longer. HIV-associated cardiomyopathy (HIVAC) is a stage IV, HIV-defining illness and remains a significant cause of morbidity and mortality among HIV-infected individuals despite ART. Causes and clinical manifestations of HIVAC depend on the degree of host immunosuppression. Myocarditis from direct HIV toxicity, opportunistic infections, and nutritional deficiencies are implicated in causing HIVAC when HIV viral replication is unchecked, whereas cardiac autoimmunity, chronic inflammation, and ART cardiotoxicity contribute to HIVAC in individuals with suppressed viral loads. The initiation of ART has dramatically changed the clinical manifestation of HIVAC in high income countries from one of severe, left ventricular systolic dysfunction to a pattern of subclinical cardiac dysfunction characterized by abnormal diastolic function and strain. In low and middle income countries, however, HIVAC is the most common HIV-associated cardiovascular disease. Clear diagnostic and treatment guidelines for HIVAC are currently lacking but should be prioritized given the global burden of HIVAC.
Lumsden, Rebecca H.; Bloomfield, Gerald S.
Antiretroviral therapy (ART) has transformed the clinical profile of human immunodeficiency virus (HIV) from an acute infection with a high mortality into a treatable, chronic disease. As a result, the clinical sequelae of HIV infection are changing as patients live longer. HIV-associated cardiomyopathy (HIVAC) is a stage IV, HIV-defining illness and remains a significant cause of morbidity and mortality among HIV-infected individuals despite ART. Causes and clinical manifestations of HIVAC depend on the degree of host immunosuppression. Myocarditis from direct HIV toxicity, opportunistic infections, and nutritional deficiencies are implicated in causing HIVAC when HIV viral replication is unchecked, whereas cardiac autoimmunity, chronic inflammation, and ART cardiotoxicity contribute to HIVAC in individuals with suppressed viral loads. The initiation of ART has dramatically changed the clinical manifestation of HIVAC in high income countries from one of severe, left ventricular systolic dysfunction to a pattern of subclinical cardiac dysfunction characterized by abnormal diastolic function and strain. In low and middle income countries, however, HIVAC is the most common HIV-associated cardiovascular disease. Clear diagnostic and treatment guidelines for HIVAC are currently lacking but should be prioritized given the global burden of HIVAC. PMID:26885518
Winer, Eric S.; Stachurski, Dariusz; Perez, Kimberly; Jabbour, Melhem; Milani, Cannon; Colvin, Gerald; Butera, James N.
Background. Plasmablastic lymphoma (PBL) is a variant of diffuse large B-cell lymphoma commonly seen in the oral cavity of HIV-infected individuals. PBL has a poor prognosis, but prognostic factors in patients who have received chemotherapy have not been adequately evaluated. Methods. An extensive literature search rendered 248 cases of PBL, from which 157 were HIV+. Seventy cases with HIV-associated PBL that received chemotherapy were identified. Whenever possible, authors of the original reports were contacted to complete clinicopathological data. Univariate analyses were performed calculating Kaplan–Meier estimates and compared using the log-rank test. Results. The mean age was 39 years, with a male predominance. The mean CD4+ count was 165 cells/mm3. Advanced clinical stage was seen in 51% and extraoral involvement was seen in 43% of the cases. The expression levels of CD20 and Epstein-Barr virus–encoded RNA were 13% and 86%, respectively. The overall survival duration was 14 months. In a univariate analysis, early clinical stage and a complete response to chemotherapy were associated with longer survival. There was no apparent difference in survival with regimens more intensive than cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP). Conclusions. Patients with HIV-associated PBL have a poor prognosis. Prognosis is strongly associated with achieving a complete clinical response to CHOP or CHOP-like chemotherapy. The role of more intensive regimens is currently unclear. Further research is needed to improve responses using novel therapeutic agents and strategies. PMID:20167839
Opravil, M; Pechère, M; Speich, R; Joller-Jemelka, H I; Jenni, R; Russi, E W; Hirschel, B; Lüthy, R
To assess the clinical and echocardiographic time course, prognosis, and possible etiology of HIV-associated primary pulmonary hypertension (PPH), we prospectively followed all 19 patients in whom PPH was diagnosed in our centers. Women (12 cases) and injecting drug use (16 cases) predominated; the median CD4 lymphocytes count was 83/microliter (range, 1 to 740). Matched control subjects without PPH were identified within the Swiss HIV Cohort Study. Frozen serum samples of both groups were then reanalyzed for autoimmune parameters, neopterin, beta-2-microglobulin, and thyroid-stimulating hormone. The median follow up of the patients was 1.3 yr. Follow-up Doppler echocardiography was available in 13 patients. The RVSP-RAP pressure gradient decreased by 3.2 mm Hg for those six patients who received antiretroviral treatment but increased by 19.0 mm Hg for untreated patients (p = 0.026). PPH was the cause of eight of 17 deaths. The probability of surviving was significantly decreased in patients with PPH in comparison with the control subjects; the median survival was 1.3 versus 2.6 yr (p < 0.05). Patients with PPH had significantly higher anticardiolipin IgM, anti SS-B, and neopterin, but all other laboratory values did not differ between cases and control subjects. In conclusion, HIV-associated PPH contributed significantly to mortality. Antiretroviral treatment may exert a beneficial effect on the pressure gradient. A possible role of an autoimmune phenomenon in the pathogenesis could not be substantiated.
Doyle, Katie L; Loft, Shayne; Morgan, Erin E; Weber, Erica; Cushman, Clint; Johnston, Elaine; Grant, Igor; Woods, Steven Paul
Strategic monitoring during a delay interval is theorized to be an essential feature of time-based prospective memory (TB PM), the cognitive architecture of which is thought to rely heavily on frontostriatal systems and executive functions. This hypothesis was examined in 55 individuals with HIV-associated neurocognitive disorders (HAND) and 108 seronegative comparison participants who were administered the Memory for Intentions Screening Test (MIST), during which time-monitoring (clock-checking) behavior was measured. Results revealed a significant interaction between HAND group and the frequency of clock checking, in which individuals with HAND checked the clock significantly less often than the comparison group across the TB PM retention intervals of the MIST. Subsequent analyses in the HAND sample revealed that the frequency of clocking checking was positively related to overall TB performance, as well as to standard clinical measures of retrospective memory and verbal fluency. These findings add support to a growing body of research elucidating TB PM's reliance on strategic monitoring processes dependent upon intact frontostriatal systems. HIV-associated TB strategic time-monitoring deficits may manifest in poorer functioning outcomes, including medication nonadherence and dependence in activities of daily living. Future research is needed to further delineate the cognitive mechanisms underlying strategic time monitoring in order to advise rehabilitation strategies for reducing HAND-related TB PM deficits.
Doyle, Katie L.; Loft, Shayne; Morgan, Erin E.; Weber, Erica; Cushman, Clint; Johnston, Elaine; Grant, Igor; Woods, Steven Paul
Strategic monitoring during a delay interval is theorized to be an essential feature of time-based prospective memory (TB PM), the cognitive architecture of which is thought to rely heavily on frontostriatal systems and executive functions. This hypothesis was examined in 55 individuals with HIV-associated neurocognitive disorders (HAND) and 108 seronegative comparison participants who were administered the Memory for Intentions Screening Test (MIST), during which time monitoring (clock checking) behavior was measured. Results revealed a significant interaction between HAND group and the frequency of clock checking, in which individuals with HAND monitored checked the clock significantly less often than the comparison group across the TB PM retention intervals of the MIST. Subsequent analyses in the HAND sample revealed that the frequency of clocking checking was positively related to overall TB performance, as well as to standard clinical measures of retrospective memory and verbal fluency. These findings add support to a growing body of research elucidating TB PM’s reliance on strategic monitoring processes dependent upon intact frontostriatal systems. HIV-associated TB strategic time monitoring deficits may manifest in poorer functioning outcomes, including medication non-adherence and dependence in activities of daily living. Future research is needed to further delineate the cognitive mechanisms underlying strategic time monitoring in order to advise rehabilitation strategies for reducing HAND related TB PM deficits. PMID:23465043
Weber, Erica; Blackstone, Kaitlin; Woods, Steven Paul
Despite significant advances in the virologic management of HIV infection over the last two decades, effective treatments for HIV-associated neurocognitive disorders (HAND) remain elusive. While pharmacological interventions have yielded some success in improving neurocognitive outcomes in HIV, there is a dearth of rigorous studies examining the efficacy of cognitive rehabilitation for remediating HIV-associated neurocognitive impairment. This qualitative review summarizes and critiques the emerging literature on cognitive and behavioral treatments for HAND, which provides many reasons for optimism, but also has major limitations that underscore the scope of the work that lies ahead. Considering the notable real-world consequences of HAND, the development, validation, and clinical deployment of cognitive neurorehabilitation interventions tailored to the needs of persons living with HIV infection is a priority for clinical neuroAIDS investigators. In describing potential future directions for this endeavor, particular attention was paid to the application of cognitive neuropsychological principles in developing theory-driven approaches to managing HAND, improving everyday functioning, and enhancing HIV health outcomes. PMID:23417497
Morgan, E.E.; Woods, S.P.; Letendre, S.L.; Franklin, D.R.; Bloss, C.; Goate, A.; Heaton, R.K.; Collier, A.C.; Marra, C.M.; Gelman, B.B.; McArthur, J.C.; Morgello, S.; Simpson, D.M.; McCutchan, J.A.; Ellis, R.J.; Abramson, I.; Gamst, A.; Fennema-Notestine, C.; Smith, D.M.; Grant, I.; Vaida, F.; Clifford, D.B.
This is a cross-sectional, observational study to evaluate the hypothesis that HIV-seropositive (HIV+) apolipoprotein E4 (APOE4) carriers are at increased risk for HIV-associated Neurocognitive Disorders (HAND) compared to APOE4 noncarriers with HIV in the CNS HIV Antiretroviral Therapy Effects Research (CHARTER) Group sample. APOE genotype was determined in 466 CHARTER participants with varying disease stages and histories of antiretroviral treatment who did not have severe psychiatric or medical comorbid conditions that preclude diagnosis of HAND. HAND diagnoses were based on results of comprehensive neurobehavioral evaluation and use of current neuroAIDS diagnostic criteria. HAND status consisting of two levels: neuropsychologically normal status (i.e., no HAND) and any HAND diagnosis (i.e., asymptomatic neurocognitive impairment, minor neurocognitive disorder, HIV-associated dementia). Logistic regression analyses revealed no association between APOE4 carrier status and HAND, and there were no interactions between APOE4 carrier status and ethnicity, age, substance use disorders, duration of infection, or nadir CD4. Results did not differ when analysis was restricted to symptomatic HAND, and no APOE4 gene dose-dependent relationship to HAND emerged. APOE4 status was not associated with concurrent HAND in this large, well-characterized sample. This does not preclude emergence of an association between APOE4 status and HAND as this population ages. Prospective, longitudinal studies are needed to examine APOE4 as a risk factor for neurocognitive decline, incident HAND at older ages, and potential associations with CSF amyloid. PMID:23408335
Gaieski, David F; Nathan, Barnett R; O'Brien, Nicole F
Bacterial meningitis and viral encephalitis, particularly herpes simplex encephalitis, are severe neurological infections that, if not treated promptly and effectively, lead to poor neurological outcome or death. Because treatment is more effective if given early, the topic of meningitis and encephalitis was chosen as an Emergency Neurological Life Support protocol. This protocol provides a practical approach to recognition and urgent treatment of bacterial meningitis and encephalitis. Appropriate imaging, spinal fluid analysis, and early empiric treatment is discussed. Though uncommon in its full form, the typical clinical triad of headache, fever, and neck stiffness should alert the clinical practitioner to the possibility of a central nervous system infection. Early attention to the airway and maintaining normotension is crucial in treatment of these patients, as is rapid treatment with anti-infectives and, in some cases, corticosteroids.
Page, E L; Eby, T L
Although the potential for CSF leakage and subsequent meningitis after cochlear implantation in the malformed cochlea has been recognized, this complication has not been previously reported. We report a case of CSF otorhinorrhea and meningitis after minor head trauma developing 2 years after cochlear implantation in a child with Mondini malformation. Leakage of CSF was identified from the cochleostomy around the electrode of the implant, and this leak was sealed with a temporalis fascia and muscle plug. Although this complication appears to be rare, care must be taken to seal the cochleostomy in children with inner ear malformations at the initial surgery, and any episode of meningitis after surgery must be thoroughly investigated to rule out CSF leakage from the labyrinth.
Gaieski, David F; O'Brien, Nicole F; Hernandez, Ricardo
Bacterial meningitis and viral encephalitis, particularly herpes simplex encephalitis, are severe neurological infections that, if not treated promptly and effectively, lead to poor neurological outcome or death. Because of the value of early recognition and treatment, meningitis and encephalitis was chosen as an Emergency Neurological Life Support protocol. This protocol provides a practical approach to recognition and urgent treatment of bacterial meningitis and encephalitis. Appropriate imaging, spinal fluid analysis, and early empiric treatment are discussed. Though uncommon in its full form, the typical clinical triad of headache, fever, and neck stiffness should alert the clinical practitioner to the possibility of a central nervous system infection. Early attention to the airway and maintaining normotension are crucial steps in the treatment of these patients, as is rapid treatment with anti-infectives and, in some cases, corticosteroids.
Stadalnik, R.C.; Goldstein, E.; Hoeprich, P.D.; McGahan, J.P.
The diagnostic utility of pentetate indium trisodium CSF studies, technetium Tc 99m brain scans, and computerized tomographic (CT) scans was evaluated in eight patients in whom coccidioidal meningitis developed following a dust storm in the Central Valley of California. The 111In flow studies and the CT scans demonstrated hydrocephalus in five patients with clinical findings suggesting this complication. Ventriculitis has not previously been diagnosed before death in patients with coccidioidal meningitis; however, it was demonstrated in two patients by the technetium Tc 99m brain scan. The finding that communicating hydrocephalus occurs early in meningitis and interferes with CSF flow into infected basilar regions has important therapeutic implications in that antifungal agents injected into the lumbar subarachnoid space may not reach these regions.
Barichello, Tatiana; Collodel, Allan; Generoso, Jaqueline S; Simões, Lutiana R; Moreira, Ana Paula; Ceretta, Renan A; Petronilho, Fabrícia; Quevedo, João
Pneumococcal meningitis is a severe infectious disease of the central nervous system (CNS) and a significant cause of morbidity and mortality worldwide. The inflammatory reaction to the disease contributes to neuronal injury and involves the meninges, the subarachnoid space and the brain parenchymal vessels. Bacterial pathogens may reach the blood-brain barrier and be recognized by antigen-presenting cells through the binding of Toll-like receptors, triggering an inflammatory cascade. This in turn produces cytokines and chemokines, increases adhesion molecule expression and attracts leukocytes from the blood. This cascade leads to lipid peroxidation, mitochondrial damage and blood-brain barrier permeability. In spite of effective antibacterial treatments, approximately one third of survivors suffer from long-term sequelae, such as hearing loss, cerebral palsy, seizures, hydrocephaly or cognitive impairment. This review summarizes the information on targets of adjuvant treatments of acute pneumococcal meningitis. Copyright © 2014 Elsevier B.V. All rights reserved.
Deresinski, S C; Lilly, R B; Levine, H B; Galgiani, J N; Stevens, D A
Twelve patients with fungal meningitis (ten cases were due to Coccidioides immitis, two were from Cryptococcus neoformans) were treated with brief courses of intravenous (IV) miconazole. Eleven patients, including patients with severe, chronic disease, had been treated unsuccessfully with amphotericin B. Four patients also received miconazole injected directly into the CSF. The drug was well tolerated by any route, with mild reversible side effects. After IV administration the miconazole concentration in the CSF rarely exceeded the minimal inhibitory concentration (MIC) of the infecting organism. Intra-CSF administration of 20 mg generally produced levels above the MIC for 24 hours. Five of ten patients with coccidiodial meningitis responded clinically. Of these five, four received only IV miconazole; three relapsed after therapy was stopped. Miconazole appears promising as a treatment of fungal meningitis, but trials of longer duration might prevent relapse.
