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.
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.
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.
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.
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
... Bacterial meningitis in the United States, 1998-2007. N Engl J Med . 2011 May 26;364(21):2016-2025. Read More Diabetes HIV/AIDS Hodgkin lymphoma Hydrocephalus Review Date 12/7/2014 Updated by: Jatin M. Vyas, MD, PhD, Associate Professor in Medicine, Harvard Medical ...
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
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.
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
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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
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.
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
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.
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
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.
Douglas-Vail, Matt; Bechamp, Taylor; Gohal, Simran; Soegtrop, Robert; Vitali, Sarah; Rugemalila, Joan; Stone, Neil R H
Cryptococcal meningitis is a common and devastating complication of advanced HIV, and is most prevalent in low resource settings in sub Saharan Africa. Raised intracranial pressure is one of the hallmarks of the disease, which can lead to visual and hearing loss and ultimately death. We present the case of a patient with visual and hearing impairment secondary to Cryptococcal meningitis successfully managed by serial cerebrospinal fluid drainage. This case highlights some of the challenges of managing this severe opportunistic infection in a low resource setting.
Douglas-Vail, Matt; Bechamp, Taylor; Gohal, Simran; Soegtrop, Robert; Vitali, Sarah; Rugemalila, Joan
Cryptococcal meningitis is a common and devastating complication of advanced HIV, and is most prevalent in low resource settings in sub Saharan Africa. Raised intracranial pressure is one of the hallmarks of the disease, which can lead to visual and hearing loss and ultimately death. We present the case of a patient with visual and hearing impairment secondary to Cryptococcal meningitis successfully managed by serial cerebrospinal fluid drainage. This case highlights some of the challenges of managing this severe opportunistic infection in a low resource setting. PMID:26753085
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.
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
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.
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.
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.
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.
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.
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.
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.
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
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.
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.
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
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
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.
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.
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.
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.
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.
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.
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
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.
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.
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
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.
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.
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
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.
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
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.
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 ...
... Emergency Room? What Happens in the Operating Room? Meningitis KidsHealth > For Kids > Meningitis A A A What's ... there are ways to prevent it. What Is Meningitis? The central nervous system (brain and spinal cord) ...
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.
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
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.
... 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 ...
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.
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.
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
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
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.
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.
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).
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.
... meningitis Fact sheet N°141 Updated November 2015 Key facts Meningococcal meningitis is a bacterial form of ... clusters throughout the world with seasonal variation and accounts for a variable proportion of epidemic bacterial meningitis. ...
... causes meningitis. Causes Staphylococcal meningitis is caused by staphylococcus bacteria. When it is caused by Staphylococcus aureus or Staphylococcus epidermidis bacteria, it usually develops ...
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.
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.
... Old Feeding Your 1- to 2-Year-Old Meningitis KidsHealth > For Parents > Meningitis A A A What's ... to Call the Doctor en español Meningitis About Meningitis Meningitis is an inflammation of the meninges, the ...
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 ...
... 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.
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.
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
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.
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
... have severe illness from viral meningitis. Causes Non-polio enteroviruses are the most common cause of viral ... following viruses spread by visiting CDC’s websites: Non-polio enteroviruses Mumps virus Herpesviruses, including Epstein-Barr virus , ...
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.
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.
Sawanyawisuth, Kittisak; Chotmongkol, Verajit
Eosinophilic meningitis is defined by the presence of at least 10% eosinophils in the total cerebrospinal fluid (CSF) leukocyte count. Although there are several possible causes of eosinophils in the CSF, parasitic infection is the main cause. The three common parasites causing eosinophilic meningitis include Angiostrongylus cantonensis, Gnathostoma spinigerum, and Taenia solium. Even though these parasites are endemic in tropical countries, they are now spreading globally due to extensive traveling, and physicians worldwide should pay more attention to this condition. This chapter will review risk factors, clinical manifestations, and treatment of these three parasites.
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
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
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
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.
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
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.
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.
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
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.
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.
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
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.
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.
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.
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.
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.
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.
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
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
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.
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
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.
... or syphilitic meningitis, is a complication of untreated syphilis . It involves inflammation of the tissues covering the ... This condition is a life-threatening complication of syphilis infection. Syphilis is a sexually transmitted infection. Syphilitic ...
... damage or die of this type of meningitis. Young children and adults over age 50 have the highest risk for death. How well you do depends on: Your age How soon treatment is started Your overall health
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
... not infections can cause chronic meningitis. They include Sarcoidosis Certain disorders that cause inflammation, such as systemic ... For disorders that are not infections, such as sarcoidosis and Behçet syndrome: Corticosteroids or other drugs that ...
... Resources for Healthcare Professionals Related Links Vaccine Schedules Preteen & Teen Vaccines Meningococcal Disease Sepsis Non-Infectious Meningitis ... confusion) Top of Page Related Links Vaccine Schedules Preteen & Teen Vaccines Meningococcal Disease Sepsis File Formats Help: ...
(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
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.
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
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.
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.
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.
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.
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.
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.
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
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.
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
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.
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.
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.
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.
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.
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.
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.
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
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.
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.
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.
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.
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.
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
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
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.
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 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.
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
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.
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
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.
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.
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.
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
Honigberg, Michael C; Papavassiliou, Efstathios; Cohen, Yehuda Z
We report a patient with primary leptomeningeal melanocytosis presenting as chronic meningitis. A previously healthy 27-year-old man presented with 2 months of severe headaches and photophobia. A lumbar puncture was notable for a highly elevated cerebrospinal fluid (CSF) protein level without pleocytosis. Imaging at the time of admission suggested only meningitis without the presence of parenchymal lesions. On the basis of the CSF findings, early meningeal biopsy was performed, leading to the diagnosis of a meningeal melanocytic neoplasm. Early meningeal biopsy should be considered in patients with meningitis when the CSF profile suggests the possibility of a central nervous system neoplasm.
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.
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
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).
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
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.
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.
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.
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
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
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
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.
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.
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.
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
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.
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
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.
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
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
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
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.
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.
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
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
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
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.
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.
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
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
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.
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
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.
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.
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.
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.
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.
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
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
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
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.
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
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.
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.
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.
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.
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.
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.
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
... headaches or body aches. Reviewed by: Nicole A. Green, MD and Elana Pearl Ben-Joseph, MD Date reviewed: February 2016 previous 1 • 2 • 3 For Teens For Kids For Parents MORE ON THIS TOPIC Encephalitis Hand Washing Spinal Tap Why Should I Care About Germs? Lyme Disease Contact Us Print Resources ...
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.
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
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
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.
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.
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
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.
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.
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
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
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
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
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.
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.
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
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.
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
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.
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
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
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
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
Stupar, Maja; Tibbles, Anthony
Plantar fasciitis is diagnosed based on a pathognomonic clinical presentation and physical examination including plantar heel pain with the initial few steps after a period of inactivity. People living with HIV/AIDS, who are taking anti-retroviral medications, often have an associated redistribution of body fat (lipodystrophy). Lipoatrophy of the extremities may involve the heel fat-pad in this population and result in the signs and symptoms of plantar fasciitis. Two cases of plantar heel pain in HIV-associated lipodystrophy are presented to discuss the possible clinical association between the two conditions. Although conservative therapies have limited evidence, they are commonly used and have been seen, clinically, to result in a resolution of symptoms. In the presented cases, the individuals benefited from soft tissue therapy, modalities, activity modification and education on proper footwear. Clinicians should be aware that the association between these two conditions may be a significant cause of morbidity in a population of patients with HIV. PMID:18516231
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
Pitcher, Jonathan; Abt, Anna; Myers, Jaclyn; Han, Rachel; Snyder, Melissa; Graziano, Alessandro; Festa, Lindsay; Kutzler, Michele; Garcia, Fernando; Gao, Wen-Jun; Fischer-Smith, Tracy; Rappaport, Jay; Meucci, Olimpia
Interaction of the chemokine CXCL12 with its receptor CXCR4 promotes neuronal function and survival during embryonic development and throughout adulthood. Previous studies indicated that μ-opioid agonists specifically elevate neuronal levels of the protein ferritin heavy chain (FHC), which negatively regulates CXCR4 signaling and affects the neuroprotective function of the CXCL12/CXCR4 axis. Here, we determined that CXCL12/CXCR4 activity increased dendritic spine density, and also examined FHC expression and CXCR4 status in opiate abusers and patients with HIV-associated neurocognitive disorders (HAND), which is typically exacerbated by illicit drug use. Drug abusers and HIV patients with HAND had increased levels of FHC, which correlated with reduced CXCR4 activation, within cortical neurons. We confirmed these findings in a nonhuman primate model of SIV infection with morphine administration. Transfection of a CXCR4-expressing human cell line with an iron-deficient FHC mutant confirmed that increased FHC expression deregulated CXCR4 signaling and that this function of FHC was independent of iron binding. Furthermore, examination of morphine-treated rodents and isolated neurons expressing FHC shRNA revealed that FHC contributed to morphine-induced dendritic spine loss. Together, these data implicate FHC-dependent deregulation of CXCL12/CXCR4 as a contributing factor to cognitive dysfunction in neuroAIDS. PMID:24401274
Pozniak, Anton; Rackstraw, Simon; Deayton, Jane; Barber, Tristan; Taylor, Steve; Manji, Hadi; Melvin, Diane; Croston, Michelle; Nightingale, Sam; Kulasegaram, Ranubabu; Pitkanen, Mervi; Winston, Alan
The incidence of HIV-associated dementia has decreased significantly with the introduction of combination antiretroviral therapy; however, milder or more subtle forms of neurocognitive disorders associated with HIV appear to remain common. There is a lack of consensus on when to screen and on which methods are most appropriate for identifying patients at risk of neurocognitive impairment. Multiple factors (demographic, social, genetic, psychological and medical) can play a role in its aetiology and progression, including potential central nervous system toxicity of antiviral therapy. It is important to identify these factors in order to apply relevant management strategies. In this review, we discuss a series of case studies that address some of the challenges presented by the diagnosis and management of HIV-associated neurocognitive impairment in different patient types.
Lahey, Timothy; Czechura, Tom; Crabtree, Scott; Arbeit, Robert D; Matee, Mecky; Horsburgh, C Robert; MacKenzie, Todd; Bakari, Muhammad; Pallangyo, Kisali; von Reyn, C Fordham
The role of preexisting interferon (IFN) γ responses in controlling bacillary burden in human immunodeficiency virus (HIV)-associated tuberculosis is not known. Among BCG-immunized HIV-infected adults who developed tuberculosis in a phase III trial of an investigational tuberculosis vaccine, greater baseline IFN-γ responses to early secretory antigenic target 6 and Mycobacterium tuberculosis whole-cell lysate were associated with reduced bacillary burden on sputum smear grade, days to culture positivity on agar, and sputum culture grade during subsequent tuberculosis. This association was most consistent among recipients of the investigational vaccine. When HIV-associated tuberculosis develops, greater preexisting IFN-γ responses to mycobacterial antigens are associated with reduced tuberculosis bacillary burden. ClinicalTrials.gov Identifier. NCT0052195.
Mulligan, Kathleen; Schambelan, Morris
Wasting, and particularly loss of metabolically active lean tissue, contributes to increased mortality, accelerated disease progression, and impairment of strength and functional status in patients with HIV infection. A variety of protein anabolic agents, including growth hormone, insulin-like growth factor-I, testosterone, nandrolone decanoate, oxandrolone, and oxymetholone, have been studied in patients with HIV-associated wasting. Overall, these studies have demonstrated that treatment with protein anabolic agents can increase lean body mass (LBM) and in some cases provide functional benefits and improvements in quality of life. Further research is needed to determine whether such treatment prolongs survival or reduces the overall health care burden of HIV infection. The advances in identification of successful treatments for HIV-associated wasting can provide a model for using these therapies in other catabolic states, including end-stage renal disease, cancer, chronic obstructive pulmonary disease, and cardiac cachexia.
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.
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
Kume, Kodai; Ikeda, Kazuyo; Kamada, Masaki; Touge, Tetsuo; Deguchi, Kazushi; Masaki, Tsutomu
A 47-year-old man with HIV infection presented with lower leg dominant dysesthesia, muscle weakness and sensory ataxia of 3 month's duration. Nerve conduction studies (NCS) showed demyelination change in the median and tibial nerves and sensory nerve action potential (SNAP) in the sural nerve was not evoked. Somatosensory evoked potential (SEP) showed the delayed N9 latency. Diagnose of HIV-associated chronic inflammatory demyelinating polyneuropathy (CIDP) was made. Although the CD4 lymphocyte counts were relatively preserved (466/μl), highly active anti-retroviral therapy (HAART) was started according to a new guideline for the use of antiretroviral agents in HIV-1-infected adults and adolescents recommending early initiation of treatment. After six months, HIV1-RNA was not detected and the CD4 lymphocyte counts showed a recovering trend (585/μl). His symptoms had disappeared, except for dysesthesia in the tip of a toe. Repeated NCS demonstrated full recovery from the demyelination and appearance of SNAP in the sural nerve. The improvement of his symptoms and NCS findings has been maintained for two years. Although effectiveness of immunotherapies such as oral prednisone, high-dose immunoglobulins and plasmapheresis have been reported in HIV-associated CIDP, early initiation of HAART may be also important for favorable prognosis in HIV-associated CIDP.
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.
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.
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.
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.
Harries, A D; Lin, Y; Satyanarayana, S; Lönnroth, K; Li, L; Wilson, N; Chauhan, L S; Zachariah, R; Baker, M A; Jeon, C Y; Murray, M B; Maher, D; Bygbjerg, I C; Enarson, D A; Billo, N E; Kapur, A
The prevalence of diabetes mellitus is increasing at a dramatic rate, and countries in Asia, particularly India and China, will bear the brunt of this epidemic. Persons with diabetes have a significantly increased risk of active tuberculosis (TB), which is two to three times higher than in persons without diabetes. In this article, we argue that the epidemiological interactions and the effects on clinical presentation and treatment resulting from the interaction between diabetes and TB are similar to those observed for human immunodeficiency virus (HIV) and TB. The lessons learned from approaches to reduce the dual burden of HIV and TB, and especially the modes of screening for the two diseases, can be adapted and applied to the screening, diagnosis, treatment and prevention of diabetes and TB. The new World Health Organization (WHO) and The Union Collaborative Framework for care and control of TB and diabetes has many similarities to the WHO Policy on Collaborative Activities to reduce the dual burden of TB and HIV, and aims to guide policy makers and implementers on how to move forward and combat this looming dual epidemic. The response to the growing HIV-associated TB epidemic in the 1980s and 1990s was slow and uncoordinated, despite clearly articulated warnings about the scale of the forthcoming problem. We must not make the same mistake with diabetes and TB. The Framework provides a template for action, and it is now up to donors, policy makers and implementers to apply the recommendations in the field and to 'learn by doing'.
Heaps, Jodi; Valcour, Victor; Chalermchai, Thep; Paul, Robert; Rattanamanee, Somprartthana; Siangphoe, Umaporn; Sithinamsuwan, Pasiri; Chairangsaris, Parnsiri; Nidhinandana, Samart; Tipsuk, Somporn; Suttichom, Duanghathai; Fletcher, James; Shikuma, Cecilia; Ananworanich, Jintanat
International studies of HIV-associated neurocognitive disorder (HAND) are needed to determine the viral and host factors associated with cognitive impairment particularly as more than 80% of HIV+ subjects reside in resource-limited settings. Recent diagnostic nomenclature of HAND requires comparison of cognitive performance specifically to local normative data. To evaluate this need for local norms, we compared normative data obtained locally in Thailand to Western norms. The current study examined cognitive performance in 477 seronegative Thai participants (male = 211, female = 266) who completed a battery of tests sensitive to cognitive changes in HIV. The cohort was divided into three age brackets (20-34; 35-49; 50-65 years) and four educational levels (no education or primary education, less than secondary certificate, high-school/associates degree, bachelor's degree or greater). The Thai cohort was compared (using analysis of covariance, ANCOVA) on a number of measures to a seronegative US cohort (n = 236; male = 198, female = 38) to examine cultural differences in performance. Normative data are provided with age and education stratification. The Thai and US groups performed significantly differently on all neuropsychological measures with the exception of verbal fluency. The Thai group performed better on measures of verbal learning (p < .001) and memory (p < .001) and measures of psychomotor speed (p < .001). Education was a more powerful predictor of performance in the Thai cohort than in the US group. These results highlight the continued need for the development of normative data within local populations. The use of Western norms as a comparison group could lead to inaccurate identification of HAND in culturally distinct groups.
Liu, Fengming; Dai, Shen; Gordon, Jennifer; Qin, Xuebin
The various neurological complications associated with HIV-1 infection, specifically HIV-associated neurocognitive disorders (HAND) persist as a major public health burden worldwide. Despite the widespread use of anti-retroviral therapy, the prevalence of HAND is significantly high. HAND results from the direct effects of an HIV-1 infection as well as secondary effects of HIV-1-induced immune reaction and inflammatory response. Complement, a critical mediator of innate and acquired immunity, plays important roles in defeating many viral infections by the formation of a lytic pore or indirectly by opsonization and recruitment of phagocytes. While the role of complement in the pathogenesis of HIV-1 infection and HAND has been previously recognized for over fifteen years, it has been largely underestimated thus far. Complement can be activated through HIV-1 envelope proteins, mannose binding lectins (MBL) and anti-HIV-1 antibodies. Complement not only fights against HIV-1 infection but also enhances HIV-1 infection. Also, HIV-1 can hijack complement regulators such as CD59 and CD55 and can utilize these regulators and factor H to escape from complement attack. Normally, complement levels in brain are much lower than plasma levels and there is no or little complement deposition in brain cells. Interestingly, local production and deposition of complement are dramatically increased in HIV-1-infected brain, indicating that complement may contribute to the pathogenesis of HAND. Here, we review the current understanding of the role of complement in HIV-1 infection and HAND as well as potential therapeutic approaches targeting to the complement system for the treatment and eradications of HIV-1 infection. PMID:24639397
Franklin, Donald R.; Deutsch, Reena; Woods, Steven P.; Vaida, Florin; Ellis, Ronald J.; Letendre, Scott L.; Marcotte, Thomas D.; Atkinson, J.H.; Collier, Ann C.; Marra, Christina M.; Clifford, David B.; Gelman, Benjamin B.; McArthur, Justin C.; Morgello, Susan; Simpson, David M.; McCutchan, John A.; Abramson, Ian; Gamst, Anthony; Fennema-Notestine, Christine; Smith, Davey M.; Heaton, Robert K.
Objective: While HIV-associated neurocognitive disorders (HAND) remain prevalent despite combination antiretroviral therapy (CART), the clinical relevance of asymptomatic neurocognitive impairment (ANI), the most common HAND diagnosis, remains unclear. We investigated whether HIV-infected persons with ANI were more likely than those who were neurocognitively normal (NCN) to experience a decline in everyday functioning (symptomatic decline). Methods: A total of 347 human participants from the CNS HIV Anti-Retroviral Therapy Effects Research (CHARTER) cohort were NCN (n = 226) or had ANI (n = 121) at baseline. Neurocognitive assessments occurred approximately every 6 months, with median (interquartile range) follow-up of 45.2 (28.7–63.7) months. Symptomatic decline was based on self-report (SR) or objective, performance-based (PB) problems in everyday functioning. Proportional hazards modeling was used to generate risk ratios for progression to symptomatic HAND after adjusting for baseline and time-dependent covariates, including CD4+ T-lymphocyte count (CD4), virologic suppression, CART, and mood. Results: The ANI group had a shorter time to symptomatic HAND than the NCN after adjusting for baseline predictors: adjusted risk ratios for symptomatic HAND were 2.0 (confidence interval [CI] 1.1–3.6; p = 0.02) for SR, 5.8 (CI 3.2–10.7; p < 0.0001) for PB, and 3.2 (CI 2.0–5.0; p < 0.0001) for either SR or PB. Current CD4 and depression were significant time-dependent covariates, but antiretroviral regimen, virologic suppression, and substance abuse or dependence were not. Conclusions: This longitudinal study demonstrates that ANI conveys a 2-fold to 6-fold increase in risk for earlier development of symptomatic HAND, supporting the prognostic value of the ANI diagnosis in clinical settings. Identifying those at highest risk for symptomatic decline may offer an opportunity to modify treatment to delay progression. PMID:24814848
Levine, Andrew J; Quach, Austin; Moore, David J; Achim, Cristian L; Soontornniyomkij, Virawudh; Masliah, Eliezer; Singer, Elyse J; Gelman, Benjamin; Nemanim, Natasha; Horvath, Steve
HIV infection leads to age-related conditions in relatively young persons. HIV-associated neurocognitive disorders (HAND) are considered among the most prevalent of these conditions. To study the mechanisms underlying this disorder, researchers need an accurate method for measuring biological aging. Here, we apply a recently developed measure of biological aging, based on DNA methylation, to the study of biological aging in HIV+ brains. Retrospective analysis of tissue bank specimens and pre-mortem data was carried out. Fifty-eight HIV+ adults underwent a medical and neurocognitive evaluation within 1 year of death. DNA was obtained from occipital cortex and analyzed with the Illumina Infinium Human Methylation 450K platform. Biological age determined via the epigenetic clock was contrasted with chronological age to obtain a measure of age acceleration, which was then compared between those with HAND and neurocognitively normal individuals. The HAND and neurocognitively normal groups did not differ with regard to demographic, histologic, neuropathologic, or virologic variables. HAND was associated with accelerated aging relative to neurocognitively normal individuals, with average relative acceleration of 3.5 years. Age acceleration did not correlate with pre-mortem neurocognitive functioning or HAND severity. This is the first study to demonstrate that the epigenetic age of occipital cortex samples is associated with HAND status in HIV+ individuals pre-mortem. While these results suggest that the increased risk of a neurocognitive disorder due to HIV might be mediated by an epigenetic aging mechanism, future studies will be needed to validate the findings and dissect causal relationships and downstream effects.