Baldwin, Kelly J; Zunt, Joseph R
Chronic meningitis is defined as an inflammatory cerebrospinal fluid (CSF) profile that persists for at least 1 month. The presentation often includes headache, nausea, vomiting, cranial neuropathies, symptoms of elevated intracranial pressure, or focal neurologic deficits. The most common etiologies of chronic meningitis fall into 3 broad categories: infectious, autoimmune, and neoplastic. Evaluation of the patient with suspected chronic meningitis should include a detailed history and physical examination as well as repeated CSF diagnostics, serologic studies, and biopsy of the brain or other abnormal tissue (eg, lymph node or lung), when indicated. Early identification of the etiology and rapid treatment are crucial for improving morbidity and mortality, but potential infectious and neoplastic conditions should be excluded prior to empirically starting steroids or immunosuppressive medications.
Zunt, Joseph R.
Chronic meningitis is defined as an inflammatory cerebrospinal fluid (CSF) profile that persists for at least 1 month. The presentation often includes headache, nausea, vomiting, cranial neuropathies, symptoms of elevated intracranial pressure, or focal neurologic deficits. The most common etiologies of chronic meningitis fall into 3 broad categories: infectious, autoimmune, and neoplastic. Evaluation of the patient with suspected chronic meningitis should include a detailed history and physical examination as well as repeated CSF diagnostics, serologic studies, and biopsy of the brain or other abnormal tissue (eg, lymph node or lung), when indicated. Early identification of the etiology and rapid treatment are crucial for improving morbidity and mortality, but potential infectious and neoplastic conditions should be excluded prior to empirically starting steroids or immunosuppressive medications. PMID:25360204
Gopal, Satish; Liomba, N George; Montgomery, Nathan D; Moses, Agnes; Kaimila, Bongani; Nyasosela, Richard; Chikasema, Maria; Dhungel, Bal M; Kampani, Coxcilly; Sanders, Marcia K; Krysiak, Robert; Dittmer, Dirk P; Fedoriw, Yuri
Introduction Clinical reports of multicentric Castleman disease (MCD) from sub-Saharan Africa (SSA) are scarce despite high prevalence of HIV and Kaposi sarcoma-associated herpesvirus (KSHV). Our objective is to describe characteristics and survival for HIV-associated MCD patients in Malawi. To our knowledge, this is the first HIV-associated MCD case series from the region. Methods We describe HIV-positive patients with MCD in Lilongwe, and compare them to HIV-associated lymph node Kaposi sarcoma (KS) and non-Hodgkin lymphoma (NHL) patients treated at our centre. All patients were enrolled into a prospective longitudinal cohort study at a national teaching hospital and cancer referral centre serving half of Malawi's 16 million people. We included adult patients≥18 years of age with HIV-associated MCD (n=6), lymph node KS (n=5) or NHL (n=31) enrolled between 1 June 2013 and 31 January 2015. Results and discussion MCD patients had a median age of 42.4 years (range 37.2–51.8). All had diffuse lymphadenopathy and five had hepatosplenomegaly. Concurrent KS was present for one MCD patient, and four had performance status ≥3. MCD patients had lower median haemoglobin (6.4 g/dL, range 3.6–9.3) than KS (11.0 g/dL, range 9.1–12.0, p=0.011) or NHL (11.2 g/dL, range 4.5–15.1, p=0.0007). Median serum albumin was also lower for MCD (2.1 g/dL, range 1.7–3.2) than KS (3.7 g/dL, range 3.2–3.9, p=0.013) or NHL (3.4 g/dL, range 1.8–4.8, p=0.003). All six MCD patients were on antiretroviral therapy (ART) with median CD4 count 208 cells/µL (range 108–1146), and all with HIV RNA <400 copies/mL. Most KS and NHL patients were also on ART, although ART duration was longer for MCD (56.4 months, range 18.2–105.3) than KS (14.2 months, range 6.8–21.9, p=0.039) or NHL (13.8 months, range 0.2–98.8, p=0.017). Survival was poorer for MCD patients than lymph node KS or NHL. Conclusions HIV-associated MCD occurs in Malawi, is diagnosed late and is associated with high
Attout, H; Guez, S; Seriès, C
Subarachnoid hemorrhage is the most common cause of cerebral salt wasting syndrome. There are few reports of this condition in infectious meningitis. We describe a patient with hyponatremia and bacterial meningitis. Hyponatremia rapidly improved after administration of sodium chloride. The purpose of this report is to alert clinicians to the fact that hyponatremic patients with central nervous system disease do not necessarily have a syndrome of inappropriate secretion of antidiuretic hormone (SIADH), but may have cerebral salt wasting syndrome. By contrast with SIADH, the treatment requires saline administration.
Denning, D W; Gill, S S
A woman developed meningitis due to Neisseria lactamica in association with a cribriform plate fracture. Cerebrospinal fluid antigen tests for Neisseria meningitidis were negative. The patient recovered with intravenous penicillin therapy. N. lactamica can be rapidly distinguished from N. meningitidis by the hydrolysis of ONPG (o-nitrophenyl-beta-D-galactopyranoside). In contrast to N. meningitidis and Neisseria gonorrhoeae, N. lactamica lacks virulence properties. As 100% of N. lactamica strains are susceptible to penicillin and all three previously described patients with N. lactamica meningitis have recovered with penicillin treatment, the reason for distinguishing the organisms in this context is primarily to prevent unnecessary anxiety and prophylaxis among contacts.
Rose, Winsley; Ghosh, Urmi; Punnen, Anu; Sarkar, Rajiv; Prakash, John Jude Antony; Verghese, Valsan Philip
To compare the children admitted with scrub typhus with and without meningitis. All children admitted with scrub typhus over a 62 mo period were reviewed. Statistical analysis was performed to compare those with and without meningitis for demographic, clinical, investigations and outcome parameters. Four hundred twenty seven children were admitted with scrub typhus and 63 (14.8%) had meningitis. The mean cerebrospinal fluid white blood cell (CSF WBC) count was 71 cells/cu.mm. with mean lymphocyte proportion of 92%. The mean CSF protein was 67 mg/dl and mean CSF glucose, 55 mg/dl. Of those who had meningitis, 24 (38.1%) had seizures, 17 (27%) had altered sensorium and 37 (58.7%) had nuchal rigidity. Finding an eschar, being male, breathing difficulty, and hepatomegaly were significantly more common in those without meningitis. Children with meningitis also had shorter duration of fever at presentation (median [IQR] 7  days vs. 10  days; p = 0.028). Headache and vomiting were significantly more common in those with meningitis. Hemoglobin and platelet were significantly lower in those without meningitis. Duration of hospitalization was significantly longer in those with meningitis, whereas acute respiratory distress syndrome (ARDS) was significantly more common in those without meningitis. There was no neurological deficit in both the groups. There was no mortality in the meningitis group compared to 3.6% mortality in the non-meningitis group (p = 0.213). Meningitis occurs in 15% of those with scrub typhus; those with meningitis have good neurological outcome with little mortality; those without meningitis have more complications and poorer outcome.
Katchanov, Juri; Blechschmidt, Cristiane; Nielsen, Kirsten; Branding, Gordian; Arastéh, Keikawus; Tintelnot, Kathrin; Meintjes, Graeme; Boulware, David R.; Stocker, Hartmut
We report a case of a symptomatic relapse of HIV-related cryptococcal meningoencephalitis 8 years after the first diagnosis on the background of immune reconstitution. The findings as well as the clinical course suggests a combination of smouldering localized infection and enhanced inflammatory reaction related to immune restoration due to antiretroviral therapy. A combination of antifungal and anti-inflammatory therapy resulted in clinical and radiological improvement. Our case challenges the concept that immune reconstitution inflammatory syndrome and microbiological relapse are dichotomous entities. PMID:25505049
Katchanov, Juri; Blechschmidt, Cristiane; Nielsen, Kirsten; Branding, Gordian; Arastéh, Keikawus; Tintelnot, Kathrin; Meintjes, Graeme; Boulware, David R; Stocker, Hartmut
We report a case of a symptomatic relapse of HIV-related cryptococcal meningoencephalitis eight years after the first diagnosis on the background of immune reconstitution. The findings as well as the clinical course suggests a combination of smouldering localised infection and enhanced inflammatory reaction related to immune restoration due to antiretroviral therapy. A combination of antifungal and anti-inflammatory therapy resulted in clinical and radiological improvement. Our case challenges the concept that immune reconstitution inflammatory syndrome and microbiological relapse are dichotomous entities. © The Author(s) 2015.
Chan, Phillip; Brew, Bruce J
The introduction of combination antiretroviral treatment (cART) has significantly reduced the mortality secondary to opportunistic infections in HIV patients by restoring the immune system. In the central nervous system (CNS), there has also been benefit with a marked reduction of HIV associated dementia. However, the milder forms of HIV associated neurocognitive disorder (HAND), namely asymptomatic neurocognitive impairment and mild neurocognitive disorder, remain prevalent in the cART era. In this article, we will discuss how cART interacts with HAND in terms of clinical characteristics and biomarkers. We will then review the outcomes of recent clinical studies focused on the CNS penetrating antiretroviral regimens and some novel therapeutic approaches.
Levy, C; Bidet, Ph; Bonacorsi, S; Béchet, S; Cohen, R
Group A streptococcal (GAS) meningitis in children are rare. The aim of this study was to analyze the clinical, biological and outcome data on GAS meningitis recorded in the Bacterial Meningitis (BM) French Surveillance Network (GPIP/ACTIV). From 2001 through 2012, 4,564 children suffering from proven bacterial meningitis were recorded in the data base. Among them, 0.7 % were GAS infections. The median age was 5.6 years. A history of community acquired infection before the onset of GAS meningitis was frequent. Apart from the identification of the bacterial species, GAS meningitis were clinically and biologically indistinguishable from meningitis caused by other pathogens notably S. pneumoniae. Case fatality rate was 8 %.
Héry-Arnaud, Geneviève; Doloy, Alexandra; Ansart, Séverine; Le Lay, Geneviève; Le Flèche-Matéos, Anne; Seizeur, Romuald; Garré, Michel; Payan, Christopher; Bouvet, Anne
Globicatella sanguinis is a rare cause of acute meningitis. We demonstrated human carriage of Globicatella by identifying cefotaxime-resistant strains in groin and rectal specimens 9 months after invasive infection. The pathogenic strain isolated from the cerebrospinal fluid and the carriage strains were accurately identified by sodA gene sequence analysis. PMID:20147641
Héry-Arnaud, Geneviève; Doloy, Alexandra; Ansart, Séverine; Le Lay, Geneviève; Le Flèche-Matéos, Anne; Seizeur, Romuald; Garré, Michel; Payan, Christopher; Bouvet, Anne
Globicatella sanguinis is a rare cause of acute meningitis. We demonstrated human carriage of Globicatella by identifying cefotaxime-resistant strains in groin and rectal specimens 9 months after invasive infection. The pathogenic strain isolated from the cerebrospinal fluid and the carriage strains were accurately identified by sodA gene sequence analysis.
Pollara, Gabriele; Savy, Lloyd; Cropley, Ian; Hopkins, Susan
We present a rare case of meningitis caused by Citrobacter koseri in an immunocompetent adult who had recently been freediving. Middle ear pressure changes from this recreational activity, and the subsequent inflammatory response, are likely to have provided this environmental organism access to the central nervous system, and thus the ability to cause clinically significant infection.
Mook-Kanamori, Barry B.; Geldhoff, Madelijn; van der Poll, Tom; van de Beek, Diederik
Summary: Pneumococcal meningitis continues to be associated with high rates of mortality and long-term neurological sequelae. The most common route of infection starts by nasopharyngeal colonization by Streptococcus pneumoniae, which must avoid mucosal entrapment and evade the host immune system after local activation. During invasive disease, pneumococcal epithelial adhesion is followed by bloodstream invasion and activation of the complement and coagulation systems. The release of inflammatory mediators facilitates pneumococcal crossing of the blood-brain barrier into the brain, where the bacteria multiply freely and trigger activation of circulating antigen-presenting cells and resident microglial cells. The resulting massive inflammation leads to further neutrophil recruitment and inflammation, resulting in the well-known features of bacterial meningitis, including cerebrospinal fluid pleocytosis, cochlear damage, cerebral edema, hydrocephalus, and cerebrovascular complications. Experimental animal models continue to further our understanding of the pathophysiology of pneumococcal meningitis and provide the platform for the development of new adjuvant treatments and antimicrobial therapy. This review discusses the most recent views on the pathophysiology of pneumococcal meningitis, as well as potential targets for (adjunctive) therapy. PMID:21734248
Nguyen, Huy T V; Juurlink, David N
To report a case of recurrent aseptic meningitis temporally associated with the use of ibuprofen. A previously well 51-year-old white man presented with acute confusion and aphasia 7 days after taking a variety of nonprescription medications, including ibuprofen. Imaging of the brain was unremarkable, and lumbar puncture revealed lymphocytic pleocytosis with an elevated protein level. The symptoms improved shortly after admission, and no infectious cause was identified. Two weeks later, the patient was readmitted with similar symptoms beginning immediately after resumption of ibuprofen. His symptoms resolved promptly after ibuprofen was discontinued. Drug-induced aseptic meningitis is an unusual complication of drug therapy. Nonsteroidal antiinflammatory drugs (NSAIDs), particularly ibuprofen, are among the most commonly implicated agents, but rechallenge with the suspected agent is uncommon. Use of an objective causality tool indicated a probable relationship between ibuprofen and development of aseptic meningitis in our patient. Clinicians should consider NSAIDs as potential causes of aseptic meningitis, especially in patients with recurrent illness and no obvious infectious cause. A detailed drug history is invaluable in the assessment of such patients, with particular attention to nonprescription medications such as ibuprofen.
Ruiz-Ares, Gerardo; Collantes-Bellido, Elena; Rodriguez de Rivera, Francisco; Medina-Báez, Josmarlin; Palomo-Ferrer, Farnando; Morales-Bastos, Carmen; Arpa, Javier
Primary diffuse leptomeningeal gliomatosis (PDLG) is a rare condition, with only 45 cases recorded to date, characterized by infiltration of the meninges by glial cells without evidence of primary tumor in the brain or spinal cord parenchyma. Here, we describe a patient with PDLG who was managed with tuberculostatic drugs owing to multiple findings that were suggestive of tuberculous meningitis. A 19-year-old woman presented with headaches and behavioral changes. A sudden decrease in visual acuity with papilledema, bilateral sixth nerve palsies, and neck stiffness developed. Lumbar puncture showed elevated opening pressure (50 cm H2O). Cerebrospinal fluid (CSF) analysis showed glucose 30 mg/dL, protein 26.5 mg/dL, white blood cell count 150 (60% lymphocytes, 40% neutrophils). The second sample of CSF provided adenosine deaminase activity 21.9 U/L. Polymerase chain reaction for Koch's bacillus was positive in the third CSF sample. Magnetic resonance imaging revealed meningeal thickening of the quadrigeminal cistern, tentorium cerebelli, cerebral convexity, and spinal cord, with gadolinium enhancement in nodular lesions. The patient died 22 weeks after symptom onset owing to brainstem infarction. Postmortem pathologic studies revealed PDLG. This entity should be included in the differential diagnosis of tuberculous meningitis that does not respond to treatment with antituberculous drugs. Surgical biopsy should be considered in contrast-enhanced areas in magnetic resonance imaging.
Michalicek, J; Gordon, V; Lambert, G
In cats anesthetized with alpha-chloralose, autoregulation of blood flow (F) in the middle meningeal and common carotid arteries was assessed by bleeding and subsequently reinfusing the animals to achieve a 25% step reduction in mean arterial blood pressure (P), while maintaining the systolic blood pressure >80 mmHg. The integrity of autoregulation was assessed by calculating the gain factor Gf = 1 - [(deltaF/F)/(deltaP/P)]. Cats were examined intact, after hexamethonium (10 mg/kg), and after papaverine (6 mg/kg). Reduction of blood pressure of 25 to 60 mmHg produced equivalent drops in carotid blood flow (Gf = 0.041 +/- 0.34; mean +/- standard deviation, n = 12). There were only small changes in flow in the middle meningeal artery during this procedure (Gf = 0.91 +/- 0.29). Hexamethonium did not block autoregulation in the middle meningeal artery (Gf = 0.92 +/- 0.13, n = 4). However, papaverine almost completely abolished the ability of the artery to autoregulate (Gf = 0.10 +/- 0.16, n = 7). The results suggest that the middle meningeal artery possesses an ability similar to that of the cortical circulation to autoregulate its blood flow through intrinsic, non-neuronal mechanisms. This will have important implications for the study of disturbances of dural arterial control in migraine and other headaches.
Van Horn, Alixis
The incidence of central nervous system (CNS) metastases has increased steadily since 1999, likely because of the use of drugs with poor access to the CNS as well as the successful treatment of extraneural cancers, resulting in longer survival.Lymphomatous meningitis is a profoundly morbid and often fatal CNS metastasis that develops in at least 4%-8% of patients with non-Hodgkin lymphoma.Risk factors for lymphomatous meningitis include uncontrolled systemic and extranodal disease, testicular and parasinus tumors, and being younger than age 60. A high index of suspicion for the condition may result in earlier detection and improved outcome.Lymphomatous meningitis diagnostic methods include a thorough neurologic examination, magnetic resonance imaging (MRI), and multiple samplings of cerebrospinal fluid (CSF). Treatment regimens typically include radiation to areas of bulky disease or intrathecal chemotherapy.Available chemotherapeutic agents include methotrexate, cytarabine, and liposomal cytarabine.In addition to follow-up CSF and MRI monitoring, questioning patients and caregivers can provide insight into treatment response in terms of quality of life.Special care to avoid a nihilistic outlook in patients and clinicians is essential in treating patients with lymphomatous meningitis.
Mori, Nicanor; Guevara, Jose M; Tilley, Drake H; Briceno, Jesus A; Zunt, Joseph R; Montano, Silvia M
A 59-year-old man with a history of fever, unsteadiness, hemiparesis, motor aphasia and consciousness disturbance was hospitalized for Streptococcus equi subsp. zooepidemicus meningitis. He denied contact with farm animals, but had a practice of consuming unpasteurized goats' cheese from an uncertain source.
Guevara, Jose M.; Tilley, Drake H.; Briceno, Jesus A.; Zunt, Joseph R.; Montano, Silvia M.
A 59-year-old man with a history of fever, unsteadiness, hemiparesis, motor aphasia and consciousness disturbance was hospitalized for Streptococcus equi subsp. zooepidemicus meningitis. He denied contact with farm animals, but had a practice of consuming unpasteurized goats’ cheese from an uncertain source. PMID:23105024
Decimo, Ilaria; Fumagalli, Guido; Berton, Valeria; Krampera, Mauro; Bifari, Francesco
Meninges are a three tissue membrane primarily known as coverings of the brain. More in depth studies on meningeal function and ultrastructure have recently changed the view of meninges as a merely protective membrane. Accurate evaluation of the anatomical distribution in the CNS reveals that meninges largely penetrate inside the neural tissue. Meninges enter the CNS by projecting between structures, in the stroma of choroid plexus and form the perivascular space (Virchow-Robin) of every parenchymal vessel. Thus, meninges may modulate most of the physiological and pathological events of the CNS throughout the life. Meninges are present since the very early embryonic stages of cortical development and appear to be necessary for normal corticogenesis and brain structures formation. In adulthood meninges contribute to neural tissue homeostasis by secreting several trophic factors including FGF2 and SDF-1. Recently, for the first time, we have identified the presence of a stem cell population with neural differentiation potential in meninges. In addition, we and other groups have further described the presence in meninges of injury responsive neural precursors. In this review we will give a comprehensive view of meninges and their multiple roles in the context of a functional network with the neural tissue. We will highlight the current literature on the developmental feature of meninges and their role in cortical development. Moreover, we will elucidate the anatomical distribution of the meninges and their trophic properties in adult CNS. Finally, we will emphasize recent evidences suggesting the potential role of meninges as stem cell niche harbouring endogenous precursors that can be activated by injury and are able to contribute to CNS parenchymal reaction. PMID:23671802
Huong, Nguyen Thi Cam; Altibi, Ahmed M A; Hoa, Nguyen My; Tuan, Le Anh; Salman, Samar; Morsy, Sara; Lien, Nguyen Thi Bich; Truong, Nguyen Thanh; Mai, Nguyen Thi Hoang; Hoa, Pham Thi Le; Thang, Nguyen Ba; Trung, Van The
Cryptococcosis is an opportunistic infection caused by the encapsulated yeast Cryptococcus neoformans and most remarkably manifests in HIV-infected individuals, especially in the settings of very low CD4 count. Development of cryptococcosis in HIV-uninfected individuals is exceedingly rare and usually signifies a marked immunodeficiency. Cryptococcosis in association with myasthenia gravis or thymoma has been previously documented in only very few cases in the literature. We reported a complicated case of severe cutaneous cryptococcosis in a 39-year-old Vietnamese male patient with myasthenia gravis on long-term immunosuppressive therapy. The patient presented with a five month history of recurrent and progressive skin lesions that later on progressed into cryptococcal meningitis. Through this case, we aimed to emphasize the importance of including cutaneous cryptococcosis in the differential diagnosis of cutaneous lesions in patients on chronic immunosuppressive therapy. The cutaneous manifestations of cryptococcosis can be the first clue for a disseminated disease, which makes early recognition crucial and life-saving.
Doyle, Katie L.; Morgan, Erin E.; Weber, Erica; Woods, Steven Paul
Objective The ability to accurately perceive the passage of time relies on several neurocognitive abilities, including attention, memory, and executive functions, which are domains commonly affected in persons living with HIV disease. Method The current study examined time estimation and production and their neurocognitive correlates in a sample of 53 HIV+ individuals with HIV-associated neurocognitive disorders (HAND), 120 HIV+ individuals without HAND, and 113 HIV− individuals. Results Results revealed a moderate main effect of HAND on time estimation and a trend-level effect on time production, but no interaction between HAND and time interval duration. Correlational analyses revealed that time estimation in the HIV+ group was associated with attention, episodic memory and time-based prospective memory. Conclusions Findings indicate that individuals with HAND evidence deficits in time interval judgment suggestive of failures in basic attentional and memory processes. PMID:25854272
Doyle, Katie L; Morgan, Erin E; Weber, Erica; Woods, Steven Paul
The ability to accurately perceive the passage of time relies on several neurocognitive abilities, including attention, memory, and executive functions, which are domains commonly affected in persons living with HIV disease. The current study examined time estimation and production and their neurocognitive correlates in a sample of 53 HIV+ individuals with HIV-associated neurocognitive disorders (HAND), 120 HIV+ individuals without HAND, and 113 HIV- individuals. Results revealed a moderate main effect of HAND on time estimation and a trend-level effect on time production, but no interaction between HAND and time interval duration. Correlational analyses revealed that time estimation in the HIV+ group was associated with attention, episodic memory and time-based prospective memory. Findings indicate that individuals with HAND evidence deficits in time interval judgment suggestive of failures in basic attentional and memory processes.
Bryant, Vaughn E; Whitehead, Nicole E; Burrell, Larry E; Dotson, Vonetta M; Cook, Robert L; Malloy, Paul; Devlin, Kathryn; Cohen, Ronald A
Depression and apathy are common among people living with HIV (PLWH). However, in PLWH, it is unclear whether depression and apathy are distinct conditions, which contribute to different patterns of disruption to cognitive processing and brain systems. Understanding these conditions may enable the development of prognostic indicators for HIV associated neurocognitive disorders (HAND). The present study examined substance use behavior and cognitive deficits, associated with depression and apathy, in 120 PLWH, using hierarchical regression analyses. Higher levels of depression were associated with a history of alcohol dependence and greater deficits in processing speed, motor and global cognitive functioning. Higher levels of apathy were associated with a history of cocaine dependence. It is recommended that PLWH get screened appropriately for apathy and depression, in order to receive the appropriate treatment, considering the comorbidities associated with each condition. Future research should examine the neurological correlates of apathy and depression in PLWH.
Cysique, Lucette A; Maruff, Paul; Bain, Margaret P; Wright, Edwina; Brew, Bruce J
The authors investigated the combined age and HIV effects on cognitive functions in 146 individuals, 116 of whom had HIV infection. Forty-two percent had HIV-associated neurocognitive disorder, and all were receiving highly active antiretroviral therapy. Using linear and nonlinear regression modeling, the authors found only a trending effect of the quadratic term HIV status × age, both including dementia cases (p=0.12) and excluding dementia cases (p<0.06). Our results suggest that either this early-2000 cohort is not old enough to detect a clear interactive age and HIV effect or that there may be a survivor bias for individuals with long-term infection. Further longitudinal studies are warranted.
Whitehead, Nicole E.; Burrell, Larry E.; Dotson, Vonetta M.; Cook, Robert L.; Malloy, Paul; Devlin, Kathryn; Cohen, Ronald A.
Depression and apathy are common among people living with HIV (PLWH). However, in PLWH, it is unclear whether depression and apathy are distinct conditions, which contribute to different patterns of disruption to cognitive processing and brain systems. Understanding these conditions may enable the development of prognostic indicators for HIV associated neurocognitive disorders (HAND). The present study examined substance use behavior and cognitive deficits, associated with depression and apathy, in 120 PLWH, using hierarchical regression analyses. Higher levels of depression were associated with a history of alcohol dependence and greater deficits in processing speed, motor and global cognitive functioning. Higher levels of apathy were associated with a history of cocaine dependence. It is recommended that PLWH get screened appropriately for apathy and depression, in order to receive the appropriate treatment, considering the comorbidities associated with each condition. Future research should examine the neurological correlates of apathy and depression in PLWH. PMID:25533921
Champagne, Courtney; Moore, Lindsey; Reule, Ross; Dyer, Jonathan A.; Rady, Peter; Tyring, Stephen K.
Abstract: Epidermodysplasia verruciformis (EV) is an uncommon inherited skin condition with increased vulnerability to widespread infection by certain human papillomavirus types, resulting in extensive verruca plana-like papules coalescing to large confluent plaques. Since the AIDS epidemic starting in the 1980s, an acquired type of EV has been described in patients infected with human immunodeficiency virus. The histopathologic features of EV consist of papillated epidermal hyperplasia with hypergranulosis and a distinct bluish-gray color in the large human papillomavirus-infected keratinocytes in the stratum granulosum. The authors present a case of HIV-associated EV with a unique histopathologic finding of multiple cornoid lamella-like structures. To the authors' knowledge, this finding has not been previously described in the literature. PMID:26588337
Champagne, Courtney; Moore, Lindsey; Reule, Ross; Dyer, Jonathan A; Rady, Peter; Tyring, Stephen K; North, Jeffrey P
Epidermodysplasia verruciformis (EV) is an uncommon inherited skin condition with increased vulnerability to widespread infection by certain human papillomavirus types, resulting in extensive verruca plana-like papules coalescing to large confluent plaques. Since the AIDS epidemic starting in the 1980s, an acquired type of EV has been described in patients infected with human immunodeficiency virus. The histopathologic features of EV consist of papillated epidermal hyperplasia with hypergranulosis and a distinct bluish-gray color in the large human papillomavirus-infected keratinocytes in the stratum granulosum. The authors present a case of HIV-associated EV with a unique histopathologic finding of multiple cornoid lamella-like structures. To the authors' knowledge, this finding has not been previously described in the literature.
Cherry, Catherine L; Wadley, Antonia L; Kamerman, Peter R
HIV-associated sensory neuropathy (HIV-SN) is a common complication of HIV and remains highly prevalent even with modern HIV management strategies, causing debilitating pain in millions globally. We review HIV-SN diagnosis and management. We suggest most HIV-SN cases are easily recognized using clinical screening tools, with physician assessment and/or specialized testing prioritized for atypical cases. Management aims to prevent further nerve damage and optimize symptom control. Symptom relief is difficult and rarely complete, with a lack of proven pharmacological strategies. Work is needed to clarify optimal use of available medications. This includes understanding the marked placebo effect in HIV-SN analgesic trials and exploring 'responder phenotypes'. Limited data support nondrug strategies including hypnosis, meditation, psychology, physical activity and a positive therapeutic relationship.
Abidin, Anas Zainul; D'Souza, Adora M.; Nagarajan, Mahesh B.; Wismüller, Axel
The use of functional Magnetic Resonance Imaging (fMRI) has provided interesting insights into our understanding of the brain. In clinical setups these scans have been used to detect and study changes in the brain network properties in various neurological disorders. A large percentage of subjects infected with HIV present cognitive deficits, which are known as HIV associated neurocognitive disorder (HAND). In this study we propose to use our novel technique named Mutual Connectivity Analysis (MCA) to detect differences in brain networks in subjects with and without HIV infection. Resting state functional MRI scans acquired from 10 subjects (5 HIV+ and 5 HIV-) were subject to standard preprocessing routines. Subsequently, the average time-series for each brain region of the Automated Anatomic Labeling (AAL) atlas are extracted and used with the MCA framework to obtain a graph characterizing the interactions between them. The network graphs obtained for different subjects are then compared using Network-Based Statistics (NBS), which is an approach to detect differences between graphs edges while controlling for the family-wise error rate when mass univariate testing is performed. Applying this approach on the graphs obtained yields a single network encompassing 42 nodes and 65 edges, which is significantly different between the two subject groups. Specifically connections to the regions in and around the basal ganglia are significantly decreased. Also some nodes corresponding to the posterior cingulate cortex are affected. These results are inline with our current understanding of pathophysiological mechanisms of HIV associated neurocognitive disease (HAND) and other HIV based fMRI connectivity studies. Hence, we illustrate the applicability of our novel approach with network-based statistics in a clinical case-control study to detect differences connectivity patterns.
Odone, Anna; Matteelli, Alberto; Chiesa, Valentina; Cella, Paola; Ferrari, Antonio; Pezzetti, Federica; Signorelli, Carlo; Getahun, Haileyesus
In 2010, the WHO issued 77 priority research questions (PRQs) to address HIV-associated TB. Objective of the this study was to assess the impact of defining the research agenda in stimulating and directing research around priority research questions. We used number and type of scientific publications as a proxy to quantitatively assess the impact of research agenda setting. We conducted 77 single systematic reviews - one for every PRQ - building 77 different search strategies using PRQs' keywords. Multivariate logistic regression models were applied to assess the quantity and quality of research produced over time and accounting for selected covariates. In 2009-2015, PRQs were addressed by 1631 publications (median: 11 studies published per PRQ, range 1-96). The most published area was 'Intensified TB case finding' (median: 23 studies/PRQ, range: 2-74). The majority (62.1%, n = 1013) were published as original studies, and more than half (58%, n = 585) were conducted in the African region. Original studies' publication increased over the study period (P trend = <0.001). They focused more on the 'Intensified TB case finding' (OR = 2.17, 95% CI: 1.56-2.93) and 'Drug-resistant TB and HIV infection' (OR = 2.12, 95% CI: 1.47-3.06) areas than non-original studies. Original studies were published in journals of lower impact factor and received a smaller number of citations than non-original studies (OR = 0.54, 95% CI: 0.42-0.69). The generation of evidence to address PRQs has increased over time particularly in selected fields. Setting a priority research agenda for HIV-associated TB might have positively influenced the direction and the conduct of research and contributed to the global response to such a major threat to health. © 2016 John Wiley & Sons Ltd.
Booth, John W; Hamzah, Lisa; Jose, Sophie; Horsfield, Catherine; O'Donnell, Patrick; McAdoo, Stephen; Kumar, Emil A; Turner-Stokes, Tabitha; Khatib, Nadia; Das, Partha; Naftalin, Claire; Mackie, Nicola; Kingdon, Ed; Williams, Debbie; Hendry, Bruce M; Sabin, Caroline; Jones, Rachael; Levy, Jeremy; Hilton, Rachel; Connolly, John; Post, Frank A
The pathogenesis and natural history of HIV-associated immune complex kidney disease (HIVICK) is not well understood. Key questions remain unanswered, including the role of HIV infection and replication in disease development and the efficacy of antiretroviral therapy (ART) in the prevention and treatment of disease. In this multicentre study, we describe the renal pathology of HIVICK and compare the clinical characteristics of patients with HIVICK with those with IgA nephropathy and HIV-associated nephropathy (HIVAN). Poisson regression models were used to identify risk factors for each of these pathologies. Between 1998 and 2012, 65 patients were diagnosed with HIVICK, 27 with IgA nephropathy and 70 with HIVAN. Black ethnicity and HIV RNA were associated with HIVICK, receipt of ART with IgA nephropathy and black ethnicity and CD4 cell count with HIVAN. HIVICK was associated with lower rates of progression to end-stage kidney disease compared with HIVAN and IgA nephropathy (P < 0.0001). Patients with HIVICK who initiated ART and achieved suppression of HIV RNA experienced improvements in estimated glomerular filtration rate and proteinuria. These findings suggest a pathogenic role for HIV replication in the development of HIVICK and that ART may improve kidney function in patients who have detectable HIV RNA at the time of HIVICK diagnosis. Our data also suggest that IgA nephropathy should be viewed as a separate entity and not included in the HIVICK spectrum. © The Author 2016. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.