Ellis, Ronald J.; Letendre, Scott; Vaida, Florin; Haubrich, Richard; Heaton, Robert K.; Sacktor, Ned; Clifford, David B.; Best, Brookie M.; May, Susanne; Umlauf, Anya; Cherner, Mariana; Sanders, Chelsea; Ballard, Craig; Simpson, David M.; Jay, Cheryl; McCutchan, J. Allen
Background. Antiretroviral (ARV) medications differentially penetrate across the blood-brain barrier into central nervous system (CNS) tissues, potentially influencing their effectiveness in treating brain infection. Methods. This randomized controlled clinical trial (RCT) called for 120 participants at 5 study sites to be randomized 1:1 to CNS-targeted (CNS-T) or non–CNS-T ART. Entry clinical factors such as ARV experience were balanced across arms using an adaptive randomization approach. The primary outcome, change in neurocognitive performance, was measured as the difference in global deficit score (GDS) from baseline to week 16. Results. The study was terminated early on the recommendation of its data safety monitoring board on the basis of slow accrual and a low likelihood of detecting a difference in the primary outcome. No safety concerns were identified. Of 326 participants screened, 59 met entry criteria and were randomized. The primary intent-to-treat analysis included 49 participants who completed week 16. These comprised 39 men and 10 women with a mean age of 44 years (SD, 10 years), and median nadir and current CD4+ T-cell counts of 175 cells/µL and 242 cells/µL, respectively. The proportional improvement in GDS from baseline was nonsignificantly larger (7%; 95% confidence interval [CI], −31% to 62%) in the CNS-T arm than in the non-CNS-T arm, representing a treatment effect size of 0.09 (95% CI, −.48 to .65). Prespecified secondary analysis showed a trend interaction (P = .087), indicating that participants who had baseline plasma virologic suppression may have benefited from CNS-T. Conclusions. This study found no evidence of neurocognitive benefit for a CNS-T strategy in HIV-associated neurocognitive disorders. A benefit for a subgroup or small overall benefits could not be excluded. Clinical Trials Registration NCT00624195. PMID:24352352
Jumare, Jibreel; Sunshine, Sara; Ahmed, Hayat; El-Kamary, Samer S; Magder, Laurence; Hungerford, Laura; Burdo, Tricia; Eyzaguirre, Lindsay M; Umlauf, Anya; Cherner, Mariana; Abimiku, Alash'le; Charurat, Man; Li, Jonathan Z; Blattner, William A; Royal, Walter
Mononuclear cells play key roles in the pathogenic mechanisms leading to HIV-associated neurocognitive disorders (HANDs). We examined the association between HIV DNA within peripheral blood mononuclear cell (PBMC) subsets and HAND in Nigeria. PBMCs were collected at baseline from 36 antiretroviral naive participants. CD14+ cells and T&B lymphocyte fractions were isolated by, respectively, positive and negative magnetic bead separation. Total HIV DNA within CD14+ and T&B cells were separately quantified using real-time PCR assay targeting HIV LTR-gag and cell input numbers determined by CCR5 copies/sample. Utilizing demographically adjusted T scores obtained from a 7-domain neuropsychological test battery, cognitive status was determined by the global deficit score (GDS) approach, with a GDS of ≥0.5 indicating cognitive impairment. In a linear regression adjusting for plasma HIV RNA, CD4 and lymphocyte count, Beck's depression score, and years of education, there was 0.04 lower log10 HIV DNA copies within T&B lymphocytes per unit increase in global T score (p = 0.02). Adjusting for the same variables in a logistic regression, the odds of cognitive impairment were 6.2 times greater per log10 increase in HIV DNA within T&B lymphocytes (p = 0.048). The association between cognitive impairment and HIV DNA within CD14+ monocytes did not reach statistical significance. In this pretreatment cohort with mild cognitive dysfunction, we found a strong association between levels of HIV DNA within the lymphocyte subset and HAND independent of plasma HIV RNA. These findings likely reflect the neurologic impact of a larger HIV reservoir and active viral replication.
Morris, Sheldon R.; Woods, Steven Paul; Deutsch, Reena; Little, Susan J.; Wagner, Gabriel; Morgan, Erin E.; Heaton, Robert K.; Letendre, Scott L.; Grant, Igor; Smith, Davey M.
Background HIV coreceptor usage of CXCR4 (X4) is associated with decreased CD4+ T-cell counts and accelerated disease progression, but the role of X4 tropism in HIV-associated neurocognitive disorders (HAND) has not previously been described. Methods This longitudinal study evaluated data on 197 visits from 72 recently HIV-infected persons who had undergone up to 4 sequential neurocognitive assessments over a median of 160 days (IQR 138–192). Phenotypic tropism testing (Trofile ES, Monogram, Biosciences) was performed on stored blood samples. Multivariable mixed model repeated measures regression was used to determine the association between HAND and dual-mixed (DM) viral tropism, estimated duration of infection (EDI), HIV RNA, CD4 count and problematic methamphetamine use. Results Six subjects (8.3%) had dual mixed tropism (DM) at their first neurocognitive assessment and four converted to DM in subsequent sampling (for total of 10 DM) at a median EDI of 10.1 months (IQR 7.2–12.2). There were 44 (61.1%) subjects who demonstrated HAND on at least one study visit. HAND was associated with DM tropism (odds ratio 4.4, 95% CI 0.9–20.5) and shorter EDI (odds ratio 1.1 per month earlier, 95% CI 1.0–1.2). Conclusion This study found that recency of HIV-1 infection and the development of DM tropism may be associated with HAND in the relatively early stage of infection. Together these data suggest that viral interaction with cellular receptors may play an important role in the early manifestation of HAND. PMID:24078557
Soontornniyomkij, Virawudh; Moore, David J.; Gouaux, Ben; Soontornniyomkij, Benchawanna; Tatro, Erick T.; Umlauf, Anya; Masliah, Eliezer; Levine, Andrew J.; Singer, Elyse J.; Vinters, Harry V.; Gelman, Benjamin B.; Morgello, Susan; Cherner, Mariana; Grant, Igor; Achim, Cristian L.
Objective The apolipoprotein E (APOE) ε4 allele enhances cerebral accumulation of β-amyloid (Aβ) and is a major risk factor for sporadic Alzheimer’s disease (AD). We hypothesized that HIV-associated neurocognitive disorders (HAND) would be associated with the APOE ε4 genotype and cerebral Aβ deposition. Design Clinico-pathological study of HIV-infected adults from four prospective cohorts in the U.S. National NeuroAIDS Tissue Consortium. Methods We used multivariable logistic regressions to model outcomes (Aβ plaques [immunohistochemistry] and HAND [standard criteria]) on predictors (APOE ε4 [allelic discrimination assay], older age [≥ 50 years], Aβ plaques, and their two-way interactions) and co-morbid factors. Results Isocortical Aβ deposits generally occurred as diffuse plaques and mild to moderate amyloid angiopathy. Isocortical phospho-Tau-immunoreactive neurofibrillary lesions were sparse. The APOE ε4 and older age were independently associated with the presence of Aβ plaques (adjusted odds ratio [OR] 10.16 and 5.77 [95% confidence interval (CI) 2.89–35.76 and 1.91–17.48], P=0.0003 and 0.0019, respectively, n=96). The probability of HAND was increased in the presence of Aβ plaques among APOE ε4 carriers (adjusted OR 30.00 [95% CI 1.41–638.63], P=0.029, n=15), but not in non-ε4 carriers (n=57). Conclusion The APOE ε4 and older age increased the likelihood of cerebral Aβ plaque deposition in HIV-infected adults. Generally Aβ plaques in HIV brains were immunohistologically different from those in symptomatic AD brains. Nonetheless, Aβ plaques were associated with HAND among APOE ε4 carriers. The detection of APOE ε4 genotype and cerebral Aβ deposition biomarkers may be useful in identifying living HAND subjects who could benefit from Aβ-targeted therapies. PMID:23018443
Uldrick, Thomas S.; Wyvill, Kathleen M.; Kumar, Pallavi; O'Mahony, Deirdre; Bernstein, Wendy; Aleman, Karen; Polizzotto, Mark N.; Steinberg, Seth M.; Pittaluga, Stefania; Marshall, Vickie; Whitby, Denise; Little, Richard F.; Yarchoan, Robert
Purpose Alternatives to cytotoxic agents are desirable for patients with HIV-associated Kaposi's sarcoma (KS). Vascular endothelial growth factor-A (VEGF-A) contributes to KS pathogenesis. We evaluated the humanized anti–VEGF-A monoclonal antibody, bevacizumab, in patients with HIV-KS. Patients and Methods Patients with HIV-KS who either experienced progression while receiving highly active antiretroviral therapy (HAART) for at least 1 month or did not regress despite HAART for at least 4 months were administered bevacizumab 15 mg/kg intravenously on days 1 and 8 and then every 3 weeks. The primary objective was assessment of antitumor activity using modified AIDS Clinical Trial Group (ACTG) criteria for HIV-KS. HIV-uninfected patients were also eligible and observed separately. Results Seventeen HIV-infected patients were enrolled. Fourteen patients had been receiving effective HAART for at least 6 months (median, 1 year). Thirteen patients had advanced disease (ACTG T1), 13 patients had received prior chemotherapy for KS, and seven patients had CD4 count less than 200 cells/μL. Median number of cycles was 10 (range, 1 to 37 cycles); median follow-up was 8.3 months (range, 3 to 36 months). Of 16 assessable patients, best tumor responses observed were complete response (CR) in three patients (19%), partial response (PR) in two patients (12%), stable disease in nine patients (56%), and progressive disease in two patients (12%). Overall response rate (CR + PR) was 31% (95% CI, 11% to 58.7%). Four of five responders had received prior chemotherapy for KS. Over 202 cycles, grade 3 to 4 adverse events at least possibly attributed to therapy included hypertension (n = 7), neutropenia (n = 5), cellulitis (n = 3), and headache (n = 2). Conclusion Bevacizumab is tolerated in patients with HIV-KS and has activity in a subset of patients. PMID:22430271
Haque, Shabirul; Lan, Xiqian; Wen, Hongxiu; Lederman, Rivka; Chawla, Amrita; Attia, Mohamed; Bongu, Ramchandra P.; Husain, Mohammad; Mikulak, Joanna; Saleem, Moin A.; Popik, Waldemar; Malhotra, Ashwani; Chander, Praveen N.; Singhal, Pravin C.
Dysregulated growth and loss of podocytes are important features of HIV-associated nephropathy. Recently, HIV was reported to induce a new type of programed cell death, pyroptosis, in T lymphocytes through induction of Nod-like receptor protein 3 (NLRP3) inflammasome complexes. We evaluated the role of HIV in podocyte NLRP3 inflammasome formation both in vivo and in vitro. Renal cortical sections of HIV-transgenic mice (Tg26) displayed increased expression of NLRP3, ASC (a CARD protein), caspase-1, and IL-1β proteins, confirming NLRP3 inflammasome complex formation in podocytes of Tg26 mice. Renal tissues of Tg26 mice also displayed enhanced mRNA levels and protein expressions of inflammasome markers (NLRP3, ASC, and caspase-1, and IL-1β). Serum of Tg26 mice also showed elevated concentrations of IL-1β cytokine compared with FVBN mice. HIV induced pyroptosis in a dose- and time-dependent manner within podocytes, a phenotype of inflammasome activation. Caspase-1 inhibitor not only attenuated podocyte expression of caspase-1 and IL-1β but also provided protection against pyroptosis, suggesting that HIV-induced podocyte injury was mediated by caspase-1 activation. Interestingly, HIV-induced podocyte pyroptosis could be partially inhibited by Tempol (a superoxide dismutase-mimetic agent) and by glyburide (an inhibitor of potassium efflux). These findings suggest that generation of reactive oxygen species and potassium efflux contribute to HIV-induced pyroptosis and NLRP3 inflammasome activation in podocytes. PMID:26683666
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 %.
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
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.
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.
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.
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.
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.
Hong, Suzi; Banks, William A
Individuals living with HIV who are optimally treated with combination antiretroviral therapy (cART) can now lead an extended life. In spite of this remarkable survival benefit from viral suppression achieved by cART in peripheral blood, the rate of mild to moderate cognitive impairment remains high. A cognitive decline that includes impairments in attention, learning and executive function is accompanied by increased rates of mood disorders that together adversely impact the daily life of those with chronic HIV infection. The evidence is clear that cells in the brain are infected with HIV that has crossed the blood-brain barrier both as cell-free virus and within infected monocytes and T cells. Viral proteins that circulate in blood can induce brain endothelial cells to release cytokines, invoking another source of neuroinflammation. The difficulty of efficient delivery of cART to the central nervous system (CNS) contributes to elevated viral load in the CNS, resulting in a persistent HIV-associated neurocognitive disorders (HAND). The pathogenesis of HAND is multifaceted, and mounting evidence indicates that immune cells play a major role. HIV-infected monocytes and T cells not only infect brain resident cells upon migration into the CNS but also produce proinflammatory cytokines such as TNF and IL-1ß, which in turn, further activate microglia and astrocytes. These activated brain resident cells, along with perivascular macrophages, are the main contributors to neuroinflammation in HIV infection and release neurotoxic factors such as excitatory amino acids and inflammatory mediators, resulting in neuronal dysfunction and death. Cytokines, which are elevated in the blood of patients with HIV infection, may also contribute to brain inflammation by entering the brain from the blood. Host factors such as aging and co-morbid conditions such as cytomegalovirus co-infection and vascular pathology are important factors that affect the HIV-host immune interactions in
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
Casal, Diogo; Bexiga, Joaquim; Sousa, Juliana; Martins, João; Teófilo, Eugénio; Maltez, Fernando; Germano, Isabel; Videira e Castro, José
Objectives: HIV-associated lipodystrophy is a common comorbidity in HIV-infected patients, having a profound impact on every aspect of patients’ lives, particularly when involving the face. Hence, it is of the utmost importance to evaluate the result of any potential therapies that may help solve HIV-associated facial lipodystrophy. The aim of this article was to evaluate the outcome of patients undergoing facial lipodystrophy correction surgery within our institution. Methods: A retrospective analysis of the clinical charts and iconographic information of patients regarding demographics, morphologic changes, surgical option, postoperative complications, results, and patient satisfaction assessed by a 1- to 10-point scale and by the Assessment of Body Change and Distress questionnaire. Results: Twenty-three patients were operated on from March 2011 to April 2015. Seventy-five percent of cases were treated with fat graft injection, whereas dermis-fat grafts were applied in 25% of patients. The former had their fat harvested more commonly from the abdomen, whereas in the latter case, the graft was harvested mostly from the inner aspect of arms. The mean volume of fat injected on each side of the face was 28.5 ± 22.7 mL. On a scale from 1 to 10, mean patient satisfaction was 7.7 ± 2.8. The Assessment of Body Change and Distress questionnaire revealed statistically significant improvements. Complications occurred in 25% of cases, the most frequent being significant reabsorption. No major complications occurred. Conclusions: Treatment of HIV-associated facial lipodystrophy with autologous fat or dermis-fat compound graft is a safe procedure with long-lasting results and unquestionable aesthetic and social benefits. PMID:28123628
Spitsin, Sergei; Stevens, Kathleen E; Douglas, Steven D
The tachykinin neuropeptide substance P (SP) has an important signaling role in both the nervous and the immune systems. Two naturally occurring variants of the neurokinin-1 receptor (NK1R) mediate the effects of SP, full-length receptor (NK1R-F) and a truncated form (NK1R-T) that lacks 96 amino acid residues at the C-terminus. We previously reported decreased expression of the NK1R-F in the CNS of HIV-positive individuals in comparison to HIV-negative control subjects. There were no differences in the expression of the NK1R-T in the same groups. In the current study, we quantified the expressions of SP precursor mRNA preprotachykinin (TAC1), NK1R (full and truncated forms), viral load (HIV-gag) and several proinflammatory and immune markers (CD4, CCR5, CXCR4, fractalkine, IL-6, IL-10, CCL2, CCL20 and CD163) in the frontal cortex of autopsied brains from HIV-1-positive individuals with or without HIV-associated neuropathology. The expressions of SP and, to lesser extent, NK1R-F were decreased while the expressions of CXCR4, CCR5 and CCL2 were increased in CNS of individuals with HIV-associated neuropathology. There was no change in HIV loads associated with neuropathology; however, we found a positive correlation between viral loads and the expression of haptoglobin-hemoglobin scavenger receptor CD163. An analysis of CSF from corresponding samples demonstrated an increase in proinflammatory markers (CCL2 MIP-1α and MIP-1β) associated with neuropathology. Although our data confirm the overall inflammatory nature of HIV-associated neuropathology, we observed a decrease in the expression of SP and NK1R-F, which is also associated with other forms of neuroinflammation.
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.
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.
Kosker, Muhammet; Sener, Dicle; Kilic, Omer; Hasiloglu, Zehra Isik; Islak, Civan; Kafadar, Ali; Batur, Sebnem; Oz, Buge; Cokugras, Haluk; Akcakaya, Necla; Camcioglu, Yildiz
Primary diffuse leptomeningeal gliomatosis is a disease with an aggressive course that can result in death. To date, 82 cases have been reported. Here, the case of a 3-year-old male patient presenting with strabismus, headache, and restlessness is reported. Physical examination revealed paralysis of the left abducens nerve, neck stiffness, and bilateral papilledema. Tuberculous meningitis was tentatively diagnosed, and antituberculosis treatment was initiated when cranial imaging revealed contrast enhancement around the basal cistern. Craniocervical magnetic resonance imaging (MRI) was performed when there was no response to treatment, and it revealed diffuse leptomeningeal contrast enhancement around the basilar cistern, in the supratentorial and infratentorial compartments, and in the spinal region. Primary diffuse leptomeningeal gliomatosis was diagnosed by a meningeal biopsy.
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.
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.
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
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.
pulsation and particle interaction with the arachnoid. The data of the functional investigation of the diameter of meningeal pores draining CSF to the...particle clearance from the CSF, and virion interaction with normal arachnoid components. The interplay of these factors defines the bioavailability and...arachnoid and spinal cord parenchyma, and too hydro- philic to interact with the lipidic components of the tissue. Consequently, their behavior in CSF is
Vassallo, Matteo; Dunais, Brigitte; Durant, Jacques; Carsenti-Dellamonica, Helene; Harvey-Langton, Alexandra; Cottalorda, Jacqueline; Ticchioni, Michel; Laffon, Muriel; Lebrun-Frenay, Christine; Dellamonica, Pierre; Pradier, Christian
Contributory factors to HIV-associated neurocognitive disorders (HAND) have been shown to include age, co-morbid infections, medication toxicity, virological, genetic and vascular mechanisms, as well as microbial translocation of lipopolysaccharide (LPS), which is suspected to trigger monocyte activation and increase trafficking of infected cells into the brain. In this study, our aim was to assess the degree of neurocognitive impairment in a group of randomly selected HIV-infected patients and investigate potential risk factors, including LPS plasma levels. Furthermore, we evaluated the relevance of LPS as a potential marker for screening patients with mild neurocognitive impairment. LPS plasma levels were compared among patients with HAND and those with no HAND. As LPS has also been shown to be elevated in hepatitis C co-infection, the analysis was stratified according to the presence or not of hepatitis C virus (HCV) co-infection. Differences between groups were evaluated using chi-square tests and Kruskal-Wallis non-parametric tests. Stepwise logistic regression was performed to identify independent risk factors for HAND in the subgroups of HCV-positive and negative patients. A p value <0.05 was considered significant. Analyses were conducted using SPSS® software. From December 2007 to July 2009, 179 patients were tested (mean age 44, 73 % male, 87 % on treatment, 30 % HCV co-infected, median CD4 504/ml and 67 % with viral load below 40 copies/ml). HAND was identified in 40/179 patients (22 %), the majority displaying asymptomatic neurocognitive impairment or mild neurocognitive disorder. Univariate analysis showed that age, illicit drug use, hepatitis C co-infection, prior AIDS-defining events, CD4/CD8 ratio and LPS plasma levels were significantly associated with HAND. The median LPS level was 98.2 pg/ml in the non-HAND group versus 116.1 pg/ml in the HAND group (p < 0.014). No differences were found in LPS values between subgroups of impairment. There was a
Kallianpur, Asha R.; Wang, Quan; Jia, Peilin; Hulgan, Todd; Zhao, Zhongming; Letendre, Scott L.; Ellis, Ronald J.; Heaton, Robert K.; Franklin, Donald R.; Barnholtz-Sloan, Jill; Collier, Ann C.; Marra, Christina M.; Clifford, David B.; Gelman, Benjamin B.; McArthur, Justin C.; Morgello, Susan; Simpson, David M.; McCutchan, J. A.; Grant, Igor
Background. Anemia has been linked to adverse human immunodeficiency virus (HIV) outcomes, including dementia, in the era before highly active antiretroviral therapy (HAART). Milder forms of HIV-associated neurocognitive disorder (HAND) remain common in HIV-infected persons, despite HAART, but whether anemia predicts HAND in the HAART era is unknown. Methods. We evaluated time-dependent associations of anemia and cross-sectional associations of red blood cell indices with neurocognitive impairment in a multicenter, HAART-era HIV cohort study (N = 1261), adjusting for potential confounders, including age, nadir CD4+ T-cell count, zidovudine use, and comorbid conditions. Subjects underwent comprehensive neuropsychiatric and neuromedical assessments. Results. HAND, defined according to standardized criteria, occurred in 595 subjects (47%) at entry. Mean corpuscular volume and mean corpuscular hemoglobin were positively associated with the global deficit score, a continuous measure of neurocognitive impairment (both P < .01), as well as with all HAND, milder forms of HAND, and HIV-associated dementia in multivariable analyses (all P < .05). Anemia independently predicted development of HAND during a median follow-up of 72 months (adjusted hazard ratio, 1.55; P < .01). Conclusions. Anemia and red blood cell indices predict HAND in the HAART era and may contribute to risk assessment. Future studies should address whether treating anemia may help to prevent HAND or improve cognitive function in HIV-infected persons. PMID:26690344
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.