Fields, Jerel; Dumaop, Wilmar; Langford, T D; Rockenstein, Edward; Masliah, E
Migration of HIV infected cells into the CNS is associated with a spectrum of neurological disorders, ranging from milder forms of HIV-associated neurocognitive disorders (HAND) to HIV-associated dementia (HAD). These neuro-psychiatric syndromes are related to the neurodegenerative pathology triggered by the release of HIV proteins and cytokine/chemokines from monocytes/macrophages into the CNS -a condition known as HIV encephalitis (HIVE). As a result of more effective combined anti-retroviral therapy patients with HIV are living longer and thus the frequency of HAND has increased considerably, resulting in an overlap between the neurodegenerative pathology associated with HIV and that related to aging. In fact, HIV infection is believed to hasten the aging process. The mechanisms through which HIV and aging lead to neurodegeneration include: abnormal calcium flux, excitotoxicity, signaling abnormalities, oxidative stress and autophagy defects. Moreover, recent studies have shown that defects in the processing and transport of neurotrophic factors such as fibroblast growth factors (FGFs), neural growth factor (NGF) and brain-derived growth factor (BDNF) might also play a role. Recent evidence implicates alterations in neurotrophins in the pathogenesis of neurodegeneration associated with HAND in the context of aging. Here, we report FGF overexpression curtails gp120-induced neurotoxicity in a double transgenic mouse model. Furthermore, our data show disparities in brain neurotrophic factor levels may be exacerbated in HIV patients over 50 years of age. In this review, we discuss the most recent findings on neurotrophins and HAND in the context of developing new therapies to combat HIV infection in the aging population.
Okuku, Fred; Krantz, Elizabeth M; Kafeero, James; Kamya, Moses R; Orem, Jackson; Casper, Corey; Phipps, Warren
HIV-associated Kaposi sarcoma (KS) is commonly staged using the AIDS Clinical Trials Group criteria, which classify 3 variables- tumor extent (T), immune status (I), and systemic symptoms (S)-into good risk (0) and poor risk (1). Although validated in the United States and Europe, these criteria have not been systematically evaluated in sub-Saharan Africa, where the burden of KS is greatest. We reviewed medical charts of adult patients with HIV-associated KS seen at the Uganda Cancer Institute from 1992 to 2007. Vital status at 2 years after KS diagnosis was determined from the medical chart, or by contacting the patient or next of kin. Survival estimates used Kaplan-Meier methods. Predictors were evaluated for 2 periods: 0-4 months and 4-24 months after diagnosis. At 2 years after diagnosis, 167 (41%) patients were alive, 156 (39%) had died, and 81 (20%) were lost to follow-up. The Kaplan-Meier estimate of 2-year survival was 57%. S1 was associated with death in months 0-4 [hazard ratio: 6.4, 95% confidence interval: 1.9-21.1], whereas T1 was associated with death in months 4-24 [hazard ratio: 4.0, 95% confidence interval: 1.4 to 11.5]. Immune status was not associated with survival. Systemic symptoms were strongly associated with death in the early period after KS diagnosis, whereas tumor status was most predictive of death in the 4- to 24-month period. These findings suggest that different processes may influence outcomes in early and late periods following KS diagnosis. Further studies are needed to confirm these observations and to identify better predictors of KS survival in sub-Saharan Africa.
Adenis, Antoine; Nacher, Mathieu; Hanf, Matthieu; Vantilcke, Vincent; Boukhari, Rachida; Blachet, Denis; Demar, Magalie; Aznar, Christine; Carme, Bernard; Couppie, Pierre
Histoplasmosis is an endemic fungal infection in French Guiana. It is the most common AIDS-defining illness and the leading cause of AIDS-related deaths. Diagnosis is difficult, but in the past 2 decades, it has improved in this French overseas territory which offers an interesting model of Amazonian pathogen ecology. The objectives of the present study were to describe the temporal trends of incidence and mortality indicators for HIV-associated histoplasmosis in French Guiana. A retrospective study was conducted to describe early mortality rates observed in persons diagnosed with incident cases of HIV-associated Histoplasma capsulatum var. capsulatum histoplasmosis admitted in one of the three main hospitals in French Guiana between 1992 and 2011. Early mortality was defined by death occurring within 30 days after antifungal treatment initiation. Data were collected on standardized case report forms and analysed using standard statistical methods. There were 124 deaths (45.3%) and 46 early deaths (16.8%) among 274 patients. Three time periods of particular interest were identified: 1992-1997, 1998-2004 and 2005-2011. The two main temporal trends were: the proportion of early deaths among annual incident histoplasmosis cases significantly declined four fold (χ2, p<0.0001) and the number of annual incident histoplasmosis cases increased three fold between 1992-1997 and 1998-2004, and subsequently stabilized. From an occasional exotic diagnosis, AIDS-related histoplasmosis became the top AIDS-defining event in French Guiana. This was accompanied by a spectacular decrease of early mortality related to histoplasmosis, consistent with North American reference center mortality rates. The present example testifies that rapid progress could be at reach if awareness increases and leads to clinical and laboratory capacity building in order to diagnose and treat this curable disease.
Adenis, Antoine; Nacher, Mathieu; Hanf, Matthieu; Vantilcke, Vincent; Boukhari, Rachida; Blachet, Denis; Demar, Magalie; Aznar, Christine; Carme, Bernard; Couppie, Pierre
Background Histoplasmosis is an endemic fungal infection in French Guiana. It is the most common AIDS-defining illness and the leading cause of AIDS-related deaths. Diagnosis is difficult, but in the past 2 decades, it has improved in this French overseas territory which offers an interesting model of Amazonian pathogen ecology. The objectives of the present study were to describe the temporal trends of incidence and mortality indicators for HIV-associated histoplasmosis in French Guiana. Methods A retrospective study was conducted to describe early mortality rates observed in persons diagnosed with incident cases of HIV-associated Histoplasma capsulatum var. capsulatum histoplasmosis admitted in one of the three main hospitals in French Guiana between 1992 and 2011. Early mortality was defined by death occurring within 30 days after antifungal treatment initiation. Data were collected on standardized case report forms and analysed using standard statistical methods. Results There were 124 deaths (45.3%) and 46 early deaths (16.8%) among 274 patients. Three time periods of particular interest were identified: 1992–1997, 1998–2004 and 2005–2011. The two main temporal trends were: the proportion of early deaths among annual incident histoplasmosis cases significantly declined four fold (χ2, p<0.0001) and the number of annual incident histoplasmosis cases increased three fold between 1992–1997 and 1998–2004, and subsequently stabilized. Conclusion From an occasional exotic diagnosis, AIDS-related histoplasmosis became the top AIDS-defining event in French Guiana. This was accompanied by a spectacular decrease of early mortality related to histoplasmosis, consistent with North American reference center mortality rates. The present example testifies that rapid progress could be at reach if awareness increases and leads to clinical and laboratory capacity building in order to diagnose and treat this curable disease. PMID:25144374
Evans, Robert J; Li, Zhongming; Hughes, William S; Djordjevic, Julianne T; Nielsen, Kirsten; May, Robin C
Cryptococcus neoformans is an opportunistic fungal pathogen and a leading cause of fungal-infection-related fatalities, especially in immunocompromised hosts. Several virulence factors are known to play a major role in the pathogenesis of cryptococcal infections, including the enzyme phospholipase B1 (Plb1). Compared to other well-studied Cryptococcus neoformans virulence factors such as the polysaccharide capsule and melanin production, very little is known about the contribution of Plb1 to cryptococcal virulence. Phospholipase B1 is a phospholipid-modifying enzyme that has been implicated in multiple stages of cryptococcal pathogenesis, including initiation and persistence of pulmonary infection and dissemination to the central nervous system, but the underlying reason for these phenotypes remains unknown. Here we demonstrate that a Δplb1 knockout strain of C. neoformans has a profound defect in intracellular growth within host macrophages. This defect is due to a combination of a 50% decrease in proliferation and a 2-fold increase in cryptococcal killing within the phagosome. In addition, we show for the first time that the Δplb1 strain undergoes a morphological change during in vitro and in vivo intracellular infection, resulting in a subpopulation of very large titan cells, which may arise as a result of the attenuated mutant's inability to cope within the macrophage.
Cabello Úbeda, Alfonso; Fortes Alen, José; Gadea, Ignacio; Mahillo, Ignacio; Górgolas, Miguel; Fernández Guerrero, Manuel L
Cryptococcal meningoencephalitis (CM) is an uncommon entity, but remains a major cause of morbidity and mortality in patients with AIDS. Review of CM cases in a university hospital. The diagnosis was determined by isolation of Cryptococcus neoformans in cerebrospinal fluid. Morbidity and mortality was assessed at 12 weeks (early mortality) and between 3 and 18 months after diagnosis (late mortality). We analyzed 32 patients from 2,269 AIDS cases (1.41%). 10 patients between 1990-1996 and 22 between 1997-2014. Cryptococcal antigen in CSF was positive in all cases, with titers>1,024 in 19 patients (63%); this group had lower CD4+ counts (40 ± 33 vs. 139 ± 78 cel/μL) and greater disseminated involvement. After a first CM episode the relapse rate was 34%. Global mortality rate was 28% (9/32), much higher in the pre-HAART era. CM morbidity and mortality is related to severe immunodeficiency, disseminated disease, high titers of antigen in CSF and delayed initiation of HAART. Copyright © 2016 Elsevier España, S.L.U. All rights reserved.
Xu, Jintao; Flaczyk, Adam; Neal, Lori M; Fa, Zhenzong; Eastman, Alison J; Malachowski, Antoni N; Cheng, Daphne; Moore, Bethany B; Curtis, Jeffrey L; Osterholzer, John J; Olszewski, Michal A
The scavenger receptor macrophage receptor with collagenous structure (MARCO) promotes protective innate immunity against bacterial and parasitic infections; however, its role in host immunity against fungal pathogens, including the major human opportunistic fungal pathogen Cryptococcus neoformans, remains unknown. Using a mouse model of C. neoformans infection, we demonstrated that MARCO deficiency leads to impaired fungal control during the afferent phase of cryptococcal infection. Diminished fungal containment in MARCO(-/-) mice was accompanied by impaired recruitment of Ly6C(high) monocytes and monocyte-derived dendritic cells (moDC) and lower moDC costimulatory maturation. The reduced recruitment and activation of mononuclear phagocytes in MARCO(-/-) mice was linked to diminished early expression of IFN-γ along with profound suppression of CCL2 and CCL7 chemokines, providing evidence for roles of MARCO in activation of the CCR2 axis during C. neoformans infection. Lastly, we found that MARCO was involved in C. neoformans phagocytosis by resident pulmonary macrophages and DC. We conclude that MARCO facilitates early interactions between C. neoformans and lung-resident cells and promotes the production of CCR2 ligands. In turn, this contributes to a more robust recruitment and activation of moDC that opposes rapid fungal expansion during the afferent phase of cryptococcal infection.
Voelz, Kerstin; Johnston, Simon A; Rutherford, Julian C; May, Robin C
The human fungal pathogens Cryptococcus neoformans and C. gattii cause life-threatening infections of the central nervous system. One of the major characteristics of cryptococcal disease is the ability of the pathogen to parasitise upon phagocytic immune effector cells, a phenomenon that correlates strongly with virulence in rodent models of infection. Despite the importance of phagocyte/Cryptococcus interactions to disease progression, current methods for assaying virulence in the macrophage system are both time consuming and low throughput. Here, we introduce the first stable and fully characterised GFP-expressing derivatives of two widely used cryptococcal strains: C. neoformans serotype A type strain H99 and C. gattii serotype B type strain R265. Both strains show unaltered responses to environmental and host stress conditions and no deficiency in virulence in the macrophage model system. In addition, we report the development of a method to effectively and rapidly investigate macrophage parasitism by flow cytometry, a technique that preserves the accuracy of current approaches but offers a four-fold improvement in speed.
Voelz, Kerstin; Johnston, Simon A.; Rutherford, Julian C.; May, Robin C.
The human fungal pathogens Cryptococcus neoformans and C. gattii cause life-threatening infections of the central nervous system. One of the major characteristics of cryptococcal disease is the ability of the pathogen to parasitise upon phagocytic immune effector cells, a phenomenon that correlates strongly with virulence in rodent models of infection. Despite the importance of phagocyte/Cryptococcus interactions to disease progression, current methods for assaying virulence in the macrophage system are both time consuming and low throughput. Here, we introduce the first stable and fully characterised GFP–expressing derivatives of two widely used cryptococcal strains: C. neoformans serotype A type strain H99 and C. gattii serotype B type strain R265. Both strains show unaltered responses to environmental and host stress conditions and no deficiency in virulence in the macrophage model system. In addition, we report the development of a method to effectively and rapidly investigate macrophage parasitism by flow cytometry, a technique that preserves the accuracy of current approaches but offers a four-fold improvement in speed. PMID:21209844
Ellis, Carla L
Patients with HIV infection have a wide spectrum of renal diseases. Some are known to be the direct effect of the viral infection while others are renal diseases that also occur in uninfected populations. HIV associated nephropathy (HIVAN) is considered to be a subtype of primary focal and segmental glomerulosclerosis that is distinct in HIV infected patients. It is more frequent in the African-American population and associated with mutations of the apolipoprotein L1 (APOL1) gene. HIV associated immune complex kidney disease (HIVICD) encompasses a spectrum of HIV associated renal diseases characterized by the presence of immune complex deposition within glomeruli. Thrombotic microangiopathy (TMA) is a complication of HIV infection that presents with hemolytic anemia, thrombocytopenia, and renal failure. TMA in HIV patients is associated with very high mortality. Lastly, the multitude of antiretroviral drugs used for treatment of HIV infections can result in nephrotoxicity. Although a kidney biopsy may not be the first line study for renal disease, knowledge of the different histopathologic features of HIV-associated and unassociated diseases is of paramount importance in the treatment and subsequent outcome of renal function in HIV infected patients. In this review we will describe the histopathologic features and discuss the pathophysiology of the entities previously named. Copyright © 2017 Elsevier Inc. All rights reserved.
Le Rhun, Emilie; Taillibert, Sophie; Chamberlain, Marc C
Neoplastic meningitis, a central nervous system (CNS) complication of cancer metastatic to the meninges and cerebrospinal fluid (CSF), is relevant to oncologists due to the impact of the disease on patient quality of life and survival rates. A review of the literature of articles published in English was conducted with regard to neoplastic meningitis. The incidence of neoplastic meningitis is increasing because patients with cancer are surviving longer in part because of the use of novel therapies with poor CNS penetration. Up to 5% of patients with solid tumors develop neoplastic meningitis during the disease course (breast cancer, lung cancer, and melanoma being the predominantly causative cancers). The rate of median survival in patients with untreated neoplastic meningitis is 1 to 2 months, although it can be as long as 5 months in some cases. Therapeutic options for the treatment of neoplastic meningitis include systemic therapy (cancer-specific, CNS-penetrating chemotherapy or targeted therapies), intra-CSF administration of chemotherapy (methotrexate, cytarabine, thiotepa) and CNS site-specific radiotherapy. Determining whom to treat with neoplastic meningitis remains challenging and, in part, relates to the extent of systemic disease, the neurological burden of disease, the available systemic therapies, and estimated rates of survival. The prognosis of neoplastic meningitis remains poor. The increasing use of novel, targeted therapies and immunotherapy in solid tumors and its impact on neoplastic meningitis remains to be determined and is an area of active research. Thus, well conducted trials are needed.
Mehta, Anish; Mahale, Rohan R.; Sudhir, Uchil; Javali, Mahendra; Srinivasa, Rangasetty
Background: Meningitis remains a serious clinical problem in developing as well as developed countries. Delay in diagnosis and treatment results in significant morbidity and mortality. The role and levels of intrathecal endogenous cortisol is not known. Objective: To study the cerebrospinal fluid (CSF) cortisol levels and to evaluate its role as a diagnostic and therapeutic marker in acute bacterial meningitis. Materials and Methods: Thirty patients with acute bacterial meningitis with no prior treatment were evaluated. Cortisol levels were compared with 20 patients with aseptic (viral) meningitis and 25 control subjects. Results: Mean CSF cortisol level was 13.85, 3.47, and 1.05 in bacterial meningitis, aseptic meningitis, and controls, respectively. Mean CSF cortisol level in bacterial meningitis was significantly higher as compared to controls (P < 0.001). There was significant difference in CSFcortisol levels in bacterial and aseptic meningitis (P < 0.001). Conclusions: Cortisol levels in CSF are highly elevated in patients with acute bacterial meningitis. This suggests that intrathecalcortisol may serve as a valuable, rapid, relatively inexpensive diagnostic marker in discriminatingbetween bacterial and aseptic meningitis. This helps in earlier institution of appropriate treatment and thereby decreasing morbidity and mortality. PMID:26019421
Tsegaw, Million; Andargie, Gashaw; Alem, Getnet; Tareke, Minale
The vast majority of people living with HIV/AIDS reside in low and middle income countries, particularly in Sub-Saharan Africa, including Ethiopia. Despite the huge number of service users in the local area, cognitive disorder among HIV patients has not been extensively studied and there is a dearth of knowledge on the subject. The objective of this study was to assess the prevalence and associated factors of HIV-associated neurocognitive disorder among people living with HIV/AIDS in antiretroviral therapy (ART) clinics. Institution based cross sectional study was conducted from April to May, 2015 at Dessie Referral Hospital & Kombolcha Health Center. International HIV Dementia Scale was used to screen HIV associated neurocognitive deficits. Logistic regression analysis was used to assess predictors of neurocognitive disorders. The risk of HIV associated neurocognitive disorder was 36.4%. Those who had CD4 count of 500 cells/dl or less (AOR = 2.368 (1.524, 3.680)), no formal education (AOR = 4.287 (2.619, 7.016)), poor medication adherence (AOR = 1.487 (1.010, 2.180)) and older age (AOR = 3.309 (1.259, 8.701)) were found to be significantly associated with HIV associated neurocognitive disorders. The risk of HIV-associated neurocognitive disorder was found to be high among people living with HIV/AIDS. This emphasizes the need of regular cognitive screening for early identification and appropriate intervention. Copyright © 2016 Elsevier Ltd. All rights reserved.
Rigakos, Georgios; Liakou, Chrysoula I; Felipe, Naillid; Orkoulas-Razis, Dennis; Razis, Evangelia
Neoplastic meningitis is a complication of solid and hematological malignancies. It consists of the spread of malignant cells to the leptomeninges and subarachnoid space and their dissemination within the cerebrospinal fluid. A literature review was conducted to summarize the clinical presentation, differential diagnosis, laboratory values, and imaging findings of neoplastic meningitis. Neoplastic meningitis is an event in the course of cancer with a variable clinical presentation and a wide differential diagnosis. In general, characteristic findings on gadolinium-enhanced magnetic resonance imaging and the presence of malignant cells in the cerebrospinal fluid remain the cornerstones of diagnosis. However, both modalities do not always confirm the diagnosis of neoplastic meningitis despite a typical clinical picture. Clinicians treating patients with cancer should be aware of the possibility of neoplastic meningitis, especially when multilevel neurological symptoms are present. Neoplastic meningitis can be an elusive diagnosis, so clinician awareness is important so that this malignant manifestation is recognized in a timely manner.
Pai, Shivanand; Madi, Deepak; Achappa, Basavaprabhu; Mahalingam, Soundarya; Kendambadi, Rakshith
Angiostrongylus cantonensis is one of the causative agents of eosinophilic meningitis. Humans get infected when they ingest raw or partially cooked snails or monitor lizards (Varanus bengalensis). There is a popular belief that the tongue and the liver of the monitor lizard has aphrodisiac properties. A 20-year-old man was admitted to our hospital with a history of fever, headache and vomiting. His cerebrospinal fluid revealed eosinophilia. He gave a history of the ingestion of a monitor lizard, ten days prior to the onset of the symptoms. So, a diagnosis of eosinophilic meningitis due to Angiostrongylus cantonensis was made. He was treated with oral albendazole and prednisolone. His symptoms improved gradually within two weeks from his admission.
Pai, Shivanand; Madi, Deepak; Achappa, Basavaprabhu; Mahalingam, Soundarya; Kendambadi, Rakshith
Angiostrongylus cantonensis is one of the causative agents of eosinophilic meningitis. Humans get infected when they ingest raw or partially cooked snails or monitor lizards (Varanus bengalensis). There is a popular belief that the tongue and the liver of the monitor lizard has aphrodisiac properties. A 20-year-old man was admitted to our hospital with a history of fever, headache and vomiting. His cerebrospinal fluid revealed eosinophilia. He gave a history of the ingestion of a monitor lizard, ten days prior to the onset of the symptoms. So, a diagnosis of eosinophilic meningitis due to Angiostrongylus cantonensis was made. He was treated with oral albendazole and prednisolone. His symptoms improved gradually within two weeks from his admission. PMID:23730662
Pereira, P Ricardo; Borges, Fernando; Mansinho, Kamal
The duration of antibiotic therapy in bacterial meningitis is a controversial issue. Antibiotic regimens have changed over time along with the criteria used to determine the ideal antibiotic therapy duration. The authors aim to make an historical overview on this matter and simultaneously add the evidence of recent studies, pointing out some issues in results interpretation, namely, their design and the associated demographic and epidemiological questions. Clinical assays on this subject, with statistically significant results, are quite recent. Most of the scientific knowledge has been acquired empirically through the times. The actual investigation paradigm, in what concerns to antibiotic therapy in bacterial meningitis, lays on the dichotomy: "short versus long duration regimens". Nevertheless, so far, the existing studies have not completely cleared this doubt. Thus, despite some evidence suggests that short duration antibiotic regimens are effective for some patients, in patients with severe disease presentations or with other morbidities its use may be questioned.
Rakotoarivelo, Rivonirina A.; Randriamampionona, Njary; Rakotomalala, Angelot F.; Razafinambinintsoa, Tiana; Bénet, Thomas; Vanhems, Philippe; Randria, Mamy J. D. D.; Cornet, Muriel
Cryptococcal meningoencephalitis is considered rare in HIV-negative individuals. In Madagascar, the epidemiology of cryptococcosis has not yet been well described, neither in immunocompetent nor in immunocompromised patients. We report here the first Malagasy detailed case of cryptococcal meningoencephalitis in a non-HIV immunocompromised adult patient carrying a low fluconazole susceptibility isolate. We emphasize the importance of early and accurate diagnosis to meet the challenges of managing cryptococcosis in developing countries. PMID:28078149
Pierzchała, K; Grudzińska, B; Bara, M; Kłosińska, E
In autumn 1982 during an epidemic of meningitis caused by Coxsackie A9 and ECHO4 viruses 36 patients, usually young, were hospitalized. After 3-4 years 22 of them were subjected to control examinations, carrying out medical examination. EEG, ACG, motor nerve conduction velocity measurements and psychological examinations by the tests od Eysenck, Bender-Koppitz and Wechsler. The studied group comprised 14 men and 8 women with mean age 29.8 years.
Kim, Suk Ran; Kwon, Min Jung; Lee, Jang Ho; Lee, Nam Yong
A 47-year-old man presented with headache, nausea, vomiting and fever. Laboratory findings including analysis of cerebrospinal fluid suggested bacterial meningitis. Erysipelothrix rhusiopathiae was identified in cultures of cerebrospinal fluid. The patient recovered without any neurological sequelae after antimicrobial treatment. It is interesting that intracranial infection by E. rhusiopathiae reappeared after scores of years and that it presented with absence of an underlying cause or bacteraemia.
THROAT CULTURE FROM PATIENTS-’WITH MENINGOCOCCAL MENINGITIS BY J.E. Sippel and N.I. Girigs U.S. NAVAL MEDICAL RESEARCH UNIT NO. 3 (CAIRO, ARAB REPUBLIC...lowv albumin eoncen rations, characteristically, have a centra fpit and are throat swabs from teenage or young dults but that it als’q underestimites...8217described would’/cletzrly facilitate recognition read at 590 tim against commensal staphylococci and strep - NP IIRENWALD The procedure is linear t thie
Gupta, Anu; Jogi, Vishal; Goyal, Manoj Kumar; Modi, Manish; Khurana, Dheeraj
Chronic aseptic meningitis is a rare manifestation of systemic lupus erythematosus (SLE). Apart from immunological causes and drugs, the aseptic meningitis group can include some unidentified viral infections that cannot be detected by routine microbiological testing. It is imperative to do complete cerebrospinal fluid (CSF) workup before implicating the symptoms to disease activity or drugs, as untreated infections cause significant mortality in SLE. We present a case of young female with SLE who presented with chronic meningitis of an uncommon etiology.
Gupta, Anu; Jogi, Vishal; Goyal, Manoj Kumar; Modi, Manish; Khurana, Dheeraj
Chronic aseptic meningitis is a rare manifestation of systemic lupus erythematosus (SLE). Apart from immunological causes and drugs, the aseptic meningitis group can include some unidentified viral infections that cannot be detected by routine microbiological testing. It is imperative to do complete cerebrospinal fluid (CSF) workup before implicating the symptoms to disease activity or drugs, as untreated infections cause significant mortality in SLE. We present a case of young female with SLE who presented with chronic meningitis of an uncommon etiology. PMID:25506165
de Melo, Cláudia Raquel Ferrão; de Sá, Mário Correia; Carvalho, Sónia
A healthy 6-year-old boy presented with an erythematous macular exanthema, meningeal signs and fever, initially diagnosed with probable bacterial meningitis and treated with antibiotic and anti-inflammatory drugs. Enteroviral meningitis was confirmed, but the skin lesions continued to evolve and the patient was ultimately diagnosed with erythema dyschromicum perstans. The boy was followed during three years until the spontaneous resolution of the dermatosis. PMID:28225976
Mrelashvili, Anna; Braksick, Sherri A; Murphy, Lauren L; Morparia, Neha P; Natt, Neena; Kumar, Neeraj
Rathke's cleft cysts (RCC) are usually benign, sellar and/or suprasellar lesions originating from the remnants of Rathke's pouch. Rarely, RCC can present with chemical meningitis, sellar abscess, lymphocytic hypophysitis, or intracystic hemorrhage. We describe an unusual presentation of RCC in which the patient presented with a clinical picture of chemical meningitis consisting of meningeal irritation, inflammatory cerebrospinal fluid profile, and enhancing pituitary and hypothalamic lesions, in addition to involvement of the optic tracts and optic nerve.
Albuquerque, Priscila C; Cordero, Radames J B; Fonseca, Fernanda L; Peres da Silva, Roberta; Ramos, Caroline L; Miranda, Kildare R; Casadevall, Arturo; Puccia, Rosana; Nosanchuk, Joshua D; Nimrichter, Leonardo; Guimaraes, Allan J; Rodrigues, Marcio L
The cell wall of the yeast form of the dimorphic fungus Paracoccidioides brasiliensis is enriched with α1,3-glucans. In Cryptococcus neoformans, α1,3-glucans interact with glucuronoxylomannan (GXM), a heteropolysaccharide that is essential for fungal virulence. In this study, we investigated the occurrence of P. brasiliensis glycans sharing properties with cryptococcal GXM. Protein database searches in P. brasiliensis revealed the presence of sequences homologous to those coding for enzymes involved in the synthesis of GXM and capsular architecture in C. neoformans. In addition, monoclonal antibodies (mAbs) raised to cryptococcal GXM bound to P. brasiliensis cells. Using protocols that were previously established for extraction and analysis of C. neoformans GXM, we recovered a P. brasiliensis glycan fraction composed of mannose and galactose, in addition to small amounts of glucose, xylose and rhamnose. In comparison with the C. neoformans GXM, the P. brasiliensis glycan fraction components had smaller molecular dimensions. The P. brasiliensis components, nevertheless, reacted with different GXM-binding mAbs. Extracellular vesicle fractions of P. brasiliensis also reacted with a GXM-binding mAb, suggesting that the polysaccharide-like molecule is exported to the extracellular space in secretory vesicles. An acapsular mutant of C. neoformans incorporated molecules from the P. brasiliensis extract onto the cell wall, resulting in the formation of surface networks that resembled the cryptococcal capsule. Coating the C. neoformans acapsular mutant with the P. brasiliensis glycan fraction resulted in protection against phagocytosis by murine macrophages. These results suggest that P. brasiliensis and C. neoformans share metabolic pathways required for the synthesis of similar polysaccharides and that P. brasiliensis yeast cell walls have molecules that mimic certain aspects of C. neoformans GXM. These findings are important because they provide additional evidence for
Correa, Néstor; Covarrubias, Cristian; Rodas, Paula I.; Hermosilla, Germán; Olate, Verónica R.; Valdés, Cristián; Meyer, Wieland; Magne, Fabien; Tapia, Cecilia V.