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
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.
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.
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
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
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
Campagne, G.; Schuchat, A.; Djibo, S.; Ousséini, A.; Cissé, L.; Chippaux, J. P.
In the African meningitis belt the importance of endemic meningitis is not as well recognized as that of epidemics of meningococcal meningitis that occur from time to time. Using retrospective surveillance, we identified a total of 7078 cases of laboratory-diagnosed bacterial meningitis in Niamey, Niger, from 1981 to 1996. The majority (57.7%) were caused by Neisseria meningitidis, followed by Streptococcus pneumoniae (13.2%) and Haemophilus influenzae b (Hib) (9.5%). The mean annual incidence of bacterial meningitis was 101 per 100,000 population (70 per 100,000 during 11 non-epidemic years) and the average annual mortality rate was 17 deaths per 100,000. Over a 7-year period (including one major epidemic year) for which data were available, S. pneumoniae and Hib together caused more meningitis deaths than N. meningitidis. Meningitis cases were more common among males and occurred mostly during the dry season. Serogroup A caused 85.6% of meningococcal meningitis cases during the period investigated; three-quarters of these occurred among children aged < 15 years, and over 40% among under-5-year-olds. Both incidence and mortality rates were highest among infants aged < 1 year. In this age group, Hib was the leading cause of bacterial meningitis, followed by S. pneumoniae. The predominant cause of meningitis in persons aged 1-40 years was N. meningitidis. Use of the available vaccines against meningitis due to N. meningitidis, S. pneumoniae, and Hib could prevent substantial endemic illness and deaths in sub-Saharan Africa, and potentially prevent recurrent meningococcal epidemics. PMID:10427935
Mahale, Rohan R.; Mehta, Anish; Uchil, Sudhir
Background: Central nervous system (CNS) involvement in tuberculosis is around 5–10%. Of the various manifestations of CNS tuberculosis, meningitis is the most common (70–80%). Delay in diagnosis and treatment results in significant morbidity and mortality. Objective: To study the cerebrospinal fluid (CSF) cortisol levels in tubercular meningitis and compare the levels with controls. Methods: Cross-sectional, prospective, observational, hospital-based study done in 20 patients of tubercular meningitis, 20 patients of aseptic meningitis (AM) and 25 control subjects without any preexisting neurological disorders who have undergone lumbar puncture for spinal anesthesia. Results: Cortisol was detected in all 40 CSF samples of patients (100%). Mean CSF cortisol level was 8.82, 3.47 and 1.05 in tubercular meningitis, AM and controls, respectively. Mean CSF cortisol level in tubercular meningitis was significantly higher as compared to AM and controls (P < 0.0001). Conclusion: Cortisol level estimation in CSF is one of the rapid, relatively inexpensive diagnostic markers in early identification of tubercular meningitis along with CSF findings of elevated proteins, hypoglycorrhachia and lymphocytic pleocytosis. This aids in earlier institution of appropriate treatment and thereby decreasing morbidity and mortality. This is the first study on the estimation of CSF cortisol level in tuberculous meningitis. PMID:26752900
Chen, Jenny X; Alkire, Blake C; Lam, Allen C; Curry, William T; Holbrook, Eric H
Objectives While bacterial meningitis is a concerning complication after endoscopic skull base surgery, the diagnosis can be made without consideration for aseptic meningitis. This article aims to (1) present a patient with recurrent craniopharyngioma and multiple postoperative episodes of aseptic meningitis and (2) discuss the diagnosis and management of aseptic meningitis. Design Case report and literature review. Results A 65-year-old female patient with a symptomatic craniopharyngioma underwent transsphenoidal resection. She returned postoperatively with symptoms concerning for cerebrospinal fluid (CSF) leak and bacterial meningitis. Lumbar puncture demonstrated mildly elevated leukocytes with normal glucose levels. Cultures were sterile and she was discharged on antibiotics. She returned 18 days postoperatively with altered mental status and fever. Again, negative CSF cultures suggested aseptic meningitis. Radiological and intraoperative findings were now concerning for widespread cerebrovascular vasospasm due to leaked craniopharyngioma fluids. In the following months, her craniopharyngioma recurred and required multiple surgical resections. Days after her last operation, she returned with mental status changes and a sterile CSF culture. She was diagnosed with recurrent aseptic meningitis and antibiotics were discontinued. The patient experienced near complete resolution of symptoms. Conclusions Consideration of aseptic meningitis following craniopharyngioma resection is critical to avoid unnecessary surgical re-exploration and prolonged courses of antibiotics.
Ghotaslou, Reza; Yeganeh-Sefidan, Fatemeh; Salahi-Eshlaqi, Behnaz; Ebrahimzadeh-Leylabadlo, Hamed
Acute bacterial meningitis (ABM) is one of the most severe infectious diseases, causing neurologic sequel, and a case fatality rate of 20-30%. The aim of this paper was to summarize the main causes of ABM in Iran. We searched the data for relevant articles using meningitis, etiology, and Iran as search terms. We found 23 papers for inclusion in the review that focused specifically on the ABM, addressing etiology and acute meningitis. Finally, during the 23 years, a total of 18163 cases were recorded, and 1074 cases of which met the criteria for bacterial meningitis. The most common agent associated with bacterial meningitis was S. pneumoniae, followed by H. influenzae, Enterobacter spp., N. meningitidis, and group B streptococcus. The total incidence of ABM during 1991 to 2002 was higher than during 2003-2013. S. pneumoniae still remains a main cause of bacterial meningitis. For improved outcomes, studies are needed to further clarify the etiology of meningitis in Iran, explore simple, accurate, and practical diagnostic tools as PCR, and investigate the most appropriate specific and supportive interventions to manage and prevent meningitis as vaccination.
Sosa, Lynn E.; Gupta, Shaili; Juthani-Mehta, Manisha; Hadler, James L.
The authors describe a case of aseptic meningitis in a college student that was ultimately attributed to infection with lymphocytic choriomeningitis virus (LCMV). The authors also provide a review of LCMV infection, epidemiology, and public health implications. Providers should be aware of LCMV as a cause of meningitis in college students,…
Navarro-Marí, José-María; Sánchez-Seco, María-Paz; Gegúndez, María-Isabel; Palacios, Gustavo; Savji, Nazir; Lipkin, W. Ian; Fedele, Giovanni; de Ory-Manchón, Fernando
Lymphocytic choriomeningitis virus (LCMV) was detected in 2 patients with acute meningitis in southern Spain within a 3-year period. Although the prevalence of LCMV infection was low (2 [1.3%] of 159 meningitis patients), it represents 2.9% of all pathogens detected. LCMV is a noteworthy agent of neurologic illness in immunocompetent persons. PMID:22515986
David, Kirubah Vasandhi; Pricilla, Ruby Angeline; Thomas, Beeson
Meningococcal meningitis has rarely been reported in Tamil Nadu. We report here two children diagnosed with meningococcal meningitis in Vellore, Tamil Nadu, on May 2014. The causative strain was Neisseria meningitidis serotype C. The role of the primary care physician in early diagnosis, appropriate referral, and preventive measures of this disease to the immediate family and community is stressed.
Pluot, M; Vital, C; Aubertin, J; Croix, J C; Pire, J C; Poisot, D
The authors report two cases of occupation-related anthrax meningitis; one was direct contamination from a diseased animal; the second was due to handling of bone powder imported from India. The pathological pattern of involvement of the meninges and brain is described and discussed.
Chen, Jenny X.; Alkire, Blake C.; Lam, Allen C.; Curry, William T.; Holbrook, Eric H.
Objectives While bacterial meningitis is a concerning complication after endoscopic skull base surgery, the diagnosis can be made without consideration for aseptic meningitis. This article aims to (1) present a patient with recurrent craniopharyngioma and multiple postoperative episodes of aseptic meningitis and (2) discuss the diagnosis and management of aseptic meningitis. Design Case report and literature review. Results A 65-year-old female patient with a symptomatic craniopharyngioma underwent transsphenoidal resection. She returned postoperatively with symptoms concerning for cerebrospinal fluid (CSF) leak and bacterial meningitis. Lumbar puncture demonstrated mildly elevated leukocytes with normal glucose levels. Cultures were sterile and she was discharged on antibiotics. She returned 18 days postoperatively with altered mental status and fever. Again, negative CSF cultures suggested aseptic meningitis. Radiological and intraoperative findings were now concerning for widespread cerebrovascular vasospasm due to leaked craniopharyngioma fluids. In the following months, her craniopharyngioma recurred and required multiple surgical resections. Days after her last operation, she returned with mental status changes and a sterile CSF culture. She was diagnosed with recurrent aseptic meningitis and antibiotics were discontinued. The patient experienced near complete resolution of symptoms. Conclusions Consideration of aseptic meningitis following craniopharyngioma resection is critical to avoid unnecessary surgical re-exploration and prolonged courses of antibiotics. PMID:27722072
Datta, Kausik; Lees, Andrew; Pirofski, Liise-anne
Vaccination with P13, a peptide mimotope of the cryptococcal capsular polysaccharide glucuronoxylomannan (GXM), has been shown to confer protection against a subsequent lethal Cryptococcus neoformans challenge. In this study, we sought to investigate whether P13-based vaccines could be effective in an already-established infection. To address this question, we developed a systemic chronic cryptococcal infection model. We vaccinated chronically infected mice with P13-protein conjugates and monitored their survival. Compared to the controls, the conjugates prolonged the survival of chronically infected mice. The degree of protection was a function of the mouse strain (BALB/c or C57BL/6), the carrier protein (tetanus toxoid or diphtheria toxoid), and the route of infection (intraperitoneal or intravenous). Serum GXM levels were correlated with the day of death, but the correlation was driven by the carrier protein and mouse strain. The passive transfer of heat-treated sera from P13 conjugate-vaccinated mice conferred protection to naïve BALB/c mice, indicating that antibody immunity could contribute to protection. The measurement of peripheral blood cytokine (gamma interferon [IFN-gamma], interleukin-10 [IL-10], and IL-6) gene expression showed that P13 conjugate-vaccinated BALB/c and C57BL/6 mice mounted a strong Th2 (IL-10)-like response relative to the Th1 (IFN-gamma)-like response, with the degree depending on the mouse strain and carrier protein. Taken together, our data suggest that a vaccine could hold promise in the setting of chronic cryptococcosis, and that vaccine efficacy could depend on immunomodulation and augmentation of the natural immune response of the host.
Chongtrakool, Piriyaporn; Suwannakarn, Kamol; Kiratisin, Pattarachai
Despite the strong association between Cryptococcus neoformans infection and the Human immunodeficiency virus (HIV) status of patients globally, most cryptococcosis cases in Far East Asia occur in non-HIV individuals. Molecular epidemiological studies, using multilocus sequence typing (MLST), have shown that more than 95% of cryptococcal strains belong to a specific subtype of VNI. However, this association has never been specifically examined in other parts of Asia. Therefore, in this study, we investigated the VNIc/ST5 genotype distribution among cryptococcosis patients in Thailand. Fifty-one C. neoformans isolates were collected from clinical samples in Siriraj Hospital, Bangkok, Thailand. The strains were predominantly isolated from HIV-positive patients (88.57%) and all were molecular type VNI MATα. An MLST analysis identified five sequence types (ST) in Siriraj Hospital, of which ST4 (45.10%) and ST6 (35.29%) were most common, and ST5 (15.69%), ST32 (1.96%), and ST93 (1.96) were less common. Contrary to reports from Far East Asia, ST5 was predominantly (83.33%) found in HIV patients (P = 0.657), and there was no significant change in the prevalence of ST5 over the past 10 years (P = 0.548). A further analysis of comorbidities showed higher morbidity and delays in the cryptococcal diagnosis in patients with tuberculosis coinfection or without HIV. Our study suggests that although the Thai population is genetically closely related to the Far East Asian population, ST5 is not associated with non-HIV status in Thailand. Therefore, this association may not be related to the host’s genetic background. However, its mechanism remains unclear. PMID:28323835
López, Enrique; Morales, Guadalupe; Saucedo, Carlos; Aguirre-Girón, Lizette; Mack, Sara; Goodkin, Karl
In the United States, the term "Hispanic" has been used to refer to a person or groups of persons who originate from Spanish-speaking countries. However, this term fails to account for variables such as nationality, ethnicity, race, and cultural origin as well as the extent of assimilation to a new culture. In addition, factors such as the individual's generation, specific migratory status, years of education in each country, fluency, and day-to-day language usage contribute to variance in neuropsychological testing outcomes, which are sensitive to these factors. We have noted that the usage of the terms "Hispanic" and "Latino" is problematic in HIV-associated neurocognitive disorder (HAND) research; therefore, we propose grouping individuals by nationality or by the Spanish-speaking culture to which they belong. The rationale for not using these terms is based upon the sociodemographic findings among Spanish speakers infected with HIV and how these terms inadequately describe the rich heterogeneity of this population.
Kamminga, Jody; Cysique, Lucette A; Lu, Grace; Batchelor, Jennifer; Brew, Bruce J
Various screening tools have been proposed to identify HIV-Associated Neurocognitive Disorder (HAND). However, there has been no systematic review of their strengths and weaknesses in detecting HAND when compared to gold standard neuropsychological testing. Thirty-five studies assessing HAND screens that were conducted in the era of combination antiretroviral therapy were retrieved using standard search procedures. Of those, 19 (54 %) compared their screen to standard neuropsychological testing. Studies were characterised by a wide variation in criterion validity primarily due to non-standard definition of neurocognitive impairment, and to the demographic and clinical heterogeneity of samples. Assessment of construct validity was lacking, and longitudinal useability was not established. To address these limitations, the current review proposed a summary of the most sensitive and specific studies (>70 %), as well as providing explicit caution regarding their weaknesses, and recommendations for their use in HIV primary care settings.
Paul, Robert H.
Substance abuse and co-infection with hepatitis C (HCV) are two highly relevant determinants of neurocognitive and neuroimaging abnormalities associated with HIV. Substance abuse and HCV are common in the HIV population and there is increasing evidence that the CNS is directly compromised by these comorbid conditions via additive or synergistic processes. In this article we review the current literature regarding mechanisms of neuronal injury as well as the neuropsychological and neuroimaging signatures associated with substance abuse and HCV status among HIV patients. We discuss specific methodological challenges and threats to validity associated with studies of HIV and comorbid substance use disorders or HCV and review potential strategies for minimizing their confounding effects. Efforts to understand the interactions between HIV, substance abuse and HCV co-infection will lead to more complete models of neuropathogenesis of HIV and a greater understanding of the variability in neuropsychological expression of HIV Associated Neurocognitive Disorder. PMID:19468837
Kamminga, Jody; Lal, Luxshimi; Wright, Edwina J; Bloch, Mark; Brew, Bruce J; Cysique, Lucette A
Screening tools to identify HIV-associated neurocognitive disorder (HAND) are primarily devised to detect cognitive impairment on a single occasion. With the chronicity of HIV infection and the risk of HAND developing or progressing despite viral control, it may be pertinent to repeat HAND screening at more than one time point. Despite this, there are limited data on longitudinal use of such screening tools, particularly with regard to the role of practice effects. Additionally, no guidelines currently exist on the timeframe between testing intervals, or recommendation of the magnitude of baseline impairment that warrants follow-up testing. The aim of the current paper was to review existing evidence for longitudinal validity of HAND screening tools. Only those HAND screening tools previously found to have high cross-sectional criterion validity were included. Preliminary recommendations for clinical use and future research are proposed including in international settings.
Gudjohnsen, Stefán A. H.; Atacho, Diahann A. M.; Gesbert, Franck; Raposo, Graca; Hurbain, Ilse; Larue, Lionel; Steingrimsson, Eirikur; Petersen, Petur Henry
Summary: Melanocytes are pigment producing cells derived from the neural crest. They are primarily found in the skin and hair follicles, but can also be found in other tissues including the eye, ear and heart. Here, we describe the distribution of pigmented cells in C57BL/6J mouse meninges, the membranes that envelope the brain. These cells contain melanosomes of all four stages of development and they depend on Microphthalmia associated transcription factor (MITF), the master regulator of melanocyte development, suggesting that they are bona-fide melanocytes. The location of these pigmented cells is consistent with the location of meningeal melanomas in humans and animal models. Significance: Here, we document and define pigmented cells in the meninges of the mouse brain and confirm that they are melanocytes. This is important for understanding the role of this cell type and for understanding primary meningeal melanoma, a rare disease that likely arises from normal meningeal melanocytes. PMID:26635543
Sufiawati, Irna; Tugizov, Sharof M
Herpes simplex virus (HSV) types 1 and 2 are the most common opportunistic infections in HIV/AIDS. In these immunocompromised individuals, HSV-1 reactivates and replicates in oral epithelium, leading to oral disorders such as ulcers, gingivitis, and necrotic lesions. Although the increased risk of HSV infection may be mediated in part by HIV-induced immune dysfunction, direct or indirect interactions of HIV and HSV at the molecular level may also play a role. In this report we show that prolonged interaction of the HIV proteins tat and gp120 and cell-free HIV virions with polarized oral epithelial cells leads to disruption of tight and adherens junctions of epithelial cells through the mitogen-activated protein kinase signaling pathway. HIV-induced disruption of oral epithelial junctions facilitates HSV-1 paracellular spread between the epithelial cells. Furthermore, HIV-associated disruption of adherens junctions exposes sequestered nectin-1, an adhesion protein and critical receptor for HSV envelope glycoprotein D (gD). Exposure of nectin-1 facilitates binding of HSV-1 gD, which substantially increases HSV-1 infection of epithelial cells with disrupted junctions over that of cells with intact junctions. Exposed nectin-1 from disrupted adherens junctions also increases the cell-to-cell spread of HSV-1 from infected to uninfected oral epithelial cells. Antibodies to nectin-1 and HSV-1 gD substantially reduce HSV-1 infection and cell-to-cell spread, indicating that HIV-promoted HSV infection and spread are mediated by the interaction of HSV gD with HIV-exposed nectin-1. Our data suggest that HIV-associated disruption of oral epithelial junctions may potentiate HSV-1 infection and its paracellular and cell-to-cell spread within the oral mucosal epithelium. This could be one of the possible mechanisms of rapid development of HSV-associated oral lesions in HIV-infected individuals.
Huang, Jeannie; Meixner, Linda; Fernandez, Susan; McCutchan, J. Allen
Objective To evaluate the efficacy of a single dose of intravenous zoledronate for the treatment of HIV-associated osteopenia and osteoporosis. Design A double-blinded, randomized, placebo-controlled, 12 month trial of 5 mg intravenous zoledronate dose to treat 30 HIV-infected men and women with osteopenia and osteoporosis. Methods Following zoledronate or placebo infusions, participants were followed for 12 months on daily calcium and vitamin D supplements. Lumbar spine and hip bone density was assessed at baseline, 6 and 12 months. Biomarkers of bone metabolism were measured at baseline, 2 weeks, 3, 6, 9, and 12 months. Student’s t-test and repeated measure analyses were used to evaluate bone density and bone marker changes over time. Results In the 30 HIV-infected men (27) and women (3) in the trial, median T-scores at entry were -1.7 for the lumbar spine and -1.4 for the hip. Median CD4 count was 461 cells/μL, 93% had HIV-RNA viral loads <400 copies/mL, and 97% were taking antiretroviral medications. Bone density measured either absolutely or as sex-adjusted T-scores significantly improved in zoledronate recipients as compared to minimal changes in those receiving placebo. Bone resorption markers significantly decreased over the study period in the zoledronate recipients as compared to placebo controls. No acute infusion reactions were detected, but one patient developed uveitis, a recognized complication of zoledronate, which responded to therapy. Conclusions In this small study, annual zoledronate appears to be a safe and effective therapy for HIV-associated bone loss. PMID:19050386
Claros, Pedro; Matusialk, Monika
Authors present two cases of children with reccurent meningitis and unilateral deafness. Implemented diagnostics (CT, NMR, ABR) revealed one side inner ear congenital malformation in one case and anterior fossa bony defect accompanied by labirynthine deformation in the other case. The presence of perilymphatic fistulae in oval and round windows and cerebrospinal fluid leakage has been confirmed in both cases during surgery. Carefull obliteration of the Eustachian tube and both windows has been performed. Non- complicated postoperative course (2 months and 6 years - respectively) has prooved the effectiveness of applied treatment.