Melanin is a pigment found in all biological kingdoms, and plays a key role in protection against ultraviolet radiation, oxidizing agents, and ionizing radiation damage. Melanin exerts an antimicrobial activity against bacteria, fungi, and parasites. We demonstrated an antifungal activity of synthetic and human melanin against Candida sp. The members of the Cryptococcus neoformans and C. gattii species complexes are capsulated yeasts, which cause cryptococcosis. For both species melanin is an important virulence factor. To evaluate if cryptococcal and human melanins have antifungal activity against Cryptococcus species they both were assayed for their antifungal properties and physico-chemical characters. Melanin extracts from human hair and different strains of C. neoformans (n = 4) and C. gattii (n = 4) were investigated. The following minimum inhibitory concentrations were found for different melanins against C. neoformans and C. gattii were (average/range): 13.7/(7.8–15.6) and 19.5/(15.6–31.2) μg/mL, respectively, for human melanin; 273.4/(125–>500) and 367.2/(125.5–>500) μg/mL for C. neoformans melanin and 125/(62.5–250) and 156.2/(62–250) μg/mL for C. gattii melanin. Using Scanning Electron Microscopy we observed that human melanin showed a compact conformation and cryptococcal melanins exposed an amorphous conformation. Infrared spectroscopy (FTIR) showed some differences in the signals related to C-C bonds of the aromatic ring of the melanin monomers. High Performance Liquid Chromatography established differences in the chromatograms of fungal melanins extracts in comparison with human and synthetic melanin, particularly in the retention time of the main compound of fungal melanin extracts and also in the presence of minor unknown compounds. On the other hand, MALDI-TOF-MS analysis showed slight differences in the spectra, specifically the presence of a minor intensity ion in synthetic and human melanin, as well as in some fungal melanin
Correa, Néstor; Covarrubias, Cristian; Rodas, Paula I; Hermosilla, Germán; Olate, Verónica R; Valdés, Cristián; Meyer, Wieland; Magne, Fabien; Tapia, Cecilia V
Melanin is a pigment found in all biological kingdoms, and plays a key role in protection against ultraviolet radiation, oxidizing agents, and ionizing radiation damage. Melanin exerts an antimicrobial activity against bacteria, fungi, and parasites. We demonstrated an antifungal activity of synthetic and human melanin against Candida sp. The members of the Cryptococcus neoformans and C. gattii species complexes are capsulated yeasts, which cause cryptococcosis. For both species melanin is an important virulence factor. To evaluate if cryptococcal and human melanins have antifungal activity against Cryptococcus species they both were assayed for their antifungal properties and physico-chemical characters. Melanin extracts from human hair and different strains of C. neoformans (n = 4) and C. gattii (n = 4) were investigated. The following minimum inhibitory concentrations were found for different melanins against C. neoformans and C. gattii were (average/range): 13.7/(7.8-15.6) and 19.5/(15.6-31.2) μg/mL, respectively, for human melanin; 273.4/(125->500) and 367.2/(125.5->500) μg/mL for C. neoformans melanin and 125/(62.5-250) and 156.2/(62-250) μg/mL for C. gattii melanin. Using Scanning Electron Microscopy we observed that human melanin showed a compact conformation and cryptococcal melanins exposed an amorphous conformation. Infrared spectroscopy (FTIR) showed some differences in the signals related to C-C bonds of the aromatic ring of the melanin monomers. High Performance Liquid Chromatography established differences in the chromatograms of fungal melanins extracts in comparison with human and synthetic melanin, particularly in the retention time of the main compound of fungal melanin extracts and also in the presence of minor unknown compounds. On the other hand, MALDI-TOF-MS analysis showed slight differences in the spectra, specifically the presence of a minor intensity ion in synthetic and human melanin, as well as in some fungal melanin extracts. We
Tai, Mei-Ling Sharon; Viswanathan, Shanthi; Rahmat, Kartini; Nor, Hazman Mohd; Kadir, Khairul Azmi Abdul; Goh, Khean Jin; Ramli, Norlisah; Bakar, Fatimah Kamila Abu; Zain, Norzaini Rose Mohd; Yap, Jun Fai; Ong, Beng Hooi; Rafia, Mohd Hanip; Tan, Chong Tin
Tuberculous meningitis (TBM) causes significant morbidity and mortality. The primary objective was to re-examine the concept of “TB zone” and “ischaemic zone” in cerebral infarction in patients with tuberculous meningitis. The secondary objective was to evaluate cerebral infarction, vasculitis and vasospasm in tuberculous meningitis infections. Between 2009 and 2014, TBM patients were recruited. Neuroimaging was performed and findings of cerebral infarction, vasculitis and vasospasm were recorded. Infarcts were classified based on arterial supply and Hsieh’s classification. Fifty-one TBM patients were recruited of whom 34 patients (67%) had cerebral infarction. Based on Hsieh’s classification, 20 patients (59%) had infarcts in both “TB zone” and “ischaemic zones”. 12 patients (35%) had infarcts in “ischaemic zone” and two (6%) patients had infarcts in “TB zone”. In terms of vascular supply, almost all patients (35/36) had infarcts involving perforators and cortical branches. 25 patients (73%) and 14 patients (41%) had infarcts supplied by lateral lenticulostriate and medial lenticulostriate arteries respectively. 15 patients (37%) had vasculitis. Vasospasm was present in six patients (15%). 29 patients (85%) with cerebral infarction also had leptomeningeal enhancement (p = 0.002). In summary, infarcts involved mainly perforators and cortical branches, rather than “TB zone” versus “ischaemic zone”. PMID:27958312
Stefanski, Michael; Williams, Ronald; McSherry, George; Geskey, Joseph
Viral bronchiolitis accounts for almost 20% of all-cause hospitalizations of infants (ie, children younger than age 1 year). The annual incidence of fever in viral bronchiolitis has been documented at 23% to 31%. However the incidence of concurrent serious bacterial infections is low (1%–7%), with meningitis occurring in less than 1% to 2% of cases, but lumbar puncture is performed in up to 9% of viral bronchiolitis cases. To our knowledge, no study has examined clinical factors that influence a physician’s decision to perform a lumbar puncture in the setting of viral bronchiolitis. We present a retrospective, case-control study of hospitalized infants younger than one year diagnosed with viral bronchiolitis who underwent lumbar puncture as part of an evaluation for meningitis. The objective of the study was to determine clinical factors that influence a physician’s decision to perform a lumbar puncture in the setting of viral bronchiolitis. Although the presence of apnea, cyanosis, meningeal signs, positive urine culture results, and young age were factors found to be preliminarily associated with the performance of a lumbar puncture in the setting of bronchiolitis, young age was the only significant clinical factor found after multivariable regression; no other demographic, clinical, laboratory, or radiologic variables were found to be significant. PMID:25662522
Irazuzta, Jose; Pretzlaff, Robert K; Zingarelli, Basilia
To evaluate the effects of sustained caspase inhibition during the acute phase of meningitis-induced brain injury. Changes in neurobehavioral performance were the primary outcome variables. Randomized prospective animal study. University research laboratory. Male Wistar rats. Animals underwent a basilar cistern inoculation of group B Streptococci to induce meningitis. Sixteen hours later animals were randomized to receive Bocaspartyl (OMe)-fluoromethyketone (BAF) for 4 days or placebo in addition to antibiotic therapy. The assessment of neurobehavioral performance was started 7 days after initiation of treatment and continued for the following 3 wks. A subgroup underwent early kill, at 5 days, to evaluate caspase 3 activity in brain tissue. There was a group of Sham instrumented animals. BAF decreased caspase 3 activation in meningitic animals. There were no significant motor deficit differences between the infected groups. Cognitive performance was significantly improved in the BAF group. These findings demonstrate that sustained systemic administration of BAF inhibits caspase 3 activation and decreases neurologic sequelae in a rat model of bacterial meningitis.
Saliou, P; Debois, H
In 1963, Lapeyssonnie published a masterful description of the epidemiology of cerebrospinal meningococcal meningitis in the Sahel region of Africa (essentially due to the Neisseria meningitidis sero-group A): geographic spread (meningitis belt), seasonal cycle (dry and cool season). When a combined polyosidic AC vaccine became available in the early 1970s, a disease control strategy was defined along the lines of epidemiological surveillance, prophylaxis of lethality by early treatment of cases and reactive vaccination, since the polyosidic vaccine could not be included in the Expanded Programme on Immunization (EPI). Despite some success, this strategy has not led to the control of cerebrospinal meningococcal meningitis in Africa. Amongst the obstacles encountered are the difficulty to define at what point an out-break becomes an epidemic, gaps in epidemiological surveillance, unavailable vaccine doses, delayed and complex vaccination campaigns. At the end of the 1990s, controversy ensued: since reactive vaccination was fraught with so many problems, why not consider a strategy of preventive AC vaccination for high risk areas? But this controversy may well die out with the emergence of the present-day W 135 serogroup responsible for the first large scale epidemic in Burkina Faso in 2002. If this is confirmed, a polyosidic vaCcine containing the W 135 antigen would be required, pending the availability for Africa of a conjugate tetravalent ACYW135 vaccine which could be included in the EPI.
Tudisco, Jean-Blaise; Fumeaux, Christophe; Petignat, Pierre-Auguste
Eosinophilic meningitis is a rare entity, which is a complication of an underlying disease. Its diagnosis and treatment is always a challenge for the hospital practitioner. The aim of this case report and review is to identify the most important aetiologies, and show the diagnostic and therapeutic modalities of Eosinophilic meningitis. The most frequent causes of Eosinophilic meningitis are parasitic and fungal infections. In Europe Eosinophilic meningitis is essentially seen in travellers returning from endemic areas for these agents. The treatment is directed against the underlying disease and can differ depending on the aetiology and severity of the clinical manifestations.
Wei, Benjamin P C; Shepherd, Robert K; Robins-Browne, Roy M; Clark, Graeme M; O'Leary, Stephen J
Both clinical data and laboratory studies demonstrated the risk of pneumococcal meningitis post-cochlear implantation. This review examines strategies to prevent post-implant meningitis. Medline/PubMed database; English articles after 1980. Search terms: cochlear implants, pneumococcus meningitis, streptococcus pneumonia, immunization, prevention. Narrative review. All articles relating to post-implant meningitis without any restriction in study designs were assessed and information extracted. The presence of inner ear trauma as a result of surgical technique or cochlear implant electrode array design was associated with a higher risk of post-implant meningitis. Laboratory data demonstrated the effectiveness of pneumococcal vaccination in preventing meningitis induced via the hematogenous route of infection. Fibrous sealing around the electrode array at the cochleostomy site, and the use of antibiotic-coated electrode array reduced the risk of meningitis induced via an otogenic route. The recent scientific data support the U.S. Food and Drug Administration recommendation of pneumococcal vaccination for the prevention of meningitis in implant recipients. Nontraumatic cochlear implant design, surgical technique, and an adequate fibrous seal around the cochleostomy site further reduce the risk of meningitis. Copyright © 2010 American Academy of Otolaryngology–Head and Neck Surgery Foundation. Published by Mosby, Inc. All rights reserved.
Rosales, Cecilia M; Jackson, Mary Anne; Zwick, David
We present a case of Malassezia furfur meningitis arising in a very low birth weight infant with chronic lung disease, necrotizing enterocolitis, and intraventricular hemorrhage. M. furfur meningitis was probably acquired late following successful treatment for earlier systemic central line-associated M. furfur infection. M. furfur meningitis has only once been previously reported. Unlike the previous case where meningitis was secondary to widespread blood-borne dissemination, infection was limited to the leptomeninges and arose in association with extravasation of total parenteral nutrition (TPN) and intralipid fluid into subarachnoid space via peripheral scalp catheter.
Aguado, M Teresa; Jodar, Luis; Granoff, Dan; Rabinovich, Regina; Ceccarini, Costante; Perkin, Gordon W
Polysaccharide vaccines had been used to control African meningitis epidemics for >30 years but with little or modest success, largely because of logistical problems in the implementation of reactive vaccination campaigns that are begun after epidemics are under way. After the major group A meningococcal meningitis epidemics in 1996-1997 (250,000 cases and 25,000 deaths), African ministers of health declared the prevention of meningitis a high priority and asked the World Health Organization (WHO) for help in developing better immunization strategies to eliminate meningitis epidemics in Africa. WHO accepted the challenge and created a project called Epidemic Meningitis Vaccines for Africa (EVA) that served as an organizational framework for external consultants, PATH, the US Centers for Disease Control and Prevention (CDC), and the Bill & Melinda Gates Foundation (BMGF). Consultations were initiated with major vaccine manufacturers. EVA commissioned a costing study/business plan for the development of new group A or A/C conjugate vaccines and explored the feasibility of developing these products as a public-private partnership. Representatives from African countries were consulted. They confirmed that the development of conjugate vaccines was a priority and provided information on preferred product characteristics. In parallel, a strategy for successful introduction was also anticipated and discussed. The expert consultations recommended that a group A meningococcal conjugate vaccine be developed and introduced into the African meningitis belt. The results of the costing study indicated that the "cost of goods" to develop a group A - containing conjugate vaccine in the United States would be in the range of US$0.35-$1.35 per dose, depending on composition (A vs A/C), number of doses/vials, and presentation. Following an invitation from BMGF, a proposal was submitted in the spring of 2001. In June 2001, BMGF awarded a grant of US$70 million to create the Meningitis
Aguado, M. Teresa; Jodar, Luis; Granoff, Dan; Rabinovich, Regina; Ceccarini, Costante; Perkin, Gordon W.
Background. Polysaccharide vaccines had been used to control African meningitis epidemics for >30 years but with little or modest success, largely because of logistical problems in the implementation of reactive vaccination campaigns that are begun after epidemics are under way. After the major group A meningococcal meningitis epidemics in 1996–1997 (250 000 cases and 25 000 deaths), African ministers of health declared the prevention of meningitis a high priority and asked the World Health Organization (WHO) for help in developing better immunization strategies to eliminate meningitis epidemics in Africa. Methods. WHO accepted the challenge and created a project called Epidemic Meningitis Vaccines for Africa (EVA) that served as an organizational framework for external consultants, PATH, the US Centers for Disease Control and Prevention (CDC), and the Bill & Melinda Gates Foundation (BMGF). Consultations were initiated with major vaccine manufacturers. EVA commissioned a costing study/business plan for the development of new group A or A/C conjugate vaccines and explored the feasibility of developing these products as a public–private partnership. Representatives from African countries were consulted. They confirmed that the development of conjugate vaccines was a priority and provided information on preferred product characteristics. In parallel, a strategy for successful introduction was also anticipated and discussed. Results. The expert consultations recommended that a group A meningococcal conjugate vaccine be developed and introduced into the African meningitis belt. The results of the costing study indicated that the “cost of goods” to develop a group A – containing conjugate vaccine in the United States would be in the range of US$0.35–$1.35 per dose, depending on composition (A vs A/C), number of doses/vials, and presentation. Following an invitation from BMGF, a proposal was submitted in the spring of 2001. Conclusions. In June 2001
Kirchhoff, Frank; Silvestri, Guido
HIV-associated hematological abnormalities involve all lineages of blood cells, thus implying that the virus impairs the function of early HSCs. However, the underlying mechanisms of this defect are unknown, particularly since HSCs are largely resistant to HIV-1 infection. In this issue of the JCI, Prost and colleagues show that the viral accessory protein Negative factor (Nef) plays a potentially critical role in the pathogenesis of HIV/SIV-associated hematopoietic dysfunction by affecting the clonogenic potential of HSCs (see the related article beginning on page 1765). Soluble Nef induces PPARγ in uninfected HSCs, thereby suppressing the expression of STAT5A and STAT5B, two factors necessary for proper HSC function. The identification of this novel activity of extracellular Nef defines a new mechanism of HIV/SIV pathogenesis and suggests that approaches aimed at increasing STAT5A and STAT5B expression may be considered in HIV-infected individuals with prominent hematological abnormalities. The results also raise the question of whether dysregulation of hematopoiesis by extracellular Nef plays a role in the development of T cell immunodeficiency and the high levels of chronic immune activation associated with AIDS. PMID:18431512
Mediouni, Sonia; Garibaldi Marcondes, Maria Cecilia; Miller, Courtney; McLaughlin, Jay P.; Valente, Susana T.
Antiretroviral therapy has dramatically improved the lives of human immunodeficiency virus 1 (HIV-1) infected individuals. Nonetheless, HIV-associated neurocognitive disorders (HAND), which range from undetectable neurocognitive impairments to severe dementia, still affect approximately 50% of the infected population, hampering their quality of life. The persistence of HAND is promoted by several factors, including longer life expectancies, the residual levels of virus in the central nervous system (CNS) and the continued presence of HIV-1 regulatory proteins such as the transactivator of transcription (Tat) in the brain. Tat is a secreted viral protein that crosses the blood–brain barrier into the CNS, where it has the ability to directly act on neurons and non-neuronal cells alike. These actions result in the release of soluble factors involved in inflammation, oxidative stress and excitotoxicity, ultimately resulting in neuronal damage. The percentage of methamphetamine (MA) abusers is high among the HIV-1-positive population compared to the general population. On the other hand, MA abuse is correlated with increased viral replication, enhanced Tat-mediated neurotoxicity and neurocognitive impairments. Although several strategies have been investigated to reduce HAND and MA use, no clinically approved treatment is currently available. Here, we review the latest findings of the effects of Tat and MA in HAND and discuss a few promising potential therapeutic developments. PMID:26557111
Scott, J Cobb; Woods, Steven Paul; Patterson, Katherine A; Morgan, Erin E; Heaton, Robert K; Grant, Igor; Marcotte, Thomas D
The aim of the present study was to investigate the nature and cognitive mechanisms of serial position learning effects in HIV-associated dementia (HAD). Participants were 16 persons with HAD, 50 non-demented persons with HIV-infection, and 50 demographically comparable HIV-seronegative participants. HAD participants, relative to both comparison groups, exhibited reduced middle region (p<0.01) and elevated recency region (p<0.05) recall on the Hopkins Verbal Learning Test-Revised, but no primacy region effect (p>0.10). On recognition testing, the HAD group was impaired in discriminating targets from distractors (p<0.01) in all three serial position regions; however, they were not impaired on measures of retrieval (p>0.10) within these same regions. In sum, HAD participants relied disproportionately on recency regions of the list, indicating a passive recall style of echoing only the words within their auditory attention span. Interestingly, HAD participants did not evidence significant improvement on measures of recognition, a finding that suggests that the serial position effects are most consistent with a primary encoding deficit.
Abedi, Vida; Hontecillas, Raquel; Hoops, Stefan; Leber, Andrew; Bassaganya-Riera, Josep; Ciupe, Stanca M.