Cardoso, Marta Pessoa; Pasternak, Jacyr; Giglio, Alfredo Elias; Casagrande, Rejane Rimazza Dalberto; Troster, Eduardo Juan
With the decline in the rate of infections caused by Haemophilus influenzae serotype b since the widespread vaccination, non-b serotypes should be considered as potential pathogenic agents in children with invasive disease younger than 5 years old. We report the case of an immunocompetent 1-year-old boy with Haemophilus influenzae type f meningitis. The agent was identified in cerebrospinal fluid and blood cultures. Serotyping was performed by tests using polyclonal sera and confirmed by polymerase chain reaction. All Haemophilus influenzae isolates associated with invasive disease should be serotyped and notified as a way to evaluate the changes and trends in serotype distribution of this disease.
Robert, J; Moreno, A; Martínez, J A; Almela, M; Jiménez de Anta, M T; Soriano, E
Yersinia spp infection in human people are increasing attention last thirty years. We have reviewed the bacteremia in our hospital last five years. Three episodes were Yersinia spp bacteremia. Presence of disease or predisponent therapy were present in most of episodes. All patients were more than seventy years old. The septic metastasis were present in all the cases: one with meningitis, other with liver abscess and one with septic arthritis. We have documented a good clinical evolution, though the mortality in different reports is around 50%. The election therapy for all episodes were cephalosporins, and in two cases we added quinolones.
Thunderclap headache is a sudden and severe headache that can occur after an aneurysmal subarachnoid hemorrhage (SAH). Subarachnoid hemorrhage is a medical emergency that requires prompt attention and hospitalization. Patients with thunderclap headache often undergo a noncontrast head computed tomography (CT) scan to ascertain SAH bleeding and, if the scan is negative, then undergo a lumbar puncture to look for cerebrospinal fluid (CSF) red blood cells (RBCs), which would be consistent with an aneurysmal leak. If the initial CT is negative and CSF is positive for RBCs, patients are usually admitted to the hospital for evaluation of intracranial aneurysm. We encountered a patient with thunderclap headache whose initial head CT was negative for SAH and whose CSF tested positive for RBCs. The patient was referred to our center for evaluation and management of aneurysmal SAH. However, on careful review of the patient’s medical history, serum laboratory values, and spinal fluid values, the patient was diagnosed with Ehrlichia chaffeensis meningitis. While Ehrlichia meningitis is rare, it is important to recognize the clinical clues that could help avoid formal cerebral angiography, a costly and potentially unnecessary procedure. We present how this case represented a cognitive framing bias and anchoring heuristic as well as steps that medical providers can use to prevent such cognitive errors in diagnosis. PMID:27053985
Stretz, Christoph; Song, Xianyuan; Killory, Brendan D; Ollenschleger, Martin D; Nouh, Amre M
A 75-year-old female with untreated rheumatoid arthritis presented with two weeks of behavioral changes and cognitive decline. A neurologic examination showed severe encephalopathy, brisk reflexes, and bilateral Babinski sign. A contrast-enhanced brain MRI demonstrated right meningeal enhancement and periventricular white matter disease. A computed tomographic angiogram (CTA) of the head and neck was negative for vasculitis. The cerebrospinal fluid (CSF) demonstrated lymphocytic pleocytosis. The patient's serum rheumatoid factor levels were elevated. A biopsy of the leptomeninges and cortex showed lymphocytic vasculitis of the cortical tissue and patchy lymphoplasmacytic infiltrates of dural small vessels consistent with rheumatoid meningitis. The patient received pulse-dose steroids followed by cyclophosphamide infusions. At her three month follow-up appointment, the patient's mental status had improved mildly. A follow-up brain MRI showed resolution of enhancement, but progression of subcortical bihemispheric white matter disease. Subsequently, the patient developed a respiratory infection and passed away. In rheumatoid arthritis, symptoms of encephalopathy, headaches, seizures, or focal neurologic deficits should raise suspicion for CNS involvement. This potentially treatable disease warrants prompt diagnosis.
Holt, D; Halket, S; de Louvois, J; Harvey, D
OBJECTIVES—To determine the incidence of neonatal meningitis in England and Wales. DESIGN—A national postal survey using the British Paediatric Surveillance Unit (BPSU) card scheme supplemented by information from other sources. SETTING—England and Wales 1996-1997. SUBJECTS—A total of 274 babies less than 28 days of age who were treated for meningitis. RESULTS—The incidence of neonatal meningitis in England and Wales has not changed since our previous study in 1985-1987. However, the acute phase mortality has fallen from 19.8% in 1985-1987 to 6.6% in this study. Group B streptococci (42%) and Escherichia coli (16%) remain the most common infecting microorganisms. Eight of 69 (12%) babies with group B streptococci and 4/26 (15%) with E coli died. Antibiotic regimens based on the third generation cephalosporins, notably cefotaxime, were most commonly used (84%). The BPSU scheme identified 72% of cases during the study period. Most cases of viral meningitis were not reported through the BPSU. Less than a third of samples from aseptic meningitis were examined for viruses; 56% of these were positive. CONCLUSIONS—Although the incidence of neonatal meningitis remains unchanged, mortality from this infection has fallen significantly. If this improvement is maintained as reflected in the level of sequelae at 5 years of age, then the fear surrounding meningitis during the neonatal period will have been dramatically reduced. PMID:11207221
Khanna, Suchin R.; Kralovic, Stephen M.; Prakash, Rajan
Patient: Male, 57 Final Diagnosis: Tuberculous meningitis Symptoms: Altered mental state • headache Medication: — Clinical Procedure: Lumbar puncture Specialty: Infectious Diseases Objective: Rare disease Background: Tuberculous meningitis is very rare in the United States in immunocompetent hosts. Risk factors are similar to those of pulmonary tuberculosis, including poverty, malnutrition, overcrowding, a compromised immune system, and coming from an endemic area. Meningeal tuberculosis mortality and other outcomes have changed little over time despite effective therapies due to delay in diagnosis because of its rarity, variable presentation, and often indolent course. Case Report: We describe a case of a 57-year-old male immigrant from Senegal with no significant past medical history and no previous history of tuberculosis or evidence of immune compromise. He presented to the hospital with headache and altered mental status and was subsequently diagnosed with tuberculous meningitis. Conclusions: This is a rare case of tuberculous meningitis in an immunocompetent host, questioning the conventional view that tuberculous meningitis is a disease of immunocompromised individuals. It emphasizes the importance of maintaining a strong clinical suspicion of tuberculous meningitis even in an immunocompetent patient in a geographical area with low prevalence if the patient has risk factors. Missed or delayed diagnosis is commonly fatal. PMID:28008165
Armstrong, G; Sen, R; Wilkinson, J
Pasteurella multocida is known to form part of the normal flora in the nasopharynx or gastrointestinal tract in many domestic and wild animals. Most human P multocida infections are soft tissue infections caused by dog or cat bites. Less commonly this bacterium is associated with infections affecting other organ systems of man. A case of fatal P multocida meningitis discovered at the necropsy of a 52 year old man is described. P multocida is an unusual causative agent of meningitis which tends to affect those at the extremes of age. Key Words: Pasteurella multocida • meningitis PMID:10823146
Ko, Jae-Hoon; Baek, Jin Yang; Kang, Cheol-In; Lee, Woo Joo; Lee, Ji Yong; Cho, Sun Young; Ha, Young Eun; Kim, So Hyun; Chung, Doo Ryeon; Peck, Kyong Ran; Lee, Nam Yong; Song, Jae-Hoon
A 61-year-old man with chronic hepatitis B and dyslipidemia visited the emergency department with a fever and severe headache. He was diagnosed with bacterial meningitis after a lumbar puncture, and blood culture revealed Parvimonas micra bacteremia. Although he had a history of extraction of a molar two weeks before symptom onset, there was no evidence of abscess formation on physical examination or imaging studies. He was successfully treated with oral metronidazole for 12 days after 9 days of treatment with IV ceftriaxone and vancomcycin. This is the first report of primary bacterial meningitis caused by this organism, which indicates that this organism is capable of being a bacterial meningitis pathogen.
Tenor, Jennifer L.; Oehlers, Stefan H.; Yang, Jialu L.
ABSTRACT 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. PMID:26419880
Pandey, R; Ghorpade, A
Alcohol (EtOH) abuse and HIV-1 infection remain leading public health problems not only in the United States but also across the world. Alcohol abusers have a significantly greater risk of HIV-1 infection than non-drinkers globally. In the United States, prevalence of EtOH abuse is over two-fold higher in HIV-1-positive individuals than that of the general population. Although alcohol abusers show neurodegeneration, exacerbated neuroinflammation and oxidative damage, the mechanism(s) by which EtOH regulates astrocyte inflammatory responses in HIV-associated neurocognitive disorders is unknown. Thus, we explored signaling pathway(s) involved in EtOH-mediated activation of human astrocytes with HIV-1 and subsequent alterations in their inflammatory functions. Alcohol exposure altered the morphology of astrocytes, proinflammatory responses and induced cytotoxicity in a dose-dependent manner. Time-dependent changes were also evaluated. EtOH and HIV-1 cotreatment decreased cell viability and proliferation, while increasing apoptosis and mitochondrial depolarization. EtOH and HIV-1 together increased the levels of proinflammatory molecules, interleukin-1β, tumor necrosis factor-α, CXCL8, tissue inhibitor of metalloproteinases-1 and more importantly, arachidonic acid, a known downstream target of cytosolic phospholipase A2 (cPLA2). Consistent with this observation, phospho-cPLA2 levels were augmented in HIV-1 and EtOH cotreatment as compared with HIV-1 or EtOH alone. Cyclooxygenase 2 was upregulated as measured by real-time PCR and western blot, whereas cotreatment of HIV-1 and EtOH decreased cytochrome P450-2E1 levels as compared with EtOH alone. Furthermore, we confirmed that blocking cPLA2 with arachidonyl tri floro methyl ketone, a cPLA2-specific inhibitor, effectively prevented cPLA2 phosphorylation and downstream outcomes. Thus, the present findings suggest that cPLA2 has a critical role in alcohol and HIV-induced astrocyte inflammation. In the future, cPLA2
Martínez-Lage, Juan F; Martínez-Lage Azorín, Laura; Almagro, María José; Bastida, María Encarnación; Reyes, Susana; Tellez, Cinthia
A 2-month-old girl developed meningitis, ventriculitis and brain abscess in the course of Citrobacter koseri infection. She was successfully treated with the combined use of antibiotics, intra-cavitary urokinase and surgery, thus avoiding the development of hydrocephalus and of ventricular loculation. C. koseri is a Gram-negative pathogen with a strong predilection for the neonatal brain. Brain abscesses develop in roughly 77% of cases, causing severe neurological sequels in one-half and death in one-third of patients. The authors aim to report the role of neurosurgical treatment for managing the severe complications that may arise in the course of C. koseri brain infection and the use of urokinase for preventing the development of loculated hydrocephalus.
Seixas, Diana; Lebre, Ana; Crespo, Pedro; Ferreira, Eugénia; Serra, José Eduardo; Saraiva da Cunha, José Gabriel
Streptococcus suis is a zoonotic pathogen with worldwide distribution, responsible for more than 700 human cases globally reported. This infection affects mostly men, exposed to pig or pork, which leads to its usual classification as an occupational disease. We report a case of acute bacterial meningitis in a 44 years old male. According to his past medical history, the patient had chronic alcoholism and worked in a restaurant as a piglet roaster. Microbiological examination of blood and CSF revealed S. suis. After 14 days of ceftriaxone the patient fully recovered. The authors review the clinical reports previously described in Portugal. In all of them was possible to identify risk exposition to pork. We alert to this microorganism's importance in Portugal where it is probably underdiagnosed.
Brouwer, Matthijs C.; Tunkel, Allan R.; van de Beek, Diederik
Summary: The epidemiology of bacterial meningitis has changed as a result of the widespread use of conjugate vaccines and preventive antimicrobial treatment of pregnant women. Given the significant morbidity and mortality associated with bacterial meningitis, accurate information is necessary regarding the important etiological agents and populations at risk to ascertain public health measures and ensure appropriate management. In this review, we describe the changing epidemiology of bacterial meningitis in the United States and throughout the world by reviewing the global changes in etiological agents followed by specific microorganism data on the impact of the development and widespread use of conjugate vaccines. We provide recommendations for empirical antimicrobial and adjunctive treatments for clinical subgroups and review available laboratory methods in making the etiological diagnosis of bacterial meningitis. Finally, we summarize risk factors, clinical features, and microbiological diagnostics for the specific bacteria causing this disease. PMID:20610819
Baliu, C; Sanclemente, G; Cardona, M; Castel, M A; Perez-Villa, F; Moreno, A; Cervera, C
Toxoplasma gondii is an opportunistic pathogen that causes neurologic and extraneurologic manifestations in immunosuppressed patients. Encephalitis and intracranial mass lesions are easily recognized as typical manifestations of toxoplasmosis. However, meningitis caused by T. gondii is a rare condition with very few cases described in the literature. We present the case of a heart transplant recipient who developed toxoplasmic encephalitis associated with meningitis. After an extensive review of the medical literature, we found only 1 case of meningitis in solid organ transplant recipients and <25 cases in immunosuppressed patients, such as patients infected with human immunodeficiency virus or those with Hodgkin's disease. In this report, we consider toxoplasmosis in the differential diagnosis of meningitis in immunocompromised individuals.
Ravishankar, B; Mangala; Prakash, G K; Shetty, K J; Ballal, H S
We report a case of a 65 year male with meningitis who had polyuria, severe hyponatremia, volume depletion and very high urinary sodium excretion. He was diagnosed to have cerebral salt wasting syndrome based on clinical and laboratory parameters.
Bruce, Beau B.; Tehrani, Mahtab; Newman, Nancy J.; Biousse, Valérie
We present a unique case of a patient with deafness and blindness secondary to carcinomatous meningitis from colorectal adenocarcinoma with accompanying radiologic and pathologic images and a brief review of the relevant literature. PMID:20966893
Tandon, Swati; Singh, Satinder; Sharma, Shalabh; Lahiri, Asish K.
Introduction: Congenital anomalies of the cochlea and labyrinth can be associated with meningitis and varying degrees of hearing loss or deafness. Despite antibiotics, meningitis remains a life threatening complication. Case Report: We report a case of recurrent meningitis following episodes of otitis media in a cochlear implantee child with bilateral vestibulocochlear malformation, due to fistula in the stapes footplate. Intrathecal fluorescin was used to identify the leak site. Conclusion: Recurrent meningitis can indicate for possible immunological or anatomical abnormalities as well for chronic parameningeal infections. Intraoperative use of intrathecal fluorescin is an ideal investigative tool to demonstrate cerebrospinal fluid (CSF) leak site in patients in whom other investigations fail to do so. PMID:27429952
Jennings, M T; Slatkin, N; D'Angelo, M; Ketonen, L; Johnson, M D; Rosenblum, M; Creasy, J; Tulipan, N; Walker, R
Seven children and young adults initially presented with subacute meningitis and/or increased intracranial pressure. The diagnosis of neoplastic meningitis secondary to a primitive neuroectodermal neoplasm was delayed by the absence of an obvious primary tumor. The neuroradiologic appearance was that of a basimeningeal infiltrative process, complicated by communicating hydrocephalus or "pseudotumor cerebri." Myelography was important in the diagnosis of disseminated meningeal malignancy in four cases. Cerebrospinal fluid cytologic diagnosis was insensitive but ultimately confirmed in five cases. All seven patients experienced progressive disease despite neuraxis radiotherapy and intensive chemotherapy; six have died. Systemic dissemination to bone and/or peritoneum occurred in three patients while on therapy. In two, a primary parenchymal brain or spinal cord tumor could not be identified at postmortem examination. The presentation of a primitive neuroectodermal tumor as subacute meningitis without an evident primary tumor heralds an aggressive and refractory neoplasm.
Faurholt-Jepsen, Daniel; Lillebaek, Troels; Nielsen, Ming-Yuan; Nielsen, Susanne Dam
In Denmark, tuberculous meningitis is rare. Central nervous system (CNS) involvement with Mycobacterium bovis is even rarer and has only been seen three times since 1992. We present a case of M. bovis meningitis in a previously healthy young Nigerian-born male, who had been exposed to unpasteurized dairy products in Nigeria but had no known contact with larger mammals. Before the development of meningitis, the patient had several contacts with the health system due to fever and non-specific symptoms. Finally, upon hospital admission, the patient was diagnosed with M. tuberculosis complex meningitis and treated empirically. After 13 days he was discharged without neurological sequelae. Later, the culture revealed M. bovis and treatment was adjusted accordingly.
A meningococcal serogroup A polysaccharide/tetanus toxoid conjugate vaccine (PsA-TT) (MenAfriVac#x2122;) is being deployed in countries of the African meningitis belt. Experience with other polysaccharide/protein conjugate vaccines has shown that an important part of their success has been their ability to prevent the acquisition of pharyngeal carriage and hence to stop transmission and induce herd immunity. If PsA-TT is to achieve the goal of preventing epidemics, it must be able to prevent the acquisition of pharyngeal carriage as well as invasive meningococcal disease and whether PsA-TT can prevent pharyngeal carriage needs to be determined. To address this issue, a consortium (the African Meningococcal Carriage (MenAfriCar) consortium) was established in 2009 to investigate the pattern of meningococcal carriage in countries of the African meningitis belt prior to and after the introduction of PsA-TT. This article describes how the consortium was established, its objectives and the standardised field and laboratory methods that were used to achieve these objectives. The experience of the MenAfriCar consortium will help in planning future studies on the epidemiology of meningococcal carriage in countries of the African meningitis belt and elsewhere. Un vaccin conjugué contenant un polysaccharide du sérogroupe A méningococcique et une anatoxine du tétanos (PsA-TT) (MenAfriVac™) est en cours de déploiement dans les pays de la ceinture africaine de la méningite. L’ expérience avec d’ autres vaccins conjugués polysaccharide/protéine a montré qu’ une partie importante de leur succès a été leur capacité à empêcher l’ acquisition du portage pharyngé et donc à arrêter la transmission et à induire une immunité de group. Si PsA-TT doit d’ atteindre l’ objectif de prévenir les épidémies, il devrait être en mesure d’ empêcher l’ acquisition du portage pharyngé ainsi que la méningococcie invasive et le fait que PsA-TT puisse emp
Shetter, A.G.; Fischer, D.W.; Flom, R.A.
Cranial computed tomographic (CT) scans of 22 patients with coccidioidal meningitis were reviewed and their clinical course was analyzed. Abnormalities of the ventricular system or the basilar cisterns or both were present in 16 instances. Although it is not a definitive diagnostic tool, the CT scan is helpful in suggesting a diagnosis of coccidioidal meningitis and in predicting the prognosis of patients affected by the disease. 19 references, 4 figures, 2 tables.
Hayek, Salim S; Abd, Thura T; Cribbs, Sushma K; Anderson, Albert M; Melendez, Andre; Kobayashi, Miwako; Polito, Carmen; (Wayne) Wang, Yun F
Though Elizabethkingia meningosepticum typically causes meningitis in neonates, its occurrence in adult is rare, with sixteen cases described worldwide. We report a case of E. meningosepticum meningitis in an immunocompetent adult. Bacterial identification was made a day earlier than conventional method by using matrix assisted laser desorption ionization time-of-flight (MALDI-TOF) Vitek mass spectrometry RUO (VMS), which resulted in successful treatment with rifampin, trimethoprim-sulfamethoxazole, levofloxacin and minocycline. PMID:26038458
Viswanathan, Stalin; Muthu, Vivekanandan; Iqbal, Nayyar; Remalayam, Bhavith; George, Tarun
Background Scrub typhus is prevalent in India although definite statistics are not available. There has been only one study on scrub typhus meningitis 20 years ago. Most reports of meningitis/meningoencephalitis in scrub typhus are case reports Methods A retrospective study done in Pondicherry to extract cases of scrub typhus admitted to hospital between February 2011 and January 2012. Diagnosis was by a combination of any one of the following in a patient with an acute febrile illness- a positive scrub IgM ELISA, Weil-Felix test, and an eschar. Lumbar puncture was performed in patients with headache, nuchal rigidity, altered sensorium or cranial nerve deficits. Results Sixty five cases of scrub typhus were found, and 17 (17/65) had meningitis. There were 33 males and 32 females. Thirteen had an eschar. Median cerebrospinal fluid (CSF) cell count, lymphocyte percentage, CSF protein, CSF glucose/blood glucose, CSF ADA were 54 cells/µL, 98%, 88 mg/dL, 0.622 and 3.5 U/mL respectively. Computed tomography was normal in patients with altered sensorium and cranial nerve deficits. Patients with meningitis had lesser respiratory symptoms and signs and higher urea levels. All patients had received doxycycline except one who additionally received chloramphenicol. Conclusion Meningitis in scrub typhus is mild with quick and complete recovery. Clinical features and CSF findings can mimic tuberculous meningitis, except for ADA levels. In the Indian context where both scrub typhus and tuberculosis are endemic, ADA and scrub IgM may be helpful in identifying patients with scrub meningitis and in avoiding prolonged empirical antituberculous therapy in cases of lymphocytic meningitis. PMID:23799119
Berliner, Elihay; Bar Meir, Maskit; Megged, Orli
Bacterial meningitis is a life threatening disease. Most patients will experience only one episode throughout life. Children who experience bacterial meningitis more than once, require further immunologic or anatomic evaluation. We report a 9 year old child with five episodes of bacterial meningitis due to a congenital defect of the skull base. A two and a half year old boy first presented to our medical center with pneumococcal meningitis. He was treated with antibiotics and fully recovered. Two months later he presented again with a similar clinical picture. Streptococcus pneumoniae grew in cerebrospinal fluid (CSF) culture. CT scan and later MRI of the brain revealed a defect in the anterior middle fossa floor, with protrusion of brain tissue into the sphenoidal sinus. Corrective surgery was recommended but the parents refused. Three months later, a third episode of pneumococcal meningitis occurred. The child again recovered with antibiotics and this time corrective surgery was performed. Five years later, the boy presented once again with clinical signs and symptoms consistent with bacterial meningitis. CSF culture was positive, but the final identification of the bacteria was conducted by broad spectrum 16S ribosomal RNA PCR (16S rRNA PCR) which revealed a sequence of Neisseria lactamica. CT and MRI showed recurrence of the skull base defect with encephalocele in the sphenoid sinus. The parents again refused neurosurgical intervention. A year later the patient presented with bacterial meningitis. CSF culture obtained after initiation of antibiotics was negative, but actinobacillus was identified in the CSF by 16S rRNA PCR. The patient is scheduled for neurosurgical intervention. In patients with recurrent bacterial meningitis caused by organisms colonizing the oropharynx or nasopharynx, an anatomical defect should be carefully sought and surgically repaired.
Masri, Amira; Bakri, Faris G; Birkenhäger, Ralf; Alassaf, Abeer; Musharbash, Awni F; Haroun, Azmy; Zak, Imad
The authors report the case of 5-year-old girl who presented with 4 episodes of recurrent meningitis. Her initial workup revealed a lumbosacral dermoid sinus associated with diastematomyelia and a tethered cord. Therefore, a surgical repair to correct the anomaly was performed. However, another episode of meningitis occurred after surgery, and a subsequent temporal bone scan revealed the presence of left Mondini dysplasia. To the authors' knowledge, this is the first report of Mondini dysplasia in association with diastematomyelia.
Srirama Jayamma, Savitha; Sud, Seema; Buxi, TBS; Madan, VS; Goyal, Ashish; Dhawan, Shashi
Meningeal melanocytoma is a rare pigmented tumor of the leptomeningeal melanocytes. This rare entity results in diagnostic difficulty in imaging unless clinical and histopathology correlation is performed. In this case report, we describe a case of meningeal melanocytoma of the cervical region presenting with superficial siderosis. Extensive neuroradiological examination is necessary to locate the source of the bleeding in such patients. Usually, the patient will be cured by the complete surgical excision of the lesion. PMID:26770862
Adult Nasal Type Extranodal NK/T-cell Lymphoma; AIDS-related Diffuse Large Cell Lymphoma; AIDS-related Diffuse Mixed Cell Lymphoma; AIDS-related Diffuse Small Cleaved Cell Lymphoma; AIDS-related Immunoblastic Large Cell Lymphoma; AIDS-related Lymphoblastic Lymphoma; AIDS-related Peripheral/Systemic Lymphoma; AIDS-related Small Noncleaved Cell Lymphoma; Anaplastic Large Cell Lymphoma; Angioimmunoblastic T-cell Lymphoma; Cutaneous B-cell Non-Hodgkin Lymphoma; Extranodal Marginal Zone B-cell Lymphoma of Mucosa-associated Lymphoid Tissue; Hepatosplenic T-cell Lymphoma; HIV-associated Hodgkin Lymphoma; Intraocular Lymphoma; Nodal Marginal Zone B-cell Lymphoma; Noncutaneous Extranodal Lymphoma; Peripheral T-cell Lymphoma; Recurrent Adult Burkitt Lymphoma; Recurrent Adult Diffuse Large Cell Lymphoma; Recurrent Adult Diffuse Mixed Cell Lymphoma; Recurrent Adult Diffuse Small Cleaved Cell Lymphoma; Recurrent Adult Grade III Lymphomatoid Granulomatosis; Recurrent Adult Hodgkin Lymphoma; Recurrent Adult Immunoblastic Large Cell Lymphoma; Recurrent Adult Lymphoblastic Lymphoma; Recurrent Adult T-cell Leukemia/Lymphoma; Recurrent Cutaneous T-cell Non-Hodgkin Lymphoma; Recurrent Grade 1 Follicular Lymphoma; Recurrent Grade 2 Follicular Lymphoma; Recurrent Grade 3 Follicular Lymphoma; Recurrent Mantle Cell Lymphoma; Recurrent Marginal Zone Lymphoma; Recurrent Mycosis Fungoides/Sezary Syndrome; Recurrent Small Lymphocytic Lymphoma; Refractory Hairy Cell Leukemia; Small Intestine Lymphoma; Splenic Marginal Zone Lymphoma; Stage I AIDS-related Lymphoma; Stage II AIDS-related Lymphoma; Stage III AIDS-related Lymphoma; Stage IV AIDS-related Lymphoma; T-cell Large Granular Lymphocyte Leukemia; Testicular Lymphoma; Waldenström Macroglobulinemia
Jaeger, Laura B; Nath, Avindra
It is well established that infection with the human immunodeficiency virus (HIV) leads to immune suppression. Less well known is the fact that long-term, progressive HIV disease is associated with the development of cognitive deficits. Since the introduction of combined antiretroviral therapy (cART), the clinical presentation of HIV infection has evolved into a chronic illness with very low levels of viral replication and chronic immune activation, with compliant affected individuals surviving for decades with a high quality of life. Despite these advances, many HIV-infected individuals develop some degree of neurodegeneration and cognitive impairment. The underlying pathophysiological mechanisms are not well understood, and there are no effective treatments. Thus, there is an unmet need for animal models that enable the study of HIV-associated neurocognitive disorders (HAND) and the testing of new therapeutic approaches to combat them. Here, we review the pros and cons of existing mouse models of HIV infection for addressing these aims and propose a detailed strategy for developing a new mouse model of HIV infection.
Pendyala, Gurudutt; Buescher, James L; Fox, Howard S
Methamphetamine (METH) abuse in conjunction with human immunodeficiency virus (HIV) exacerbates neuropathogenesis and accelerates neurocognitive impairments in the central nervous system (CNS), collectively termed HIV Associated Neurocognitive Disorders (HAND). Since both HIV and METH have been implicated in altering the synaptic architecture, this study focused on investigating alterations in synaptic proteins. Employing a quantitative proteomics approach on synaptosomes isolated from the caudate nucleus from two groups of rhesus monkeys chronically infected with simian immunodeficiency virus (SIV) differing by one regimen, METH treatment, we identified the neuron specific Na(+)/K(+)-ATPase alpha 1 isoform 3 (ATP1A3) to be up regulated after METH treatment, and validated its up regulation by METH in vitro. Further studies on signaling mechanisms revealed that the activation of ATP1A3 involves the extracellular regulated kinase (ERK) pathway. Given its function in maintaining ionic gradients and emerging role as a signaling molecule, changes in ATP1A3 yields insights into the mechanisms associated with HAND and interactions with drugs of abuse.
Jensen, Brigid K.; Monnerie, Hubert; Mannell, Maggie V.; Gannon, Patrick J.; Espinoza, Cagla Akay; Erickson, Michelle A.; Bruce-Keller, Annadora J.; Gelman, Benjamin B.; Briand, Lisa A.; Pierce, R. Christopher; Jordan-Sciutto, Kelly L.; Grinspan, Judith B.
Despite effective viral suppression through combined antiretroviral therapy (cART), approximately half of HIV-positive individuals suffer from HIV-Associated Neurocognitive Disorders (HAND). Studies of antiretroviral treated patients have revealed persistent white matter pathologies including diffuse myelin pallor, diminished white matter tracts, and decreased myelin protein mRNAs. Loss of myelin can contribute to neurocognitive dysfunction as the myelin membrane generated by oligodendrocytes is essential for rapid signal transduction and axonal maintenance. We hypothesized that myelin changes in HAND are partly due to effects of antiretroviral drugs on oligodendrocyte survival and/or maturation. We showed that primary mouse oligodendrocyte precursor cell cultures treated with therapeutic concentrations of HIV protease inhibitors Ritonavir or Lopinavir displayed dose-dependent decreases in oligodendrocyte maturation; however, this effect was rapidly reversed following drug removal. Conversely, nucleoside reverse transcriptase inhibitor Zidovudine had no effect. Furthermore, in vivo Ritonavir administration to adult mice reduced frontal cortex myelin protein levels. Finally, prefrontal cortex tissue from HIV-positive individuals with HAND on cART showed a significant decrease in myelin basic protein compared with untreated HIV-positive individuals with HAND or HIV-negative controls. These findings demonstrate that antiretrovirals can impact myelin integrity, and have implications for myelination in juvenile HIV patients, and myelin maintenance in adults on lifelong therapy. PMID:26469251
Adams, Lisa V; Kreiswirth, Barry N; Arbeit, Robert D; Soini, Hanna; Mtei, Lillian; Matee, Mecky; Bakari, Muhammad; Lahey, Timothy; Wieland-Alter, Wendy; Shashkina, Elena; Kurepina, Natalia; Driscoll, Jeffrey R; Pallangyo, Kisali; Horsburgh, C Robert; von Reyn, C Fordham
Molecular typing of Mycobacterium tuberculosis can be used to elucidate the epidemiology of tuberculosis, including the rates of clustering, the frequency of polyclonal disease, and the distribution of genotypic families. We performed IS6110 typing and spoligotyping on M. tuberculosis strains isolated from HIV-infected subjects at baseline or during follow-up in the DarDar Trial in Tanzania and on selected community isolates. Clustering occurred in 203 (74%) of 275 subjects: 124 (80%) of 155 HIV-infected subjects with baseline isolates, 56 (69%) of 81 HIV-infected subjects with endpoint isolates, and 23 (59%) of 39 community controls. Overall, 113 (41%) subjects had an isolate representing the East Indian "GD" family. The rate of clustering was similar among vaccine and placebo recipients and among subjects with or without cellular immune responses to mycobacterial antigens. Polyclonal disease was detected in 6 (43%) of 14 patients with multiple specimens typed. Most cases of HIV-associated tuberculosis among subjects from this study in Dar es Salaam resulted from recently acquired infection. Polyclonal infection was detected and isolates representing the East Indian GD strain family were the most common.
Ross, M J; Bruggeman, L A; Wilson, P D; Klotman, P E
Tubular microcyst formation is a prominent histopathologic feature of HIV-associated nephropathy (HIVAN), but its pathogenesis is unknown. HIV-1 has recently been shown to infect renal tubular epithelial cells in patients with HIVAN. In addition, HIV-1 gene expression in renal epithelial cells has been shown to cause a renal disease that is identical to HIVAN in HIV-1 transgenic mice. In these studies, immunohistochemistry for tubular segment-specific markers and mRNA in situ hybridization for HIV-1 was used to determine which tubular segments develop microcysts and which segments express HIV-1 in the kidneys of transgenic mice and patients with HIVAN. It was found that microcysts involve multiple nephron segments in both patients with HIVAN and HIV-1 transgenic mice. Furthermore, HIV-1 infection in HIVAN and HIV-1 transgene expression also occurs in multiple segments of the nephron. These data support a direct role for HIV-1 infection of renal epithelial cells in the pathogenesis of microcyst formation in patients with HIVAN.
Xue, Xiaonan; Wang, Dan; Tamari, Roni; Lee, Jeannette Y.; Mounier, Nicolas; Kaplan, Lawrence D.; Ribera, Josep-Maria; Spina, Michele; Tirelli, Umberto; Weiss, Rudolf; Galicier, Lionel; Boue, Francois; Wilson, Wyndham H.; Wyen, Christoph; Oriol, Albert; Navarro, José-Tomás; Dunleavy, Kieron; Little, Richard F.; Ratner, Lee; Garcia, Olga; Morgades, Mireia; Remick, Scot C.; Noy, Ariela; Sparano, Joseph A.
Limited comparative data exist for the treatment of HIV-associated non-Hodgkin lymphoma. We analyzed pooled individual patient data for 1546 patients from 19 prospective clinical trials to assess treatment-specific factors (type of chemotherapy, rituximab, and concurrent combination antiretroviral [cART] use) and their influence on the outcomes complete response (CR), progression free survival (PFS), and overall survival (OS). In our analysis, rituximab was associated with a higher CR rate (odds ratio [OR] 2.89; P < .001), improved PFS (hazard ratio [HR] 0.50; P < .001), and OS (HR 0.51; P < .0001). Compared with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP), initial therapy with more dose-intense regimens resulted in better CR rates (ACVBP [doxorubicin, cyclophosphamide, vindesine, bleomycin and prednisolone]: OR 1.70; P < .04), PFS (ACVBP: HR 0.72; P = .049; “intensive regimens”: HR 0.35; P < .001) and OS (“intensive regimens”: HR 0.54; P < .001). Infusional etoposide, prednisone, infusional vincristine, infusional doxorubicin, and cyclophosphamide (EPOCH) was associated with significantly better OS in diffuse large B-cell lymphoma (HR 0.33; P = .03). Concurrent use of cART was associated with improved CR rates (OR 1.89; P = .005) and trended toward improved OS (HR 0.78; P = .07). These findings provide supporting evidence for current patterns of care where definitive evidence is unavailable. PMID:24014242
Abidin, Anas Zainul; D'Souza, Adora M.; Nagarajan, Mahesh B.; Wismüller, Axel
About 50% of subjects infected with HIV present deficits in cognitive domains, which are known collectively as HIV associated neurocognitive disorder (HAND). The underlying synaptodendritic damage can be captured using resting state functional MRI, as has been demonstrated by a few earlier studies. Such damage may induce topological changes of brain connectivity networks. We test this hypothesis by capturing the functional interdependence of 90 brain network nodes using a Mutual Connectivity Analysis (MCA) framework with non-linear time series modeling based on Generalized Radial Basis function (GRBF) neural networks. The network nodes are selected based on the regions defined in the Automated Anatomic Labeling (AAL) atlas. Each node is represented by the average time series of the voxels of that region. The resulting networks are then characterized using graph-theoretic measures that quantify various network topology properties at a global as well as at a local level. We tested for differences in these properties in network graphs obtained for 10 subjects (6 male and 4 female, 5 HIV+ and 5 HIV-). Global network properties captured some differences between these subject cohorts, though significant differences were seen only with the clustering coefficient measure. Local network properties, such as local efficiency and the degree of connections, captured significant differences in regions of the frontal lobe, precentral and cingulate cortex amongst a few others. These results suggest that our method can be used to effectively capture differences occurring in brain network connectivity properties revealed by resting-state functional MRI in neurological disease states, such as HAND.
Cattie, Jordan E.; Doyle, Katie; Weber, Erica; Grant, Igor; Woods, Steven Paul
Executive dysfunction remains among the most prevalent cognitive domains impaired in persons with HIV-associated neurocognitive disorders (HAND). However, little is known specifically about the cognitive architecture or everyday functioning implications of planning, which is an aspect of executive functions involving the identification, organization, and completion of sequential behaviors toward the accomplishment of a goal. The current study examined these issues using the Tower of LondonDX in 53 individuals with HAND, 109 HIV-infected persons without HAND, and 82 seronegative participants. The HAND+ group performed significantly more poorly than HIV-infected individuals without HAND on number of correct moves, total moves, execution time, time violations, and rule violations. Within the HIV+ group as a whole, greater total move scores and rule violations were most strongly associated with executive dysfunction. Of clinical relevance, elevated total moves and rule violations were significant, independent predictors of self-reported declines in instrumental activities of daily living and unemployment status in HIV. These results suggest that planning accuracy, efficiency, and rule-bound control are impaired in HAND, and may meaningfully affect more cognitively complex aspects of everyday living. PMID:22731608
Cattie, Jordan E; Doyle, Katie; Weber, Erica; Grant, Igor; Woods, Steven Paul
Executive dysfunction remains among the most prevalent cognitive domains impaired in persons with HIV-associated neurocognitive disorders (HAND). However, little is known specifically about the cognitive architecture or everyday functioning implications of planning, which is an aspect of executive functions involving the identification, organization, and completion of sequential behaviours toward the accomplishment of a goal. The current study examined these issues using the Tower of London(DX) in 53 individuals with HAND, 109 HIV-infected persons without HAND, and 82 seronegative participants. The HAND+ group performed significantly more poorly than HIV-infected individuals without HAND on number of correct moves, total moves, execution time, time violations, and rule violations. Within the HIV+ group as a whole, greater total move scores and rule violations were most strongly associated with executive dysfunction. Of clinical relevance, elevated total moves and rule violations were significant, independent predictors of self-reported declines in instrumental activities of daily living and unemployment status in HIV. These results suggest that planning accuracy, efficiency, and rule-bound control are impaired in HAND and may meaningfully affect more cognitively complex aspects of everyday living.
Gongvatana, Assawin; Morgan, Erin E.; Iudicello, Jennifer E.; Letendre, Scott L.; Grant, Igor; Woods, Steven Paul
Background Excessive alcohol use is common among people living with HIV. Given the growing prevalence of older HIV+ adults, and observations indicating higher risk for neurocognitive impairment in older adults with either HIV infection or alcoholism, an increased understanding of their combined impact in the context of this increasingly aged population is crucial. Methods We conducted comprehensive neurocognitive assessment in 112 older HIV+ individuals aged 50 to 69 years. Regression analyses were conducted to examine the interaction between age and the presence of lifetime alcohol dependence on neurocognitive measures, controlling for years of education, hepatitis C serostatus, and lifetime non-alcohol substance use disorder. Results Significant interactions of age and alcohol dependence history were found for global neurocognitive function, which was driven by the domains of executive function, processing speed, and semantic memory. Follow-up analyses indicated adverse effects of alcohol use history on neurocognitive measures that were evident only in HIV+ individuals 60 years and older. Conclusions While mounting evidence in younger cohorts indicates adverse synergistic HIV/alcohol effects on neurocognitive function, our novel preliminary findings in this elderly HIV+ cohort demonstrated the importance of even a relatively distant alcohol use history on the expression of HIV-associated neurocognitive disorders that may not become apparent until much later in life. PMID:25201556
Casaletto, Kaitlin Blackstone; Doyle, Katie L; Weber, Erica; Woods, Steven Paul
HIV-associated neurocognitive disorders (HAND) are associated with deficits in prospective memory (PM; "remembering to remember"), conferring risk of daily functioning declines. However, self-perceptions of PM functioning are not reliably associated with PM performance in HIV, suggesting a possible deficit in awareness of PM abilities (meta-PM). Our study examined meta-PM in HAND and its correlates using self-predictions of laboratory-based PM performance. Performance-based PM abilities, self-reported prediction of PM performance, and PM complaints in everyday life were assessed in 49 individuals with HAND, 93 HIV+ without HAND (HIV+ noHAND), and 121 seronegative adults (HIV-). After controlling for group-level differences, HAND was associated with a greater number of PM symptoms in everyday life and worse PM performance when compared with both HIV+ noHAND and HIV- samples. Although HAND individuals reported somewhat lower predictions regarding their laboratory PM performance relative to the other study groups, they nevertheless exhibited significantly greater inaccurate overconfidence in time-based PM abilities. Within the HAND group, overconfidence in time-based meta-PM was associated with executive dysfunction and antiretroviral (ARV) nonadherence. HAND individuals evidenced a moderate deficit in awareness of PM functioning characterized by overconfidence in time-based PM abilities. Overconfidence in PM may result in absence of compensatory strategy use, and lead to increased errors in daily functioning (e.g., ARV nonadherence).