Human immunodeficiency virus (HIV)-infected patients are at an increased risk of co-infection with human papilloma virus (HPV), and subsequent malignancies such as oral cancer. To determine the role of HIV-associated immune suppression on HPV persistence and pathogenesis, and to investigate the mechanisms underlying the modulation of HPV infection and oral cancer by HIV, we developed a mathematical model of HIV/HPV co-infection. Our model captures known immunological and molecular features such as impaired HPV-specific effector T helper 1 (Th1) cell responses, and enhanced HPV infection due to HIV. We used the model to determine HPV prognosis in the presence of HIV infection, and identified conditions under which HIV infection alters HPV persistence in the oral mucosa system. The model predicts that conditions leading to HPV persistence during HIV/HPV co-infection are the permissive immune environment created by HIV and molecular interactions between the two viruses. The model also determines when HPV infection continues to persist in the short run in a co-infected patient undergoing antiretroviral therapy. Lastly, the model predicts that, under efficacious antiretroviral treatment, HPV infections will decrease in the long run due to the restoration of CD4+ T cell numbers and protective immune responses. PMID:28060843
Jun, Suhnyoung; Shin, Na-Young; Han, Sanghoon; Ahn, Jin Young; Ahn, Mi Young; Jeon, Yong Duk; Jung, In Young; Kim, Moo Hyun; Jeong, Woo Yong; Ku, Nam Su; Kim, June Myung; Smith, Davey M.; Choi, Jun Yong
Background HIV-associated neurocognitive disorder (HAND) can occur in patients without prior AIDS defining illness and can be debilitating. This study aimed to evaluate the difference in the patterns of intrinsic brain activity between patients with or without HAND for deepening our understanding of HAND. Methods We evaluated 24 HIV-infected individuals, 12 with previously diagnosed HAND and 12 previously diagnosed without HAND, and 11 seronegative individuals. These individuals then underwent repeat NP testing and a functional brain MRI scan. For functional MRI analysis, seed-based analysis with bilateral precuneus cortex seed was applied. Results Among the 12 individuals with previously diagnosed HAND, 3 showed improvement of their neurocognitive function and 1 was excluded for worsening liver disease. Among the 12 patients who previously had normal neurocognitive function, 2 showed neurocognitive impairment. Overall, the HAND group, who had impaired cognitive function at the time of MRI scan, showed significant decrease of resting status functional connectivity between bilateral precuneus and prefrontal cortex (PFC) compared with nonHAND group, those who had normal neurocognitive function (Corrected P<0.05). The functional connectivity with the right inferior frontal operculum and right superior frontal gyrus was positively correlated with memory and learning ability. Conclusions This cross-sectional study found a significant difference in fMRI patterns between patients with and without HAND. Decreased functional connectivity between precuneus and PFC could be possible functional substrate for cognitive dysfunction in HIV patients, which should be characterized in a longitudinal study. PMID:27104345
Power, Christopher; Hui, Elizabeth; Vivithanaporn, Pornpun; Acharjee, Shaona; Polyak, Maria
HIV-associated neurocognitive disorders (HAND) represent a constellation of neurological disabilities defined by neuropsychological impairments, neurobehavioral abnormalities and motor deficits. To gain insights into the mechanisms underlying the development of these disabilities, several transgenic models have been developed over the past two decades, which have provided important information regarding the cellular and molecular factors contributing to the neuropathogenesis of HAND. Herein, we concentrate on the neuropathogenic effects of HIV-1 Vpr expressed under the control of c-fms, resulting transgene expression in myeloid cells in both the central and peripheral nervous systems. Vpr's actions, possibly through its impact on cell cycle machinery, in brain culminate in neuronal and astrocyte injury and death through apoptosis involving activation of caspases-3, -6 and -9 depending on the individual target cell type. Indeed, these outcomes are also induced by soluble Vpr implying Vpr's effects stem from direct interaction with target cells. Remarkably, in vivo transgenic Vpr expression induces a neurodegenerative phenotype defined by neurobehavioral deficits and neuronal loss in the absence of frank inflammation. Implantation of another viral protein, hepatitis C virus (HCV) core, into Vpr transgenic animals' brains stimulated neuroinflammation and amplified the neurodegenerative disease phenotype, thereby recapitulating HCV's putative neuropathogenic actions. The availability of different transgenic models to study HIV neuropathogenesis represents exciting and innovative approaches to understanding disease mechanisms and perhaps developing new therapeutic strategies in the future.
Yeo, Q M; Crutchley, R; Cottreau, J; Tucker, A; Garey, K W
Secretory diarrhea has a significant impact on morbidity and mortality worldwide and may be a predominant or minor component of pathogenesis in diarrhea of various etiologies. Crofelemer is a first-in-class antidiarrheal medication with unique inhibitory mechanisms at both the cystic fibrosis transmembrane conductance regulator and the calcium-activated chloride channels which are responsible for chloride secretion and subsequent luminal hydration. The efficacy of crofelemer has been investigated in patients with HIV-associated diarrhea, diarrhea of various infectious etiologies, as well as diarrhea-predominant irritable bowel syndrome. Crofelemer was approved by the FDA in December 2012 to treat diarrhea in HIV/AIDS patients on antiretroviral therapy. Crofelemer is not absorbed in the body and well-tolerated in small trials performed to date although long-term safety data is lacking. Crofelemer may be an important addition to the currently available drugs for the management of secretory diarrhea. Copyright 2013 Prous Science, S.A.U. or its licensors. All rights reserved.
Siev, Michael; Wilson, Douglas; Kainth, Supreet; Kasprowicz, Victoria O.; Feintuch, Catherine M.; Jenny-Avital, Elizabeth R.
Serology data are limited for patients with sputum smear-negative HIV-associated active tuberculosis (TB). We evaluated the serum antibody responses against the mycobacterial proteins MPT51, MS, and echA1 and the 38-kDa protein via enzyme-linked immunosorbent assay (ELISA) in South African (S.A.) HIV-positive (HIV+) smear-negative TB patients (n = 56), U.S. HIV+ controls with a positive tuberculin skin test (TST+; n = 21), and S.A. HIV-negative (HIV−) (n = 18) and HIV+ (n = 24) controls. TB patients had positive antibody reactivity against MPT51 (73%), echA1 (59%), MS (36%), and the 38-kDa protein (11%). Little reactivity against MPT51 and echA1 was observed in control groups at low risk for TB, i.e., S.A. HIV− (0% and 6%, respectively), and at moderate risk for TB development, i.e., U.S. HIV+ TST+ controls (14% and 10%, respectively). By contrast, more reactivity was detected in the S.A. HIV+ control group at higher risk for TB (25% and 45%, respectively). Our data hold promise that antibody detection against MPT51 and echA1 might have adjunctive value in the detection of HIV+ smear-negative TB and might reflect increasing Mycobacterium tuberculosis infection activity in asymptomatic HIV+ individuals. PMID:24671553
Morgan, Erin E; Woods, Steven Paul; Smith, Christine; Weber, Erica; Scott, J Cobb; Grant, Igor
HIV-seropositive individuals with low cognitive reserve are at high risk for developing HIV-associated neurocognitive disorders (HAND). The present study evaluated the hypothesis that cognitive reserve would also play a unique role in the expression of everyday functioning complications among those with HAND (i.e., syndromic versus subsyndromic impairment). Eighty-six individuals with HIV infection were evaluated; 53 individuals evidenced normal neurocognitive performance, 16 had subsyndromic HAND (i.e., asymptomatic neurocognitive impairment), and 17 were diagnosed with syndromic HAND based on a comprehensive neurobehavioral evaluation. Cognitive reserve represented a combined score including years of education, estimated verbal IQ, and highest occupational attainment. The groups were comparable (e.g. demographics), and the HAND groups had similar rates of global neurocognitive impairment. The syndromic HAND group evidenced lower reserve scores relative to both other groups, suggesting that individuals with lower reserve may be less able to effectively counteract their neurocognitive impairment to maintain independence in daily living activities than HIV-infected individuals with high cognitive reserve.
Keltner, John R.; Fennema-Notestine, Christine; Vaida, Florin; Wang, Dongzhe; Franklin, Donald R.; Dworkin, Robert H.; Sanders, Chelsea; McCutchan, J. Allen; Archibald, Sarah L.; Miller, David J.; Kesidis, George; Cushman, Clint; Kim, Sung Min; Abramson, Ian; Taylor, Michael J.; Theilmann, Rebecca J.; Julaton, Michelle D.; Notestine, Randy J.; Corkran, Stephanie; Cherner, Mariana; Duarte, Nichole A.; Alexander, Terry; Robinson-Papp, Jessica; Gelman, Benjamin B.; Simpson, David M.; Collier, Ann C.; Marra, Christina M.; Morgello, Susan; Brown, Greg; Grant, Igor; Atkinson, J. Hampton; Jernigan, Terry L.; Ellis, Ronald J.
Despite modern antiretroviral therapy, HIV-associated sensory neuropathy affects over 50% of HIV patients. The clinical expression of HIV neuropathy is highly variable: many individuals report few symptoms, but about half report distal neuropathic pain (DNP), making it one of the most prevalent, disabling and treatment-resistant complications of HIV disease. The presence and intensity of pain is not fully explained by the degree of peripheral nerve damage, making it unclear why some patients do, and others do not, report pain. To better understand central nervous system contributions to HIV DNP, we performed a cross-sectional analysis of structural magnetic resonance imaging (MRI) volumes in 241 HIV-infected participants from an observational multi-site cohort study at five US sites (CNS HIV Antiretroviral Treatment Effects Research Study, CHARTER). The association between DNP and the structural imaging outcomes was investigated using both linear and nonlinear (Gaussian Kernel support vector) multivariable regression, controlling for key demographic and clinical variables. Severity of DNP symptoms was correlated with smaller total cerebral cortical gray matter volume (R = −0.24; p = 0.004). Understanding the mechanisms for this association between smaller total cortical volumes and DNP may provide insight into HIV DNP chronicity and treatment-resistance. PMID:24549970
Keltner, John R; Fennema-Notestine, Christine; Vaida, Florin; Wang, Dongzhe; Franklin, Donald R; Dworkin, Robert H; Sanders, Chelsea; McCutchan, J Allen; Archibald, Sarah L; Miller, David J; Kesidis, George; Cushman, Clint; Kim, Sung Min; Abramson, Ian; Taylor, Michael J; Theilmann, Rebecca J; Julaton, Michelle D; Notestine, Randy J; Corkran, Stephanie; Cherner, Mariana; Duarte, Nichole A; Alexander, Terry; Robinson-Papp, Jessica; Gelman, Benjamin B; Simpson, David M; Collier, Ann C; Marra, Christina M; Morgello, Susan; Brown, Greg; Grant, Igor; Atkinson, J Hampton; Jernigan, Terry L; Ellis, Ronald J
Despite modern antiretroviral therapy, HIV-associated sensory neuropathy affects over 50 % of HIV patients. The clinical expression of HIV neuropathy is highly variable: many individuals report few symptoms, but about half report distal neuropathic pain (DNP), making it one of the most prevalent, disabling, and treatment-resistant complications of HIV disease. The presence and intensity of pain is not fully explained by the degree of peripheral nerve damage, making it unclear why some patients do, and others do not, report pain. To better understand central nervous system contributions to HIV DNP, we performed a cross-sectional analysis of structural magnetic resonance imaging volumes in 241 HIV-infected participants from an observational multi-site cohort study at five US sites (CNS HIV Anti-Retroviral Treatment Effects Research Study, CHARTER). The association between DNP and the structural imaging outcomes was investigated using both linear and nonlinear (Gaussian Kernel support vector) multivariable regression, controlling for key demographic and clinical variables. Severity of DNP symptoms was correlated with smaller total cerebral cortical gray matter volume (r = -0.24; p = 0.004). Understanding the mechanisms for this association between smaller total cortical volumes and DNP may provide insight into HIV DNP chronicity and treatment-resistance.
Iudicello, Jennifer E; Woods, Steven Paul; Cattie, Jordan E; Doyle, Katie; Grant, Igor
Individuals infected with HIV show moderate deficits in decision-making, but the ecological relevance of such deficits on everyday functioning has not previously been described. This study sought to examine the magnitude, cognitive correlates, and everyday functioning impact of risky decision-making impairment in HIV-associated neurocognitive disorders (HAND). Participants included 68 HIV+ individuals with HAND, 78 HIV+ individuals without HAND, and 51 HIV- comparison participants, who were administered the Iowa Gambling Task (IGT) alongside a comprehensive neuropsychological test battery and self-report measures assessing aspects of everyday functioning. HIV+ individuals with HAND performed more poorly on the IGT relative to the other two groups, most notably during the last three trial blocks. Within the HIV+ group, IGT performance during the last three trial blocks was most strongly associated with cognitive flexibility, but was not significantly related to declines in instrumental activities of daily living (IADLs), unemployment, or medication non-adherence. While overall IGT performance across the last three trial blocks may be helpful diagnostically in identifying decision-making impairment in HAND, examination of alternate, more specific metrics (e.g., individual deck selections across trial blocks) may be more useful in delineating the role of poor decision-making in HIV-related disability, and should be examined in future research.
Iudicello, Jennifer E.; Woods, Steven Paul; Cattie, Jordan E.; Doyle, Katie; Grant, Igor
Individuals infected with HIV show moderate deficits in decision-making, but the ecological relevance of such deficits on everyday functioning has not previously been described. This study sought to examine the magnitude, cognitive correlates, and everyday functioning impact of risky decision-making impairment in HIV-associated neurocognitive disorders (HAND). Participants included 68 HIV+ individuals with HAND, 78 HIV+ individuals without HAND, and 51 HIV- comparison participants, who were administered the Iowa Gambling Task (IGT) alongside a comprehensive neuropsychological test battery and self-report measures assessing aspects of everyday functioning. HIV+ individuals with HAND performed more poorly on the IGT relative to the other two groups, most notably during the last three trial blocks. Within the HIV+ group, IGT performance during the last three trial blocks was most strongly associated with cognitive flexibility, but was not significantly related to declines in instrumental activities of daily living (IADLs), unemployment, or medication non-adherence. While overall IGT performance across the last three trial blocks may be helpful diagnostically in identifying decision-making impairment in HAND, examination of alternate, more specific metrics (e.g., individual deck selections across trial blocks) may be more useful in delineating the role of poor decision-making in HIV-related disability, and should be examined in future research. PMID:23181946
Morgan, Erin E.; Woods, Steven Paul; Smith, Christine; Weber, Erica; Scott, J. Cobb; Grant, Igor
HIV-seropositive individuals with low cognitive reserve are at high risk for developing HIV-associated neurocognitive disorders (HAND). The present study evaluated the hypothesis that cognitive reserve would also play a unique role in the expression of everyday functioning complications among those with HAND (i.e., syndromic versus subsyndromic impairment). Eighty-six individuals with HIV infection were evaluated; 53 individuals evidenced normal neurocognitive performance, 16 had subsyndromic HAND (i.e., Asymptomatic Neurocognitive Impairment), and 17 were diagnosed with a syndromic HAND based on a comprehensive neurobehavioral evaluation. Cognitive reserve represented a combined score including years of education, estimated verbal IQ, and highest occupational attainment. The groups were comparable (e.g. demographics), and the HAND groups had similar rates of global neurocognitive impairment. The Syndromic HAND group evidenced lower reserve scores relative to both other groups, suggesting that HIV-infected individuals with high cognitive reserve more effectively counteract their neurocognitive impairment to maintain independence in daily living activities. PMID:22677976
Saylor, Deanna; Dickens, Alex M.; Sacktor, Ned; Haughey, Norman; Slusher, Barbara; Pletnikov, Mikhail; Mankowski, Joseph L.; Brown, Amanda; Volsky, David J.; McArthur, Justin C.