Casaletto, Kaitlin Blackstone; Doyle, Katie L.; Weber, Erica; Woods, Steven Paul; Heaton, Robert K.; Grant, Igor; Atkinson, J. Hampton; Ellis, Ronald J.; Letendre, Scott; Marcotte, Thomas D.; Marquie-Beck, Jennifer; Sherman, Melanie; Ellis, Ronald J.; Letendre, Scott; McCutchan, J. Allen; Best, Brookie; Schrier, Rachel; Rosario, Debra; Heaton, Robert K.; Atkinson, J. Hampton; Woods, Steven Paul; D, Psy; Marcotte, Thomas D.; Cherner, Mariana; Moore, David J.; Dawson, Matthew; Fennema-Notestine, Christine; Buchsbaum, Monte S.; Hesselink, John; Archibald, Sarah L.; Brown, Gregory; Buxton, Richard; Dale, Anders; Liu, Thomas; Masliah, Eliezer; Achim, Cristian; Smith, David M.; Richman, Douglas; McCutchan, J. Allen; Cherner, Mariana; Achim, Cristian; Lipton, Stuart; Atkinson, J. Hampton; Marquie-Beck, Jennifer; Gamst, Anthony C.; Cushman, Clint; Abramson, Ian; Vaida, Florin; Deutsch, Reena; Umlauf, Anya
HIV-associated neurocognitive disorders (HAND) are associated with deficits in prospective memory (PM; “remembering to remember”), conferring risk of daily functioning declines. However, self-perceptions of PM functioning are not reliably associated with PM performance in HIV, suggesting a possible deficit in awareness of PM abilities (meta-PM). Our study examined meta-PM in HAND and its correlates using self-predictions of laboratory-based PM performance. Performance-based PM abilities, self-reported prediction of PM performance, and PM complaints in everyday life were assessed in 49 individuals with HAND, 93 HIV+ without HAND (HIV+ noHAND), and 121 seronegative adults (HIV−). After controlling for group-level differences, HAND was associated with a greater number of PM symptoms in everyday life and worse PM performance when compared with both HIV+ noHAND and HIV− samples. Although HAND individuals reported somewhat lower predictions regarding their laboratory PM performance relative to the other study groups, they nevertheless exhibited significantly greater inaccurate overconfidence in time-based PM abilities. Within the HAND group, overconfidence in time-based meta-PM was associated with executive dysfunction and antiretroviral (ARV) nonadherence. HAND individuals evidenced a moderate deficit in awareness of PM functioning characterized by overconfidence in time-based PM abilities. Overconfidence in PM may result in absence of compensatory strategy use, and lead to increased errors in daily functioning (e.g., ARV nonadherence). PMID:25404005
Dubos, F; Lamotte, B; Bibi‐Triki, F; Moulin, F; Raymond, J; Gendrel, D; Bréart, G; Chalumeau, M
Background Clinical decision rules have been derived to distinguish between bacterial and aseptic meningitis in the emergency room to avoid unnecessary antibiotic treatments and hospitalisations. Aims To evaluate the reproducibility and to compare the diagnostic performance of five clinical decision rules. Methods All children hospitalised for bacterial meningitis between 1995 and 2004 or aseptic meningitis between 2000 and 2004 have been included in a retrospective cohort study. Sensitivity and specificity were calculated by applying each rule to the patients. The best rule was a priori defined as the one yielding 100% sensitivity for bacterial meningitis, the highest specificity, and the greatest simplicity for a bedside application. Results Among the 166 patients included, 20 had bacterial meningitis and 146 had aseptic meningitis. Although three rules achieved 100% sensitivity (95% CI 84–100), one had a significantly lower specificity (13%, 95% CI 8–19) than those of the other two rules (57%, 95% CI 48–65; and 66%, 95% CI 57–73), which were not statistically different. The ease of manual computation of the rule developed by Nigrovic et al (a simple list of five items: seizure, blood neutrophil count, cerebrospinal fluid (CSF) Gram stain, CSF protein, CSF neutrophil count) was higher than the one developed by Bonsu and Harper. Conclusion On our population, the rule derived by Nigrovic et al had the best balance between accuracy and simplicity of manual computation and could help to avoid two thirds of unnecessary antibiotic treatments and hospitalisations. PMID:16595647
Khanna, Suchin R; Kralovic, Stephen M; Prakash, Rajan
BACKGROUND Tuberculous meningitis is very rare in the United States in immunocompetent hosts. Risk factors are similar to those of pulmonary tuberculosis, including poverty, malnutrition, overcrowding, a compromised immune system, and coming from an endemic area. Meningeal tuberculosis mortality and other outcomes have changed little over time despite effective therapies due to delay in diagnosis because of its rarity, variable presentation, and often indolent course. CASE REPORT We describe a case of a 57-year-old male immigrant from Senegal with no significant past medical history and no previous history of tuberculosis or evidence of immune compromise. He presented to the hospital with headache and altered mental status and was subsequently diagnosed with tuberculous meningitis. CONCLUSIONS This is a rare case of tuberculous meningitis in an immunocompetent host, questioning the conventional view that tuberculous meningitis is a disease of immunocompromised individuals. It emphasizes the importance of maintaining a strong clinical suspicion of tuberculous meningitis even in an immunocompetent patient in a geographical area with low prevalence if the patient has risk factors. Missed or delayed diagnosis is commonly fatal.
Wright, P. F.
Endemic acute bacterial meningitis of childhood appears to be neglected as a cause of morbidity and mortality in developing countries, probably because it has been overshadowed by the dramatic epidemics of meningococcal disease in sub-Saharan Africa. The available data based on reviews of hospitalized patients suggest that endemic meningitis is mostly a disease of young infants, Streptococcus pneumoniae and Haemophilus influenzae type b being the most important etiologic agents. The epidemiological pattern appears to be different in developing countries, compared with northern Europe or the USA, and closely resembles the early age of onset and high incidence of meningitis observed among the native American populations in Alaska. The mortality from meningitis appears to be much higher in developing countries than in industrialized countries. The availability of vaccines against the pneumococcus and haemophilus, particularly those in which the bacterial polysaccharide is conjugated to a protein, promises protection against systemic bacterial infection from these organisms. The assessment of the efficacy of such vaccines will have to include a close examination of meningitis as an outcome. It is suggested that before such vaccines become available careful clinical and epidemiological studies of meningitis will help both to define the impact of this disease and how to design an intervention strategy. PMID:2611973
Sharma, Vijai Prakash; Yadav, Ganesh; Gupta, Anil Kumar; Kumar, Dileep
Tubercular meningitis is a severe form of central nervous system tuberculosis with high morbidity and mortality. Apart from neurological deficits, musculoskeletal involvement is also seen in very few cases in the form of heterotopic ossification around immobile joints. A 35-year-old male case of tubercular meningitis with left hemiparesis presented with multiple joint restriction of range of motion. On clinical examination, palpable firm masses around multiple joints with painful restriction of movements were seen. X-ray films of multiple joints revealed heterotopic ossification over left shoulder, hip and knee joint with bony ankylosis of left hip and soft tissue contractures. Very few reports have been published in the literature for association of heterotopic ossification with tubercular meningitis with such extensive joint involvement which compels us to report this clinical association of tubercular meningitis. This report is intended to create caution among physicians and other caregivers for this debilitating complication of tubercular meningitis and in face of high prevalence of tuberculosis and tubercular meningitis, employ methods to prevent and treat. PMID:25540549
Cordero, Radames J.B.; Frases, Susana; Guimaräes, Allan J.; Rivera, Johanna; Casadevall, Arturo
SUMMARY The encapsulated fungus Cryptococcus neoformans is a common cause of life-threatening disease in immunocompromised individuals. Its major virulence determinant is the polysaccharide (PS) capsule. An unsolved problem in cryptococcal biology is whether the PSs composing the capsule are linear or complex branched polymers, as well as the implications of this structural composition in pathogenesis. In this study we approached the problem by combining static and dynamic light scattering, viscosity analysis, and high-resolution microscopy and correlated the findings with biological properties. Analysis of the dependence of capsular PS molecular mass and the radius of gyration provided strong evidence against a simple linear PS configuration. Shape factors calculated from light scattering measurements in solution revealed values consistent with polymer branching. Furthermore, viscosity measurements provided complementary evidence for structural branching. Electron microscopy showed PS spherical-like structures similar to other branched PS. Finally, we show that the capacity of capsular PS to interfere in complement-mediated phagocytosis, inhibit nitric oxide production by macrophage-like cells, protect against reactive oxygen species, antibody reactivity and half-life in serum were influenced by the degree of branching, providing evidence for the notion that PS branching is an important parameter in determining the biological activity of C. neoformans PS. PMID:21208301
Feretzaki, Marianna; Hardison, Sarah E; Wormley, Floyd L; Heitman, Joseph
Cryptococcus neoformans is a human fungal pathogen that causes lethal infections of the lung and central nervous system in immunocompromised individuals. C. neoformans has a defined bipolar sexual life cycle with a and α mating types. During the sexual cycle, which can occur between cells of opposite mating types (bisexual reproduction) or cells of one mating type (unisexual reproduction), a dimorphic transition from yeast to hyphal growth occurs. Hyphal development and meiosis generate abundant spores that, following inhalation, penetrate deep into the lung to enter the alveoli, germinate, and establish a pulmonary infection growing as budding yeast cells. Unisexual reproduction has been directly observed only in the Cryptococcus var. neoformans (serotype D) lineage under laboratory conditions. However, hyphal development has been previously associated with reduced virulence and the serotype D lineage exhibits limited pathogenicity in the murine model. In this study we show that the serotype D hyperfilamentous strain XL280α is hypervirulent in an animal model. It can grow inside the lung of the host, establish a pulmonary infection, and then disseminate to the brain to cause cryptococcal meningoencephalitis. Surprisingly, this hyperfilamentous strain triggers an immune response polarized towards Th2-type immunity, which is usually observed in the highly virulent sibling species C. gattii, responsible for the Pacific Northwest outbreak. These studies provide a technological advance that will facilitate analysis of virulence genes and attributes in C. neoformans var. neoformans, and reveal the virulence potential of serotype D as broader and more dynamic than previously appreciated.
Niizuma, H; Higuchi, H; Tajima, T
A case of cryptococcal granulomatous arachnitis of the spinal cord was reported. A 12-year-old boy suffered from sudden occipitalgia and left hemiparesis. The symptoms disappeared spontaneously in about a half year. The next year, he consulted an orthopedist because of lumbago and gait disturbance. Myelography through the cisternal route showed complete block at the level of L1. Exploratory laminectomy of D12 and L1 revealed adhesive arachnitis. Symptoms were improved immediately after the operation. At the age of 15, he was admitted to our clinic, because of sudden onset of headache and vomiting. Computed tomography showed marked hydrocephalus. He recovered by ventriculoperitoneal shunt, and was discharged. The next year, sudden back pain occurred. Gait disturbance, sensory disturbance of the legs and trunks below the mamilla, and dysuria appeared gradually. He was readmitted and laminectomy of D2-4 was performed. The arachnoid membrane was white and 2 mm in thickness diffusely. Thickened arachnoid membrane was removed at the level of D2-4. Histological diagnosis was granulomatous arachnitis. Cryptococcus was seen in the removed tissue. Symptoms were improved after operation. One thousand milligrams of amphoterisin B was injected intermittently. He was discharged on food. Spinal symptoms in cryptococcosis are rare. Operative procedures were effective before the administration of amphoterisin B.
Cordero, Radames J B; Frases, Susana; Guimaräes, Allan J; Rivera, Johanna; Casadevall, Arturo
The encapsulated fungus Cryptococcus neoformans is a common cause of life-threatening disease in immunocompromised individuals. Its major virulence determinant is the polysaccharide (PS) capsule. An unsolved problem in cryptococcal biology is whether the PSs composing the capsule are linear or complex branched polymers, as well as the implications of this structural composition in pathogenesis. In this study we approached the problem by combining static and dynamic light scattering, viscosity analysis, and high-resolution microscopy and correlated the findings with biological properties. Analysis of the dependence of capsular PS molecular mass and the radius of gyration provided strong evidence against a simple linear PS configuration. Shape factors calculated from light scattering measurements in solution revealed values consistent with polymer branching. Furthermore, viscosity measurements provided complementary evidence for structural branching. Electron microscopy showed PS spherical-like structures similar to other branched PS. Finally, we show that the capacity of capsular PS to interfere in complement-mediated phagocytosis, inhibit nitric oxide production by macrophage-like cells, protect against reactive oxygen species, antibody reactivity and half-life in serum were influenced by the degree of branching, providing evidence for the notion that PS branching is an important parameter in determining the biological activity of C. neoformans PS.
Tuberculosis (TB) can involve any organ system in the body. Extrapulmonary involvement can occur in isolation or along with a pulmonary focus as in the case of patients with disseminated tuberculosis. Tuberculosis meningitis (TBM) is the most severe form of extrapulmonary tuberculosis. TBM a medical emergency, is still a major cause of serious illness in many parts of the world. TBM remains difficult to diagnose, and it is usually due to hematogenous dissemination of the tubercle bacillus. The exact incidence and prevalence are not known. The clinical spectrum is broad and may be non-specific making early diagnosis difficult. Improved outcome requires early recognition and treatment of these conditions. Clinical features included fever for more than 7 days, headache, or neck stiffness. While TBM is a disease of childhood, tuberculomas and spinal tuberculosis are invariably an adult manifestation. In HIV infection, TB is often atypical in presentation, frequently causing extrapulmonary disease, and patients have a high incidence of TBM. Clinical response to antituberculous therapy in all forms of neurotuberculosis is excellent if the diagnosis is made early before irreversible neurological deficit is established. Diagnosis is based on the characteristic clinical picture, neuroimaging abnormalities, cerebrospinal fluid changes and the response to anti-tuberculosis drugs. Diagnosis is best made with lumbar puncture and examination of the cerebrospinal fluid (CSF). Suspect TBM if there is a CSF leucocytosis (predominantly lymphocytes), the CSF protein is raised, and the CSF plasma glucose is <50%. Rapid techniques based on nucleic acid amplification such as PCR are more sensitive and specific as they attempt to detect specific DNA sequences of the organism. The hallmark pathological processes are meningeal inflammation, basal exudates, vasculitis and hydrocephalus. Treatment delay is strongly associated with death and empirical anti-tuberculosis therapy should be
Haddow, Lewis J; Sahid, Faieza; Moosa, Mahomed-Yunus S
Atypical manifestations of Cryptococcus neoformans disease have been reported in patients with HIV-1 infection as part of the spectrum of the immune reconstitution inflammatory syndrome (IRIS). We describe a cryptococcal breast abscess in a patient presenting after 11 months of highly active antiretroviral therapy (HAART). The arguments for and against the case being a novel manifestation of IRIS are discussed. The potential hazards of using CD4 count as a surrogate marker of IRIS and the danger of misdiagnosing IRIS as failure of HAART are highlighted.
Mora Mora, Luis A; Arco Espinosa, Micke E de; Plumet, Javier; Micheli, Federico
Acute bacterial meningitis has a global mortality rate of 135000 cases per year. In Argentina over the last 12 years, the annual incidence rate has been 5.5/100 000. About 20% of patients present neurological sequelae, which are more common in patients aged 60 or older. Our objective here is to determine the clinical characteristics, the most common causes and to measure evolution in patients over 60 years old diagnosed with meningitis and treated at the Hospital de Clinicas José de San Martín. This is a retrospective study based on a review of medical records from 2003 to 2013 that takes into account patients older than 60 who were diagnosed with acute bacterial meningitis acquired in the community by a microbiological diagnosis of CSF or those included due to a high suspicion of bacterial meningitis (pleocitosis > 2000 cells/mm3, proteins > 220 mg/dl, glycorrhachia < 34 mg/dl, glycorrhachia/glucose index < 0.23). Cases of TB meningitis, nosocomial, postoperative and other nonbacterial meningitis were excluded. Sixty nine patients were included, 45 (65%) were women with an average age of 78 ± 10.6 years. Only 40% had the triad of classical meningitis symptoms (stiff neck, fever and altered mental status). In 52% of the patients germs developed in the CSF, the most frequent being Streptococcus pneumoniae present in 47% of cases. Lethality rate was 41%, all of them by methicillin-sensitive Staphylococcus aureus. Only 24 (35%) cases were admitted into intensive care. The main sequelae present were motor disorders (12%) and hearing loss (5%).
Tanriverdi, F; De Bellis, A; Teksahin, H; Alp, E; Bizzarro, A; Sinisi, A A; Bellastella, G; Paglionico, V A; Bellastella, A; Unluhizarci, K; Doganay, M; Kelestimur, F
Previous case reports and retrospective studies suggest that pituitary dysfunction may occur after acute bacterial or viral meningitis. In this prospective study we assessed the pituitary functions, lipid profile and anthropometric measures in adults with acute bacterial or viral meningitis. Moreover, in order to investigate whether autoimmune mechanisms could play a role in the pathogenesis of acute meningitis-induced hypopituitarism we also investigated the anti-pituitary antibodies (APA) and anti-hypothalamus antibodies (AHA) prospectively. Sixteen patients (10 males, 6 females; mean ± SD age 40.9 ± 15.9) with acute infectious meningitis were included and the patients were evaluated in the acute phase, and at 6 and 12 months after the acute meningitis. In the acute phase 18.7% of the patients had GH deficiency, 12.5% had ACTH and FSH/LH deficiencies. At 12 months after acute meningitis 6 of 14 patients (42.8%) had GH deficiency, 1 of 14 patients (7.1%) had ACTH and FSH/LH deficiencies. Two of 14 patients (14.3%) had combined hormone deficiencies and four patients (28.6%) had isolated hormone deficiencies at 12 months. Four of 9 (44.4%) hormone deficiencies at 6 months were recovered at 12 months, and 3 of 8 (37.5%) hormone deficiencies at 12 months were new-onset hormone deficiencies. At 12 months there were significant negative correlations between IGF-I level vs. LDL-C, and IGF-I level vs. total cholesterol. The frequency of AHA and APA positivity was substantially high, ranging from 35 to 50% of the patients throughout the 12 months period. However there were no significant correlations between AHA or APA positivity and hypopituitarism. The risk of hypopituitarism, GH deficiency in particular, is substantially high in the acute phase, after 6 and 12 months of the acute infectious meningitis. Moreover we found that 6th month after meningitis is too early to make a decision for pituitary dysfunction and these patients should be screened for at least 12 months
Li, Jinliang; Das, Jharna R; Tang, Pingtao; Han, Zhe; Jaiswal, Jyoti K; Ray, Patricio E
Studies have shown that podocytes and renal tubular epithelial cells from patients with HIV-associated nephropathy (HIVAN) express HIV-1 transcripts, suggesting that productive infection of renal epithelial cells precipitates development of HIVAN. However, podocytes and renal tubular epithelial cells do not express CD4 receptors, and it is unclear how these cells become productively infected in vivo We investigated the mechanisms underlying the infection by HIV-1 of podocytes cultured from the urine of children with HIVAN. We observed low-level productive infection on exposure of these cells to primary cell-free HIV-1 supernatants. However, envelope-defective recombinant HIV-1 did not infect the renal epithelial cell lines. Moreover, treatment of podocytes to inhibit endocytic transport or dynamin activity or remove cell surface heparan sulfate proteoglycans reduced infection efficiency. Transfection of CD4- 293T cells with a cDNA expression library developed from a podocyte cell line derived from a child with HIVAN led to the identification of TNF-α as a possible mediator of HIV-1 infection. Overexpression of transmembrane TNF-α in cultured CD4- renal tubular epithelial cells, 293T cells, and HeLa cells enabled the infection of these cells; exposure to soluble TNF-α did not. Immunohistochemistry showed TNF-α expression in podocytes of renal sections from children with HIVAN. Furthermore, we found that TNF-α enhanced NF-κB activation and integration of HIV-1 into the podocyte DNA. Finally, inhibition of dynamin activity blocked TNF-α-mediated infection. These data establish a role for transmembrane TNF-α in facilitating the viral entry and integration of HIV-1 into the DNA of renal epithelial cells.
Dahal, Santosh; Chitti, Sai V. P.; Nair, Madhavan P. N.; Saxena, Shailendra K.
Substantial epidemiological studies suggest that not only, being one of the reasons for the transmission of the human immunodeficiency virus (HIV), but drug abuse also serves its role in determining the disease progression and severity among the HIV infected population. This article focuses on the drug cocaine, and its role in facilitating entry of HIV into the CNS and mechanisms of development of neurologic complications in infected individuals. Cocaine is a powerfully addictive central nervous system stimulating drug, which increases the level of neurotransmitter dopamine (DA) in the brain, by blocking the dopamine transporters (DAT) which is critical for DA homeostasis and neurocognitive function. Tat protein of HIV acts as an allosteric modulator of DAT, where as cocaine acts as reuptake inhibitor. When macrophages in the CNS are exposed to DA, their number increases. These macrophages release inflammatory mediators and neurotoxins, causing chronic neuroinflammation. Cocaine abuse during HIV infection enhances the production of platelet monocyte complexes (PMCs), which may cross transendothelial barrier, and result in HIV-associated neurocognitive disorder (HAND). HAND is characterized by neuroinflammation, including astrogliosis, multinucleated giant cells, and neuronal apoptosis that is linked to progressive virus infection and immune deterioration. Cocaine and viral proteins are capable of eliciting signaling transduction pathways in neurons, involving in mitochondrial membrane potential loss, oxidative stress, activation of JNK, p38, and ERK/MAPK pathways, and results in downstream activation of NF-κB that leads to HAND. Tat-induced inflammation provokes permeability of the blood brain barrier (BBB) in the platelet dependent manner, which can potentially be the reason for progression to HAND during HIV infection. A better understanding on the role of cocaine in HIV infection can give a clue in developing novel therapeutic strategies against HIV-1 infection
Sekhar, Rajagopal V; Jahoor, Farook; Iyer, Dinakar; Guthikonda, Anuradha; Paranilam, Jaya; Elhaj, Fareed; Coraza, Ivonne; Balasubramanyam, Ashok
Patients with HIV-associated dyslipidemic lipodystrophy (HADL) have characteristic lipid kinetic defects: accelerated lipolysis, blunted fat oxidation and increased hepatic fatty acid reesterification. HADL patients with lipoatrophy also have leptin deficiency. Small or non-randomized studies have suggested that leptin replacement improves glucose metabolism in HADL, with very limited data regarding its effects on the lipid kinetic abnormalities. We performed a randomized, double-blind, placebo-controlled, dose-escalating (0.02 mg/kg/d for two months; 0.04 mg/kg/d for a further two months) study of the effects of metreleptin on lipid kinetics in 17 adults with HADL, hypertriglyceridemia and hypoleptinemia. Rates of lipolysis, intra-adipocyte and intrahepatic reesterification and fatty acid oxidation were measured using infusions of (13)C(1)-palmitate and (2)H(5)-glycerol, and indirect calorimetry. Fasting lipid profiles and glucose and insulin responses to oral glucose challenge were also measured. Metreleptin treatment induced significant, dose-dependent increases in fasting plasma leptin levels. There was no significant change in total lipolysis, net lipolysis, adipocyte or hepatic re-esterification or fatty acid oxidation, or in fasting triglyceride or HDL-C concentrations, with metreleptin treatment. Metreleptin decreased fasting non-HDL-C levels (P<.01) and area-under-the-curve for glucose (P<.05). In hypoleptinemic HADL patients, treatment with metreleptin at 0.02 or 0.04 mg/kg/d does not improve abnormal fasting lipid kinetics, or triglyceride or HDL-C levels. Metreleptin does, however, improve glycemia and non-HDL-C in these patients. These results suggest a dissociation between leptin's effects on glucose metabolism compared to those on lipid kinetics in HADL.