In the past two decades, several advancements have improved the care of HIV-infected individuals. Most importantly, the development and deployment of combination antiretroviral therapy (CART) has resulted in a dramatic decline in the rate of deaths from AIDS, so that people living with HIV today have nearly normal life expectancies if treated with CART. The term HIV-associated neurocognitive disorder (HAND) has been used to describe the spectrum of neurocognitive dysfunction associated with HIV infection. HIV can enter the CNS during early stages of infection, and persistent CNS HIV infection and inflammation probably contribute to the development of HAND. The brain can subsequently serve as a sanctuary for ongoing HIV replication, even when systemic viral suppression has been achieved. HAND can remain in patients treated with CART, and its effects on survival, quality of life and everyday functioning make it an important unresolved issue. In this Review, we describe the epidemiology of HAND, the evolving concepts of its neuropathogenesis, novel insights from animal models, and new approaches to treatment. We also discuss how inflammation is sustained in chronic HIV infection. Moreover, we suggest that adjunctive therapies — treatments targeting CNS inflammation and other metabolic processes, including glutamate homeostasis, lipid and energy metabolism — are needed to reverse or improve HAND-related neurological dysfunction. PMID:26965674
Hoffmann, Christian; Schmid, Holger; Müller, Markus; Teutsch, Christian; van Lunzen, Jan; Esser, Stefan; Wolf, Timo; Wyen, Christoph; Sabranski, Michael; Horst, Heinz-August; Reuter, Stefan; Vogel, Martin; Jäger, Hans; Bogner, Johannes; Arasteh, Keikawus
Although HIV-associated multicentric Castleman disease (HIV-MCD) is not classified as an AIDS-defining illness, mortality is high and progression to lymphoma occurs frequently. At present, there is no widely accepted recommendation for the treatment of HIV-MCD. In this retrospective (1998-2010), multicentric analysis of 52 histologically proven cases, outcome was analyzed with respect to the use of different MCD therapies and potential prognostic factors. After a mean follow-up of 2.26 years, 19 of 52 patients died. Median estimated overall survival (OS) was 6.2 years. Potential risk factors, such as older age, previous AIDS, or lower CD4 T cells had no impact on OS. Treatment was heterogeneous, consisting of cytostatic and/or antiviral agents, rituximab, or combinations of these modalities. There were marked differences in the outcome when patients were grouped according to MCD treatment. Patients receiving rituximab-based regimens had higher complete remission rates than patients receiving chemotherapy only. The mean estimated OS in patients receiving rituximab alone or in combination with cytostatic agents was not reached, compared with 5.1 years (P = .03). Clinical outcome and overall survival of HIV-MCD have markedly improved with rituximab-based therapies, considering rituximab-based therapies (with or without cytostatic agents) to be among the preferred first-line options in patients with HIV-MCD.
Skolasky, Richard L.; Seaberg, Eric; Munro, Cynthia; Becker, James T.; Martin, Eileen; Ragin, Ann; Levine, Andrew; Miller, Eric
Objective: To evaluate the frequency of HIV-associated neurocognitive disorder (HAND) in HIV+ individuals and determine whether the frequency of HAND changed over 4 years of follow-up. Methods: The Multicenter AIDS Cohort Study (MACS) is a prospective study of gay/bisexual men. Beginning in 2007, all MACS participants received a full neuropsychological test battery and functional assessments every 2 years to allow for HAND classification. Results: The frequency of HAND for the 364 HIV+ individuals seen in 2007–2008 was 33% and for the 197 HIV+ individuals seen at all time periods during the 2007–2008, 2009–2010, and 2011–2012 periods were 25%, 25%, and 31%, respectively. The overall frequency of HAND increased from 2009–2010 to 2011–2012 (p = 0.048). Over the 4-year study, 77% of the 197 HIV+ individuals remained at their same stage, with 13% showing deterioration and 10% showing improvement in HAND stage. Hypercholesterolemia was associated with HAND progression. A diagnosis of asymptomatic neurocognitive impairment was associated with a 2-fold increased risk of symptomatic HAND compared to a diagnosis of normal cognition. Conclusion: HAND remains common in HIV+ individuals. However, for the majority of HIV+ individuals on combination antiretroviral therapy with systemic virologic suppression, the diagnosis of HAND is not a progressive condition over 4 years of follow-up. Future studies should evaluate longitudinal changes in HAND and specific neurocognitive domains over a longer time period. PMID:26718568
Williams, Dionna W.; Veenstra, Mike; Gaskill, Peter J.; Morgello, Susan; Calderon, Tina M.; Berman, Joan W.
HIV infected people are living longer due to the success of combined antiretroviral therapy (cART). However, greater than 40-70% of HIV infected individuals develop HIV associated neurocognitive disorders (HAND) that continues to be a major public health issue. While cART reduces peripheral virus, it does not limit the low level, chronic neuroinflammation that is ongoing during the neuropathogenesis of HIV. Monocyte transmigration across the blood brain barrier (BBB), specifically that of the mature CD14+CD16+ population that is highly susceptible to HIV infection, is critical to the establishment of HAND as these cells bring virus into the brain and mediate the neuroinflammation that persists, even if at low levels, despite antiretroviral therapy. CD14+CD16+ monocytes preferentially migrate into the CNS early during peripheral HIV infection in response to chemotactic signals, including those from CCL2 and CXCL12. Once within the brain, monocytes differentiate into macrophages and elaborate inflammatory mediators. Monocytes/macrophages constitute a viral reservoir within the CNS and these latently infected cells may perpetuate the neuropathogenesis of HIV. This review will discuss mechanisms that mediate transmigration of CD14+CD16+ monocytes across the BBB in the context of HIV infection, the contribution of these cells to the neuropathogenesis of HIV, and potential monocyte/macrophage biomarkers to identify HAND and monitor its progression. PMID:24862333
Reddy, Pichili Vijaya Bhaskar; Pilakka-Kanthikeel, Sudheesh; Saxena, Shailendra K; Saiyed, Zainulabedin; Nair, Madhavan P N
HIV epidemic continues to be a severe public health problem and concern within USA and across the globe with about 33 million people infected with HIV. The frequency of drug abuse among HIV infected patients is rapidly increasing and is another major issue since injection drug users are at a greater risk of developing HIV associated neurocognitive dysfunctions compared to non-drug users infected with HIV. Brain is a major target for many of the recreational drugs and HIV. Evidences suggest that opiate drug abuse is a risk factor in HIV infection, neural dysfunction and progression to AIDS. The information available on the role of morphine as a cofactor in the neuropathogenesis of HIV is scanty. This review summarizes the results that help in understanding the role of morphine use in HIV infection and neural dysfunction. Studies show that morphine enhances HIV-1 infection by suppressing IL-8, downregulating chemokines with reciprocal upregulation of HIV coreceptors. Morphine also activates MAPK signaling and downregulates cAMP response element-binding protein (CREB). Better understanding on the role of morphine in HIV infection and mechanisms through which morphine mediates its effects may help in devising novel therapeutic strategies against HIV-1 infection in opiate using HIV-infected population.
Tugizov, Sharof M; Herrera, Rossana; Chin-Hong, Peter; Veluppillai, Piri; Greenspan, Deborah; Michael Berry, J; Pilcher, Christopher D; Shiboski, Caroline H; Jay, Naomi; Rubin, Mary; Chein, Aung; Palefsky, Joel M
The incidence of human papillomavirus (HPV)-associated epithelial lesions is substantially higher in human immunodeficiency virus (HIV)-infected individuals than in HIV-uninfected individuals. The molecular mechanisms underlying the increased risk of HPV infection in HIV-infected individuals are poorly understood. We found that HIV proteins tat and gp120 were expressed within the oral and anal mucosal epithelial microenvironment of HIV-infected individuals. Expression of HIV proteins in the mucosal epithelium was correlated with the disruption of epithelial tight junctions (TJ). Treatment of polarized oral, cervical and anal epithelial cells, and oral tissue explants with tat and gp120 led to disruption of epithelial TJ and increased HPV pseudovirion (PsV) paracellular penetration in to the epithelium. PsV entry was observed in the basal/parabasal cells, the cells in which the HPV life cycle is initiated. Our data suggest that HIV-associated TJ disruption of mucosal epithelia may potentiate HPV infection and subsequent development of HPV-associated neoplasia.
Zayyad, Zaina; Spudich, Serena
Early in the HIV epidemic, the central nervous system (CNS) was recognized as a target of infection and injury in the advanced stages of disease. Though the most severe forms of HIV-associated neurocognitive disorder (HAND) related to severe immunosuppression are rare in the current era of widespread combination antiretroviral therapy (cART), evidence now supports pathological involvement of the CNS throughout the course of infection. Recent work suggests that the stage for HIV neuropathogenesis may be set with initial viral entry into the CNS, followed by initiation of pathogenetic processes including neuroinflammation and neurotoxicity, and establishment of local, compartmentalized HIV replication that may reflect a tissue reservoir for HIV. Key questions still exist as to when HIV establishes local infection in the CNS, which CNS cells are the primary targets of HIV, and what mechanistic processes underlie the injury to neurons that produce clinical symptoms of HAND. Advances in these areas will provide opportunities for improved treatment of patients with established HAND, prevention of neurological disease in those with early stage infection, and understanding of HIV tissue reservoirs that will aid efforts at HIV eradication.
Swanepoel, Charles R; Wearne, Nicola; Duffield, Maureen S; Okpechi, Ikechi G
Human immunodeficiency virus (HIV) infection started in Africa circa 1930. South Africa has the highest prevalence rate in the world. Although reports of HIV-associated nephropathy (HIVAN) appeared in the early 1980s, the earliest report from sub-Saharan Africa (SSA) came in 1994. Geographical, socioeconomic, political, and ethical factors have worked in concert to shape the character of HIV disease as it is seen in SSA. Political leaders within SSA have, through their actions, significantly contributed to the incidence of HIV infection. Black females, who often face cultural suppression and disadvantage, have a higher prevalence of HIV than males. Too few studies and outcomes data have bedeviled the statistics in SSA in relation to HIVAN prevalence and its management. Much of what is written is approximation and anecdotal. The largest reliable biopsy series comes from the University of Cape Town, where a workable classification of HIVAN has been developed to enable standardization of terminology. Histologic and clinical prognostic indicators with outcomes have been evaluated using this classification. Patients with HIV who present with acute kidney injury appear to have mainly acute tubular necrosis due to sepsis, dehydration, and nephrotoxic drugs. Since the rollout of combination antiretroviral therapy, the extent of HIV infection and kidney disease continues to be modified and possibly retarded.
Gendelman, Howard E.; Gelbard, Harris A.
Purpose of review This review focuses on current and future strategies to modulate neuroinflammation while reducing residual viral burden in the central nervous system (CNS). This has been realized by targeted long acting antiretroviral nano- and adjunctive therapies being developed for HIV infected people. Our ultimate goal is to eliminate virus from its CNS reservoirs and, in so doing, reverse the cognitive and motor dysfunctions seen in HIV-associated neurocognitive disorders (HAND). Recent findings Herein, we highlight our laboratories development of adjunctive and nanomedicine therapies for HAND. An emphasis is placed on drug-drug interactions that target both the viral life cycle and secretory pro-inflammatory neurotoxic factors and signaling pathways. Summary Antiretroviral therapy (ART) has improved the quality and duration of life for people living with HIV-1. A significant long-term comorbid illness is HAND. Symptoms, while reduced in severity, are common. Disease occurs, in part, through continued low-level viral replication inducing secondary glial neuroinflammatory activities. Our recent works and those of others have seen disease attenuated in animal models through the use of adjunctive and long-acting reservoir targeted nanoformulated ART. The translation of these inventions from animals to humans is the focus of this review. PMID:25226025
Minocha, Vinay; Makary, Raafat; Poenariu, Andreea
Introduction. The most commonly seen glomerular disease in HIV infected patients is HIV-associated nephropathy (HIVAN); however, a multitude of other nephropathies can occur in HIV infection with an almost equal cumulative frequency. We report an unusual case of a patient with clinical and histological evidence of HIVAN in which the diagnosis was initially confounded by the finding of an elevated serum anti-glomerular basement membrane (anti-GBM) antibody. Case Presentation. We present a case of a 27-year-old African American female with a history of schizophrenia, cocaine abuse, and HIV infection who upon admission to our hospital was found to have severe acute kidney injury requiring hemodialysis. Urine studies revealed nephrotic range proteinuria and a serological workup was positive for anti-GBM antibody elevation with a value of 91 units (normal: 0-20 units). A renal biopsy revealed HIVAN with no evidence of crescentic glomerulonephritis or anti-GBM disease. Conclusion. This case highlights the need for careful interpretation of anti-GBM antibody tests in HIV infected patients with kidney disease and, in particular, the need for biopsy confirmation of the diagnosis prior to starting therapy. More research is needed to study the prognostic correlation between the degree of anti-GBM antibody elevation in HIVAN and disease severity.
Fields, Jerel Adam; Serger, Elisabeth; Campos, Sofia; Divakaruni, Ajit S; Kim, Changyoun; Smith, Kendall; Trejo, Margarita; Adame, Anthony; Spencer, Brian; Rockenstein, Edward; Murphy, Anne N; Ellis, Ronald J; Letendre, Scott; Grant, Igor; Masliah, Eliezer
HIV-associated neurocognitive disorders (HAND) still occur in approximately 50% of HIV patients, and therapies to combat HAND progression are urgently needed. HIV proteins are released from infected cells and cause neuronal damage, possibly through mitochondrial abnormalities. Altered mitochondrial fission and fusion is implicated in several neurodegenerative disorders. Here, we hypothesized that mitochondrial fission/fusion may be dysregulated in neurons during HAND. We have identified decreased mitochondrial fission protein (dynamin 1-like; DNM1L) in frontal cortex tissues of HAND donors, along with enlarged and elongated mitochondria localized to the soma of damaged neurons. Similar pathology was observed in the brains of GFAP-gp120 tg mice. In vitro, recombinant gp120 decreased total and active DNM1L levels, reduced the level of Mitotracker staining, and increased extracellular acidification rate (ECAR) in primary neurons. DNM1L knockdown enhanced the effects of gp120 as measured by reduced Mitotracker signal in the treated cells. Interestingly, overexpression of DNM1L increased the level of Mitotracker staining in primary rat neurons and reduced neuroinflammation and neurodegeneration in the GFAP-gp120-tg mice. These data suggest that mitochondrial biogenesis dynamics are shifted towards mitochondrial fusion in brains of HAND patients and this may be due to gp120-induced reduction in DNM1L activity. Promoting mitochondrial fission during HIV infection of the CNS may restore mitochondrial biogenesis and prevent neurodegeneration.
Fields, Jerel Adam; Serger, Elisabeth; Campos, Sofia; Divakaruni, Ajit S.; Kim, Changyoun; Smith, Kendall; Trejo, Margarita; Adame, Anthony; Spencer, Brian; Rockenstein, Edward; Murphy, Anne N.; Ellis, Ronald J.; Letendre, Scott; Grant, Igor; Masliah, Eliezer
HIV-associated neurocognitive disorders (HAND) still occur in approximately 50% of HIV patients, and therapies to combat HAND progression are urgently needed. HIV proteins are released from infected cells and cause neuronal damage, possibly through mitochondrial abnormalities. Altered mitochondrial fission and fusion is implicated in several neurodegenerative disorders. Here, we hypothesized that mitochondrial fission/fusion may be dysregulated in neurons during HAND. We have identified decreased mitochondrial fission protein (dynamin 1-like; DNM1L) in frontal cortex tissues of HAND donors, along with enlarged and elongated mitochondria localized to the soma of damaged neurons. Similar pathology was observed in the brains of GFAP-gp120 tg mice. In vitro, recombinant gp120 decreased total and active DNM1L levels, reduced the level of Mitotracker staining, and increased extracellular acidification rate (ECAR) in primary neurons. DNM1L knockdown enhanced the effects of gp120 as measured by reduced Mitotracker signal in the treated cells. Interestingly, overexpression of DNM1L increased the level of Mitotracker staining in primary rat neurons and reduced neuroinflammation and neurodegeneration in the GFAP-gp120-tg mice. These data suggest that mitochondrial biogenesis dynamics are shifted towards mitochondrial fusion in brains of HAND patients and this may be due to gp120-induced reduction in DNM1L activity. Promoting mitochondrial fission during HIV infection of the CNS may restore mitochondrial biogenesis and prevent neurodegeneration. PMID:26611103
Saylor, Deanna; Dickens, Alex M; Sacktor, Ned; Haughey, Norman; Slusher, Barbara; Pletnikov, Mikhail; Mankowski, Joseph L; Brown, Amanda; Volsky, David J; McArthur, Justin C
In the past two decades, several advancements have improved the care of HIV-infected individuals. Most importantly, the development and deployment of combination antiretroviral therapy (CART) has resulted in a dramatic decline in the rate of deaths from AIDS, so that people living with HIV today have nearly normal life expectancies if treated with CART. The term HIV-associated neurocognitive disorder (HAND) has been used to describe the spectrum of neurocognitive dysfunction as