Kim, WooJin; Zekas, Erin; Lodge, Robert; Susan-Resiga, Delia; Marcinkiewicz, Edwidge; Essalmani, Rachid; Mihara, Koichiro; Ramachandran, Rithwik; Asahchop, Eugene; Gelman, Benjamin; Cohen, Éric A; Power, Christopher; Hollenberg, Morley D; Seidah, Nabil G
The proprotein convertases (PCs) furin, PC5, PACE4, and PC7 cleave secretory proteins after basic residues, including the HIV envelope glycoprotein (gp160) and Vpr. We evaluated the abundance of PC mRNAs in postmortem brains of individuals exhibiting HIV-associated neurocognitive disorder (HAND), likely driven by neuroinflammation and neurotoxic HIV proteins (e.g., envelope and Vpr). Concomitant with increased inflammation-related gene expression (interleukin-1β [IL-1β]), the mRNA levels of the above PCs are significantly increased, together with those of the proteinase-activated receptor 1 (PAR1), an inflammation-associated receptor that is cleaved by thrombin at ProArg41↓ (where the down arrow indicates the cleavage location), and potentially by PCs at Arg41XXXXArg46↓. The latter motif in PAR1, but not its R46A mutant, drives its interactions with PCs. Indeed, PAR1 upregulation leads to the inhibition of membrane-bound furin, PC5B, and PC7 and inhibits gp160 processing and HIV infectivity. Additionally, a proximity ligation assay revealed that furin and PC7 interact with PAR1. Reciprocally, increased furin expression reduces the plasma membrane abundance of PAR1 by trapping it in the trans-Golgi network. Furthermore, soluble PC5A/PACE4 can target/disarm cell surface PAR1 through cleavage at Arg46↓. PACE4/PC5A decreased calcium mobilization induced by thrombin stimulation. Our data reveal a new PC-PAR1-interaction pathway, which offsets the effects of HIV-induced neuroinflammation, viral infection, and potentially the development of HAND.
Cysique, Lucette A; Brew, Bruce J
HIV-associated neurocognitive disorder is known to occur in the context of successful combination antiretroviral therapy (cART; plasma HIV RNA <50 copies/ml). Here, we newly provide an analysis of its prevalence and nature in the absence of medical or psychiatric confounds that may otherwise inflate the prevalence rate. We enrolled a cohort of 116 advanced HIV + individuals on cART (51% virally suppressed (VS)). They were screened for active Hepatitis C, current substance use disorder and were assessed with standard neuropsychological (NP) testing. Our results showed that out of the entire sample, NP impairment occurred in 18.1% (21/116) in VS individuals which was not statistically different from the 24.1% (28/116) that were found to be NP-impaired and not VS. In comparison with NP-normal-VS persons, NP impairment in VS individuals was associated with shorter duration of current cART and lower pre-morbid ability. Higher cART CNS penetration effectiveness tended to be associated with lesser cognitive severity in NP-impaired VS individuals. Current CD4 cell count, depression symptoms and past CNS HIV-related diseases did not specifically account for persistent NP impairment in VS individuals. In conclusion, despite suppression of systemic viral load, non-confounded HIV-related NP-impairment prevalence reached 18.1%. Of the potential explanations for this persistent deficit, a "burnt-out" form of the disease and immune reconstitution inflammatory syndrome were the less likely explanations, while a shorter current cART duration and lower pre-morbid intellectual capacity were significant. Nonetheless, predictive modelling with these last two factors misclassified 27% and had low sensitivity (43%) emphasising that other yet-to-be-defined factors were operative.
Phillips, Tudor J C; Brown, Matthew; Ramirez, Juan D; Perkins, James; Woldeamanuel, Yohannes W; Williams, Amanda C de C; Orengo, Christine; Bennett, David L H; Bodi, Istvan; Cox, Sarah; Maier, Christoph; Krumova, Elena K; Rice, Andrew S C
HIV-associated sensory neuropathy (HIV-SN) is a frequent complication of HIV infection and a major source of morbidity. A cross-sectional deep profiling study examining HIV-SN was conducted in people living with HIV in a high resource setting using a battery of measures which included the following: parameters of pain and sensory symptoms (7day pain diary, Neuropathic Pain Symptom Inventory [NPSI] and Brief Pain Inventory [BPI]), sensory innervation (structured neurological examination, quantitative sensory testing [QST] and intraepidermal nerve fibre density [IENFD]), psychological state (Pain Anxiety Symptoms Scale-20 [PASS-20], Depression Anxiety and Positive Outlook Scale [DAPOS], and Pain Catastrophizing Scale [PCS], insomnia (Insomnia Severity Index [ISI]), and quality of life (Short Form (36) Health Survey [SF-36]). The diagnostic utility of the Brief Peripheral Neuropathy Screen (BPNS), Utah Early Neuropathy Scale (UENS), and Toronto Clinical Scoring System (TCSS) were evaluated. Thirty-six healthy volunteers and 66 HIV infected participants were recruited. A novel triumvirate case definition for HIV-SN was used that required 2 out of 3 of the following: 2 or more abnormal QST findings, reduced IENFD, and signs of a peripheral neuropathy on a structured neurological examination. Of those with HIV, 42% fulfilled the case definition for HIV-SN (n=28), of whom 75% (n=21) reported pain. The most frequent QST abnormalities in HIV-SN were loss of function in mechanical and vibration detection. Structured clinical examination was superior to QST or IENFD in HIV-SN diagnosis. HIV-SN participants had higher plasma triglyceride, concentrations depression, anxiety and catastrophizing scores, and prevalence of insomnia than HIV participants without HIV-SN.
Winkler, Cheryl A.; Nelson, George; Oleksyk, Taras K.; Nava, M. Berenice; Kopp, Jeffrey B.
Until recently knowledge of genetic causes of glomerular disease was limited to certain rare or uncommon inherited diseases, and to a genes, either rare or with small effect, identified in candidate gene studies. These genetic factors accounted for only a very small fraction of kidney disease. However, the striking differences in frequency of many forms of kidney disease between African Americans and European Americans, which could not be completely explained by cultural or economic factors, pointed to a large unidentified genetic influence. Since FSGS and HIV-associated collapsing glomerulopathy (HVAN) have striking racial disparities, we performed an admixture mapping study to identify contributing genetic factors. Admixture mapping identified genetic variants in the non-muscle myosin gene MYH9 as having an extreme influence on both FSGS and HIVAN, with odds ratios from 4 to 8 and attributable fractions of 70–100%. Previously identified, rare inherited MYH9 disorders point to a mechanism by which MYH9 variation disrupts the actin-myosin filaments responsible for maintaining the structure of podocytes, the cells that provide one of three filtration barriers in the glomeruli. MYH9 variation has a smaller but still highly significant effect on non-diabetic kidney disease, and a weaker but significant effect on diabetic kidney disease; it is unclear whether underlying cryptic FSGS is responsible for the MYH9 association with these diseases. The strong predicted power of MYH9 variation for disease indicates a clear role for genetic testing for these variants in personalized medicine, for assessment of genetic risk, and potentially for diagnosis. PMID:20347641
Silva, Wilson P.; Vermund, Sten H.; Valverde, Emilio; Buene, Manuel; Moon, Troy D.
Abstract Mozambique's updated guideline for management of HIV-associated anemia prompts clinicians to consider opportunistic conditions, adverse drug reactions, and untreated immunosuppression in addition to iron deficiency, intestinal helminthes, and malaria. We prospectively evaluated this guideline in rural Zambézia Province. Likely cause(s) of anemia were determined through prespecified history, physical examination, and laboratory testing. Diagnoses were “etiologic” if laboratory confirmed (sputum microscopy, blood culture, Plasmodium falciparum malaria rapid test) or “syndromic” if not. To assess hemoglobin response, we used serial point-of-care measurements. We studied 324 ambulatory, anemic (hemoglobin <10 g/dl) HIV-infected adults. Study clinicians treated nearly all [315 (97.2%)] for suspected iron deficiency and/or helminthes; 56 (17.3%) had laboratory-confirmed malaria. Other assigned diagnoses included tuberculosis [30 (9.3%)], adverse drug reactions [26 (8.0%)], and bacteremia [13 (4.1%)]. Etiologic diagnosis was achieved in 79 (24.4%). Of 169 (52.2%) subjects who improved (hemoglobin increase of ≥1 g/dl without indications for hospitalization), only 65 (38.5%) received conventional management (iron supplementation, deworming, and/or antimalarials) alone. Thirty (9.3%) died and/or were hospitalized, and 125 (38.6%) were lost to follow-up. Multivariable linear and logistic regression models described better hemoglobin responses and/or outcomes in subjects with higher CD4+ T-lymphocyte counts, pre-enrollment antiretroviral therapy and/or co-trimoxazole prophylaxis, discontinuation of zidovudine for suspected adverse reaction, and smear-positive tuberculosis. Adverse outcomes were associated with fever, low body mass index, bacteremia, esophageal candidiasis, and low or missing CD4+ T cell counts. In this severely resource-limited setting, successful anemia management often required interventions other than conventional presumptive
Kim, WooJin; Zekas, Erin; Lodge, Robert; Susan-Resiga, Delia; Marcinkiewicz, Edwidge; Essalmani, Rachid; Mihara, Koichiro; Ramachandran, Rithwik; Asahchop, Eugene; Gelman, Benjamin; Cohen, Éric A.; Power, Christopher; Hollenberg, Morley D.
The proprotein convertases (PCs) furin, PC5, PACE4, and PC7 cleave secretory proteins after basic residues, including the HIV envelope glycoprotein (gp160) and Vpr. We evaluated the abundance of PC mRNAs in postmortem brains of individuals exhibiting HIV-associated neurocognitive disorder (HAND), likely driven by neuroinflammation and neurotoxic HIV proteins (e.g., envelope and Vpr). Concomitant with increased inflammation-related gene expression (interleukin-1β [IL-1β]), the mRNA levels of the above PCs are significantly increased, together with those of the proteinase-activated receptor 1 (PAR1), an inflammation-associated receptor that is cleaved by thrombin at ProArg41↓ (where the down arrow indicates the cleavage location), and potentially by PCs at Arg41XXXXArg46↓. The latter motif in PAR1, but not its R46A mutant, drives its interactions with PCs. Indeed, PAR1 upregulation leads to the inhibition of membrane-bound furin, PC5B, and PC7 and inhibits gp160 processing and HIV infectivity. Additionally, a proximity ligation assay revealed that furin and PC7 interact with PAR1. Reciprocally, increased furin expression reduces the plasma membrane abundance of PAR1 by trapping it in the trans-Golgi network. Furthermore, soluble PC5A/PACE4 can target/disarm cell surface PAR1 through cleavage at Arg46↓. PACE4/PC5A decreased calcium mobilization induced by thrombin stimulation. Our data reveal a new PC-PAR1-interaction pathway, which offsets the effects of HIV-induced neuroinflammation, viral infection, and potentially the development of HAND. PMID:26283733
Zhang, Yong; Kwon, Dongjin; Esmaeili-Firidouni, Pardis; Pfefferbaum, Adolf; Sullivan, Edith V; Javitz, Harold; Valcour, Victor; Pohl, Kilian M
HIV-Associated Neurocognitive Disorder (HAND) is the most common constellation of cognitive dysfunctions in chronic HIV infected patients age 60 or older in the U.S. Only few published methods assist in distinguishing HAND from other forms of age-associated cognitive decline, such as Mild Cognitive Impairment (MCI). In this report, a data-driven, nonparameteric model to identify morphometric patterns separating HAND from MCI due to non-HIV conditions in this older age group was proposed. This model enhanced the potential for group separation by combining a smaller, longitudinal data set containing HAND samples with a larger, public data set including MCI cases. Using cross-validation, a linear model on healthy controls to harmonize the volumetric scores extracted from MRIs for demographic and acquisition differences between the two independent, disease-specific data sets was trained. Next, patterns distinguishing HAND from MCI via a group sparsity constrained logistic classifier were identified. Unlike existing approaches, our classifier directly solved the underlying minimization problem by decoupling the minimization of the logistic regression function from enforcing the group sparsity constraint. The extracted patterns consisted of eight regions that distinguished HAND from MCI on a significant level while being indifferent to differences in demographics and acquisition between the two sets. Individually selecting regions through conventional morphometric group analysis resulted in a larger number of regions that were less accurate. In conclusion, simultaneously analyzing all brain regions and time points for disease specific patterns contributed to distinguishing with high accuracy HAND-related impairment from cognitive impairment found in the HIV uninfected, MCI cohort. Hum Brain Mapp 37:4523-4538, 2016. © 2016 Wiley Periodicals, Inc.
Yusuf, Abdulkareem Jika; Hassan, Abdulaziz; Mamman, Aisha Indo; Muktar, Haruna Mohammed; Sulieman, Aishatu Maude; Baiyewu, Olusegun
Background HIV-associated neurocognitive disorder (HAND) is a great source of morbidity in sub-Saharan African region. However, the magnitude of this problem remains largely uninvestigated despite having the largest number of population with HIV/AIDS. The aim of this study is to determine the prevalence of HAND among patients attending a tertiary health facility in Nigeria. Method We conducted a cross-sectional study among HIV-positive patients on antiretroviral therapy (ART) for at least 1 year. They were assessed using the International HIV Dementia Scale, Word Recall Test, Stick Design Test, Subjective Cognitive Complaint Questionnaire, Alcohol Use Disorder Identification Test, Drug Abuse Screening Test, Center for Epidemiological Study–Depression Scale, Instrumental Activity of Daily Living, and neurological examination. The CD4 count and viral load were determined for all the participants. A consensus diagnosis was made on each case based on the Frascati criteria. Data obtained were analyzed using “SPSS” for Windows version 15. Results A total of 418 HIV-positive patients participated in the study, of which 325 (77.8%) are females. The mean age (standard deviation) of the participants was 37.2 (9.3) years. The prevalence of HAND was 21.5% (95% confidence interval [CI] = 17.6%-25.4%), of which 9.6% were asymptomatic. The significant predictors of HAND in this study are duration of illness (odds ratio [OR] = 1.33 P < .001), detectable viral load (OR = 0.19, P < .001), CD4 count (OR = 0.99, P < .001), education (OR = 0.94, P = .011), stopping medication (OR = 3.55 P = .01), and severity of illness (OR = 1.24, P = .005). Conclusion One-fifth of the HIV-positive patients in this study had HAND. Various sociodemographic and clinical features were related to the prevalence of HAND. PMID:25331222
Sakamoto, Maiko; Marcotte, Thomas D.; Umlauf, Anya; Franklin, Donald; Heaton, Robert K.; Ellis, Ronald J.; Letendre, Scott; Alexander, Terry; McCutchan, J. Allen; Morgan, Erin E.; Woods, Steven Paul; Collier, Ann C.; Marra, Christina M.; Clifford, David B.; Gelman, Benjamin B.; McArthur, Justin C.; Morgello, Susan; Simpson, David; Grant, Igor
Background The HIV Dementia Scale (HDS) was developed to screen for HIV-associated Neurocognitive Disorders (HAND), but concerns have persisted regarding its substandard sensitivity. This study aimed to examine the classification accuracy of the HDS using raw and norm-based cutpoints, and to evaluate the contribution of the HDS subtests to predicting HAND. Methods 1,580 HIV-infected participants from 6 U.S. sites completed the HDS, and a gold standard neuropsychological battery, on which 51% of participants were impaired. Results: Sensitivity and specificity to HAND using the standard raw HDS cutpoint were 24% and 92%, respectively. The raw HDS subtests of attention, recall, and psychomotor speed significantly contributed to classification of HAND, while visuomotor construction contributed the least. A modified raw cutpoint of 14 yielded sensitivity of 66% and specificity of 61%, with cross-validation. Using norms also significantly improved sensitivity to 69% with a concomitant reduction of specificity to 56%, while the positive predictive value declined from 75% to 62% and negative predictive value improved from 54% to 64%. The HDS showed similarly modest rates of sensitivity and specificity among subpopulations of individuals with minimal comorbidity and successful viral suppression. Conclusions Findings indicate that while the HDS is a statistically significant predictor of HAND, particularly when adjusted for demographic factors, its relatively low diagnostic classification accuracy continues to hinder its clinical utility. A raw cutpoint of 14 greatly improved the sensitivity of the previously established raw cutscore, but may be subject to ceiling effects, particularly on repeat assessments. PMID:23111573
Davidson, Donna C; Hirschman, Michael P; Sun, Anita; Singh, Meera V; Kasischke, Karl; Maggirwar, Sanjay B
Despite the use of anti-retroviral therapies, a majority of HIV-infected individuals still develop HIV-Associated Neurocognitive Disorders (HAND), indicating that host inflammatory mediators, in addition to viral proteins, may be contributing to these disorders. Consistently, we have previously shown that levels of the inflammatory mediator soluble CD40L (sCD40L) are elevated in the circulation of HIV-infected, cognitively impaired individuals as compared to their infected, non-impaired counterparts. Recent studies from our group suggest a role for the CD40/CD40L dyad in blood brain barrier (BBB) permeability and interestingly, sCD40L is thought to regulate BBB permeability in other inflammatory disorders of the CNS. Using complementary multiphoton microscopy and quantitative analyses in wild-type and CD40L deficient mice, we now reveal that the HIV transactivator of transcription (Tat) can induce BBB permeability in a CD40L-dependent manner. This permeability of the BBB was found to be the result of aberrant platelet activation induced by Tat, since depletion of platelets prior to treatment reversed Tat-induced BBB permeability. Furthermore, Tat treatment led to an increase in granulocyte antigen 1 (Gr1) positive monocytes, indicating an expansion of the inflammatory subset of cells in these mice, which were found to adhere more readily to the brain microvasculature in Tat treated animals. Exploring the mechanisms by which the BBB becomes compromised during HIV infection has the potential to reveal novel therapeutic targets, thereby aiding in the development of adjunct therapies for the management of HAND, which are currently lacking.
Davidson, Donna C.; Hirschman, Michael P.; Sun, Anita; Singh, Meera V.; Kasischke, Karl; Maggirwar, Sanjay B.
Despite the use of anti-retroviral therapies, a majority of HIV-infected individuals still develop HIV-Associated Neurocognitive Disorders (HAND), indicating that host inflammatory mediators, in addition to viral proteins, may be contributing to these disorders. Consistently, we have previously shown that levels of the inflammatory mediator soluble CD40L (sCD40L) are elevated in the circulation of HIV-infected, cognitively impaired individuals as compared to their infected, non-impaired counterparts. Recent studies from our group suggest a role for the CD40/CD40L dyad in blood brain barrier (BBB) permeability and interestingly, sCD40L is thought to regulate BBB permeability in other inflammatory disorders of the CNS. Using complementary multiphoton microscopy and quantitative analyses in wild-type and CD40L deficient mice, we now reveal that the HIV transactivator of transcription (Tat) can induce BBB permeability in a CD40L-dependent manner. This permeability of the BBB was found to be the result of aberrant platelet activation induced by Tat, since depletion of platelets prior to treatment reversed Tat-induced BBB permeability. Furthermore, Tat treatment led to an increase in granulocyte antigen 1 (Gr1) positive monocytes, indicating an expansion of the inflammatory subset of cells in these mice, which were found to adhere more readily to the brain microvasculature in Tat treated animals. Exploring the mechanisms by which the BBB becomes compromised during HIV infection has the potential to reveal novel therapeutic targets, thereby aiding in the development of adjunct therapies for the management of HAND, which are currently lacking. PMID:23251626
Brentlinger, Paula E; Silva, Wilson P; Vermund, Sten H; Valverde, Emilio; Buene, Manuel; Moon, Troy D
Mozambique's updated guideline for management of HIV-associated anemia prompts clinicians to consider opportunistic conditions, adverse drug reactions, and untreated immunosuppression in addition to iron deficiency, intestinal helminthes, and malaria. We prospectively evaluated this guideline in rural Zambézia Province. Likely cause(s) of anemia were determined through prespecified history, physical examination, and laboratory testing. Diagnoses were "etiologic" if laboratory confirmed (sputum microscopy, blood culture, Plasmodium falciparum malaria rapid test) or "syndromic" if not. To assess hemoglobin response, we used serial point-of-care measurements. We studied 324 ambulatory, anemic (hemoglobin <10 g/dl) HIV-infected adults. Study clinicians treated nearly all [315 (97.2%)] for suspected iron deficiency and/or helminthes; 56 (17.3%) had laboratory-confirmed malaria. Other assigned diagnoses included tuberculosis [30 (9.3%)], adverse drug reactions [26 (8.0%)], and bacteremia [13 (4.1%)]. Etiologic diagnosis was achieved in 79 (24.4%). Of 169 (52.2%) subjects who improved (hemoglobin increase of ≥1 g/dl without indications for hospitalization), only 65 (38.5%) received conventional management (iron supplementation, deworming, and/or antimalarials) alone. Thirty (9.3%) died and/or were hospitalized, and 125 (38.6%) were lost to follow-up. Multivariable linear and logistic regression models described better hemoglobin responses and/or outcomes in subjects with higher CD4(+) T-lymphocyte counts, pre-enrollment antiretroviral therapy and/or co-trimoxazole prophylaxis, discontinuation of zidovudine for suspected adverse reaction, and smear-positive tuberculosis. Adverse outcomes were associated with fever, low body mass index, bacteremia, esophageal candidiasis, and low or missing CD4(+) T cell counts. In this severely resource-limited setting, successful anemia management often required interventions other than conventional presumptive treatment, thus
Phillips, Tudor J.C.; Brown, Matthew; Ramirez, Juan D.; Perkins, James; Woldeamanuel, Yohannes W.; Williams, Amanda C. de C.; Orengo, Christine; Bennett, David L.H.; Bodi, Istvan; Cox, Sarah; Maier, Christoph; Krumova, Elena K.; Rice, Andrew S.C.
HIV-associated sensory neuropathy (HIV-SN) is a frequent complication of HIV infection and a major source of morbidity. A cross-sectional deep profiling study examining HIV-SN was conducted in people living with HIV in a high resource setting using a battery of measures which included the following: parameters of pain and sensory symptoms (7 day pain diary, Neuropathic Pain Symptom Inventory [NPSI] and Brief Pain Inventory [BPI]), sensory innervation (structured neurological examination, quantitative sensory testing [QST] and intraepidermal nerve fibre density [IENFD]), psychological state (Pain Anxiety Symptoms Scale-20 [PASS-20], Depression Anxiety and Positive Outlook Scale [DAPOS], and Pain Catastrophizing Scale [PCS], insomnia (Insomnia Severity Index [ISI]), and quality of life (Short Form (36) Health Survey [SF-36]). The diagnostic utility of the Brief Peripheral Neuropathy Screen (BPNS), Utah Early Neuropathy Scale (UENS), and Toronto Clinical Scoring System (TCSS) were evaluated. Thirty-six healthy volunteers and 66 HIV infected participants were recruited. A novel triumvirate case definition for HIV-SN was used that required 2 out of 3 of the following: 2 or more abnormal QST findings, reduced IENFD, and signs of a peripheral neuropathy on a structured neurological examination. Of those with HIV, 42% fulfilled the case definition for HIV-SN (n = 28), of whom 75% (n = 21) reported pain. The most frequent QST abnormalities in HIV-SN were loss of function in mechanical and vibration detection. Structured clinical examination was superior to QST or IENFD in HIV-SN diagnosis. HIV-SN participants had higher plasma triglyceride, concentrations depression, anxiety and catastrophizing scores, and prevalence of insomnia than HIV participants without HIV-SN. PMID:24973717
Rovira, M; Romero, F; Torrent, O; Ibarra, B
Computed tomography is a very valuable method by which the pathogenic evolution of tuberculous meningitis may be followed, thereby facilitating its differential diagnosis and controlling the efficiency of therapy. The initial miliary tuberculosis in the brain, very often unaccompanied by neurological symptoms, may offer very evident CT images. CT may also demonstrate the fibrogelatinous exudate which fills the basal cisterns and surrounds the arterial vessels which cross this region. Because of this, secondary arteritis is frequent and may be indirectly detected by CT in the form of foci of ischemic infarcts. Tuberculomas may be multiple, and are found equally in the cerebral and the cerebellar parenchyma. These tuberculomas present different images on CT, depending on the evolution of the disease at that moment. Hydrocephalus is a common complication of TM and is caused by a lack of reabsorption of the cerebrospinal fluid, or by an obstructive lesion in the ventricular drainage pathways due to a tuberculoma. This complication is usually easily identified by CT, which, moreover, permits the control of its evolution.
Jullien, Sophie; Ryan, Hannah; Modi, Manish; Bhatia, Rohit
Background Tuberculous meningitis (TBM) is the main form of tuberculosis that affects the central nervous system and is associated with high rates of death and disability. Most international guidelines recommend longer antituberculous treatment (ATT) regimens for TBM than for pulmonary tuberculosis disease to prevent relapse. However, longer regimens are associated with poor adherence, which could contribute to increased relapse, development of drug resistance, and increased costs to patients and healthcare systems. Objectives To compare the effects of short-course (six months) regimens versus prolonged-course regimens for people with tuberculous meningitis (TBM). Search methods We searched the following databases up to 31 March 2016: the Cochrane Infectious Diseases Group Specialized Register; the Cochrane Central Register of Controlled Trials (CENTRAL), published in the Cochrane Library; MEDLINE; EMBASE; LILACS; INDMED; and the South Asian Database of Controlled Clinical Trials. We searched the World Health Organization International Clinical Trials Registry Platform (WHO ICTRP) and ClinicalTrials.gov for ongoing trials. We also checked article reference lists and contacted researchers in the field. Selection criteria We included randomized controlled trials (RCTs) and prospective cohort studies of adults and children with TBM treated with antituberculous regimens that included rifampicin for six months or longer than six months. The primary outcome was relapse, and included studies required a minimum of six months follow-up after completion of treatment. Data collection and analysis Two review authors (SJ and HR) independently assessed the literature search results for eligibility, and performed data extraction and 'Risk of bias' assessments of the included studies. We contacted study authors for additional information when necessary. Most data came from single arm cohort studies without a direct comparison so we pooled the findings for each group of cohorts and
Wiesner, Darin L; Specht, Charles A; Lee, Chrono K; Smith, Kyle D; Mukaremera, Liliane; Lee, S Thera; Lee, Chun G; Elias, Jack A; Nielsen, Judith N; Boulware, David R; Bohjanen, Paul R; Jenkins, Marc K; Levitz, Stuart M; Nielsen, Kirsten
Pulmonary mycoses are often associated with type-2 helper T (Th2) cell responses. However, mechanisms of Th2 cell accumulation are multifactorial and incompletely known. To investigate Th2 cell responses to pulmonary fungal infection, we developed a peptide-MHCII tetramer to track antigen-specific CD4+ T cells produced in response to infection with the fungal pathogen Cryptococcus neoformans. We noted massive accruement of pathologic cryptococcal antigen-specific Th2 cells in the lungs following infection that was coordinated by lung-resident CD11b+ IRF4-dependent conventional dendritic cells. Other researchers have demonstrated that this dendritic cell subset is also capable of priming protective Th17 cell responses to another pulmonary fungal infection, Aspergillus fumigatus. Thus, higher order detection of specific features of fungal infection by these dendritic cells must direct Th2 cell lineage commitment. Since chitin-containing parasites commonly elicit Th2 responses, we hypothesized that recognition of fungal chitin is an important determinant of Th2 cell-mediated mycosis. Using C. neoformans mutants or purified chitin, we found that chitin abundance impacted Th2 cell accumulation and disease. Importantly, we determined Th2 cell induction depended on cleavage of chitin via the mammalian chitinase, chitotriosidase, an enzyme that was also prevalent in humans experiencing overt cryptococcosis. The data presented herein offers a new perspective on fungal disease susceptibility, whereby chitin recognition via chitotriosidase leads to the initiation of harmful Th2 cell differentiation by CD11b+ conventional dendritic cells in response to pulmonary fungal infection.
Nunes, Joslaine de Oliveira; Pillon, Kelly Regina Alves Pereira; Bizerra, Patrícia Lira; Paniago, Anamaria Mello Miranda; Mendes, Rinaldo Poncio; Chang, Marilene Rodrigues
Simultaneous infections with Cryptococcus neoformans and Histoplasma capsulatum are rare and typically occur in immunocompromised individuals, particularly AIDS patients. Because both of those fungi can spur the development of latent infections, it is generally unknown which organism was first present. The diagnosis of one fungus can hide the diagnosis of the other, leading to underdiagnoses and poor prognosis. We report a case of C. neoformans and H. capsulatum co-infection. We also performed a systematic review of the literature. Our patient, a 69-year-old HIV-negative man, presented with a 9-month history of a productive cough, dyspnea and wheezing. His history showed chronic obstructive pulmonary disease and type II diabetes mellitus (DM). Pulmonary lesions of unidentified etiology were noted. Cryptococcal involvement of the central nervous system was confirmed, and C. neoformans and H. capsulatum were also isolated from blood cultures. In the literature, we found ten cases of simultaneous histoplasmosis and cryptococcosis. Including our patient, all of the cases were located in North America and Latin America, except for two, one Indian and one African diagnosed in France. AIDS was the main predisposing factor, followed by DM and age >60 years. Several diagnostic methods were employed. A blood culture and bronchoalveolar lavage (BAL) culture resulted in the growth of C. neoformans in most of the cases. H. capsulatum was more often detected in BAL and bone marrow cultures. Although co-infection by these pathogens is severe, it can be cured if it is diagnosed and treated early. We emphasized the importance of clinical suspicion and differential diagnosis of systemic mycoses.
Kashyap, Rajpal S; Kainthla, Rani P; Satpute, Ravindra M; Agarwal, Neha P; Chandak, Nitin H; Purohit, Hemant J; Taori, Girdhar M; Daginawala, Hatim F
Background Tuberculous meningitis (TBM) is a major global health problem, and it is sometimes difficult to perform a differential diagnosis of this disease from other diseases, particularly partially-treated pyogenic meningitis (PTPM). In an earlier study, we demonstrated the presence of a 30-kD protein antigen in cerebrospinal fluid (CSF) of TBM patients. We have also shown that lymphocytes from CSF of TBM patients respond differently to this antigen than do those from PTPM patients. The purpose of this study was to develop an assay that can discriminate between TBM and PTPM. Methods We developed a cell enzyme-linked immunosorbant assay (Cell ELISA) to quantitatively measure production of antibodies against the 30-kD protein in B cells from CSF of TBM and PTPM patients. Results The cell ELISA yielded 92% (11/12) sensitivity and 92% (11/12) specificity for the differential diagnosis of TBM from PTPM. Conclusion When induced with the 30-kD protein antigen, B cells derived from CSF of TBM patients respond to IgG production within 24 h while those derived from PTPM patients do not respond. PMID:15498107
Russi, Abigail E.; Brown, Melissa A.
The CNS is largely comprised of non-regenerating cells, including neurons and myelin-producing oligodendrocytes, which are particularly vulnerable to immune cell mediated damage. To protect the CNS, mechanisms exist that normally restrict the transit of peripheral immune cells into the brain and spinal cord, conferring an “immune specialized” status. Thus, there has been a long-standing debate as to how these restrictions are overcome in several inflammatory diseases of the CNS, including multiple sclerosis (MS). In this review, we highlight the role of the meninges, tissues that surround and protect the CNS and enclose the cerebral spinal fluid, in promoting chronic inflammation that leads to neuronal damage. Although the meninges have traditionally been considered structures that provide physical protection for the brain and spinal cord, new data has established these tissues as sites of active immunity. It has been hypothesized that the meninges are important players in normal immunosurveillance of the CNS but also serve as initial sites of anti-myelin immune responses. The resulting robust meningeal inflammation elicits loss of localized blood barrier integrity and facilitates a large-scale influx of immune cells into the CNS parenchyma. We propose that targeting of the cells and molecules mediating these inflammatory responses within the meninges offers promising therapies for MS that are free from the constraints imposed by the blood brain barrier. Importantly, such therapies may avoid the systemic immunosuppression often associated with the existing treatments. PMID:25241937
Chen, Yao-Shen; Yen, Chuan-Min
The major cause of eosinophilic meningitis in Taiwan is Angiostrongylus cantonensis. Humans are infected by ingesting terrestrial and freshwater snails and slugs. In 1998 and 1999, two outbreaks of eosinophilic meningitis caused by A. cantonensis infection were reported among 17 adult male immigrant Thai laborers who had eaten raw golden apple snails (Pomacea canaliculata). Another outbreak associated with consuming a health drink consisting of raw vegetable juice was reported in 2001. These adult cases differed from reports in the 1970s and 1980s, in which most of the cases were in children. With improvements in public health and education of foreign laborers, there have since been only sporadic cases in Taiwan. Review of clinical research indicates inconsistent association of Magnetic Resonance Imaging (MRI) results with clinical features of eosinophilic meningitis. MRI features were nonspecific but there was an association between the presence of high brain MRI signal intensities and severity of peripheral and cerebrospinal fluid (CSF) eosinophilia. Inflammatory markers have been identified in the CSF of patients with eosinophlic meningitis caused by A. cantonensis infection, and vascular endothelial growth factor (VEGF), hepatocyte growth factor (HGF), and the matrix metalloproteinase system may be associated with blood-brain barrier disruption. Eosinophilic meningitis caused by A. cantonensis infection is not a reportable disease in Taiwan. It is important that a public advisory and education program be developed to reduce future accidental infection. PMID:23901378
Tsai, Hung-Chin; Chen, Yao-Shen; Yen, Chuan-Min
The major cause of eosinophilic meningitis in Taiwan is Angiostrongylus cantonensis. Humans are infected by ingesting terrestrial and freshwater snails and slugs. In 1998 and 1999, two outbreaks of eosinophilic meningitis caused by A. cantonensis infection were reported among 17 adult male immigrant Thai laborers who had eaten raw golden apple snails (Pomacea canaliculata). Another outbreak associated with consuming a health drink consisting of raw vegetable juice was reported in 2001. These adult cases differed from reports in the 1970s and 1980s, in which most of the cases were in children. With improvements in public health and education of foreign laborers, there have since been only sporadic cases in Taiwan. Review of clinical research indicates inconsistent association of Magnetic Resonance Imaging (MRI) results with clinical features of eosinophilic meningitis. MRI features were nonspecific but there was an association between the presence of high brain MRI signal intensities and severity of peripheral and cerebrospinal fluid (CSF) eosinophilia. Inflammatory markers have been identified in the CSF of patients with eosinophilic meningitis caused by A. cantonensis infection, and vascular endothelial growth factor (VEGF), hepatocyte growth factor (HGF), and the matrix metalloproteinase system may be associated with blood-brain barrier disruption. Eosinophilic meningitis caused by A. cantonensis infection is not a reportable disease in Taiwan. It is important that a public advisory and education program be developed to reduce future accidental infection.
Rozsypal, Hanus; Smiskova, Dita; Benes, Jiri
Background. Listeria monocytogenes (LM) is currently the third most frequent pathogen of bacterial meningitis in adults. Methods. A prospective study of patients with LM meningitis in a Czech tertiary care hospital, carried out from 1997 to 2012. Results. Thirty-one patients were diagnosed with LM meningitis, which was 7% of a total of 440 adult patients with acute bacterial meningitis (ABM) over a 16-year period. Their median age was 63 years, range 26–80 years. Nineteen patients (61%) had underlying immunocompromising comorbidity; 15 patients (48%) were older than 65 years. Fourteen patients (45%) had arterial hypertension. The typical triad of fever, neck stiffness, and altered mental status was present in 21 patients (68%). The median count of cerebrospinal fluid (CSF) leukocytes was 680/μL, protein level 2.6 g/L, and glucose ratio 0.28. Four patients (13%) died, and nine (29%) survived with moderate to severe sequelae. Conclusion. LM meningitis is known to affect immunosuppressed and elderly patients. Arterial hypertension seems to be another important predisposing factor. Clinical symptoms, CSF findings, and disease outcomes, did not significantly differ from other community-acquired ABM in our study, although the CSF leukocyte count was lower. Ampicillin showed good clinical and bacteriological efficacy in the majority of patients. PMID:24106719
Fujikawa, Keita; Suenaga, Akihito; Motomura, Masakatsu; Fukuda, Taku; Ooe, Nobuharu; Eguchi, Katsumi
A 57-year-old woman had undergone surgery for meningioma. After the surgery, she suffered from repeated fever and headache. One year after surgery, she was admitted to our hospital for further examination. Cerebro-spinal fluid (CSF) findings indicated bacterial meningitis infection. Germ culture, acid-fast bacterium culture, PCR for mycobacteriosis and cryptococcus antigens as well as cytological examination of CSF were checked repeatedly. However, all examinations were negative and etiology was unknown. We treated with many anti-bacterial, anti-fungal and anti-tubercular drugs, but CSF findings were not improved. We repeated CSF examination and finally Mycobacterium fortuitum (M. fortuitum) was isolated. Clarithromycin (CAM) was started for M. fortuitum meningitis. After drug sensitivity testing, levofloxacin (LVFX), which was effective against M. fortuitum, was added to CAM, after which clinical and CSF findings improved dramatically. M. fortuitum rarely causes CNS infection. Several English literatures on M. fortuitum meningitis after traumatic injury and surgery have been published. Its CSF findings distinctly resemble those of bacterial meningitis, but are resistant to the usual antituberculosis drugs. We reported a case of M. fortuitum meningitis associated with surgery for meningioma.
Doenmez, Halil Mavili, Ertugrul Ikizceli, Tuerkan; Durak, Ahmet Candan; Kurtsoy, Ali
Aseptic meningitis related to hydrogel-coated coils is a known complication, but it is extremely rare after platinum bare coil aseptic meningitis. Here we report the development of aseptic meningitis causing brain stem and cerebellar infarct in a patient with a giant aneurysm treated with bare platinum coils. We conclude that aneurysm size is an important factor affecting the occurrence of aseptic meningitis associated with stroke.
Chen, Juan; Liu, Shaoyan; Xiong, Zhongtang; Yang, Yuexin; Tan, Xuexian; Luo, Qiuping; Peng, Juan; Chen, Hui; Jiang, Qingping
A rare case is presented of a 62-year-old man with primary isolated cryptococcal femoral osteomyelitis. Magnetic resonance imaging (MRI) revealed osteolytic destruction of his left femur. Biopsy was performed firstly. Under microscope, the lesion was compose of numerous large mononuclear cells, scattered multinucleated giant cells, a few lymphocytes and neutrophils, necrosis with serious artificial deformation. By immunohistochemistry (IHC), only CD31 and CD68 were positive, while CK, CK8/18, EMA, P63, CK7, CK20, PSAP, PSA, CD34 negative. It was considered a low grade vascularsarcoma, but not confirmed. Then the operation was done. Surgical specimen showed a lot of red-sphere materials in most cells cytoplasm. The Gomorra methenamine silver staining and PAS revealed the mucopolysaccharide-containing capsule of the Cryptococcus. Laboratory culture of lesion liquid grew a kind of yeast at 37°C. Cryptococcal femoral osteomyelitis was diagnosed at last. The patient is good now after the thorough debridement and anti-fungal treatment.
Wang, Guizhen; Fang, Wei; Ye, Chen; Hu, Hanhua; Fa, Zhenzong; Yi, Jiu; Liao, Wan-qing
Silver nanoparticles have received considerable interest as new “nanoantibiotics” with the potential to kill drug-resistant microorganisms. Recently, a class of new core-shell nanostructures, Pd@Ag nanosheets (Pd@Ag NSs), were created using deposition techniques and demonstrated excellent inhibitory effects on various bacteria in vitro. In this study, we evaluated the antifungal activity of Pd@Ag NSs against common invasive fungal pathogens. Among these organisms, Cryptococcus neoformans complex species was most susceptible to Pd@Ag NSs, which exhibited potent antifungal activity against various molecular types or sources of cryptococcal strains including fluconazole-resistant isolates. The anticryptococcal activity of Pd@Ag NSs was significantly greater than fluconazole and similar to that of amphotericin B (AmB). At relatively high concentrations, Pd@Ag NSs exhibited fungicidal activity against Cryptococcus spp., which can likely be attributed to the disruption of cell integrity, intracellular protein synthesis, and energy metabolism. Intriguingly, Pd@Ag NSs also exhibited strong synergistic anti-cryptococcal fungicidal effects at low concentrations in combination with AmB but exhibited much better safety in erythrocytes than AmB, even at the minimal fungicidal concentration. Therefore, Pd@Ag NSs may be a promising adjunctive agent for treating cryptococcosis, and further investigation for clinical applications is required. PMID:27271376
Boukadida, Jalel; Hannachi, Neila
We bring back an adult case of purulent meningitis to Haemophilus influenzae. We insist on the particular aspects of the host of this meningitis type at the adult. These aspects must be searched every time that Haemophilus influenzae is isolated in cerebrospinal fluid in adult's meningitis.
Robinson, E N
Ventricular obstruction and hydrocephalus are recognized complications of neurosurgical procedures and meningitis that has been previously treated. The confinement of bacterial meningitis solely to a lateral ventricle in an otherwise healthy individual, however, is rare. I describe a case in which a ventricular abscess occurred as the presenting manifestation of staphylococcal meningitis in a man who had no history of head trauma or neurosurgery.
Nussinovitch, Moshe; Finkelstein, Yaron; Elishkevitz, Keren Politi; Volovitz, Benjamin; Harel, Daniella; Klinger, Gil; Razon, Yaron; Nussinovitch, Udi; Nussinovitch, Naomi
Differentiation of bacterial from aseptic meningitis may be difficult. Our aim was to determine the pattern of distribution of lactate dehydrogenase (LDH) isoenzymes in the cerebrospinal fluid (CSF) of patients with bacterial and aseptic meningitis. One hundred and fifty-seven patients with suspected meningitis were enrolled in the study. They were divided into 3 groups according to the culture- or bacterial antigen assay-proven diagnosis and CSF findings: bacterial meningitis (n = 31), aseptic meningitis (n = 65), and non-meningitis (n = 61). Total LDH level and percentages of LDH isoenzymes in the CSF were measured in each patient. Each group showed a distinct LDH isoenzyme distribution pattern, with a statistically significant difference among the groups in the percentages of the various isoenzymes. Compared with the non-meningitis group, total LDH activity in the CSF was high in the aseptic meningitis group (49.82+/-35.59 U/L, P < 0.001) and exaggerated in the bacterial meningitis group (944.53+/-112.3 U/L, P < 0.001). Low LDH-2 levels were unique to bacterial meningitis (P < 0.01), whereas high LDH-3 levels were characteristic of aseptic meningitis (P < 0.05). Both groups had low levels of LDH-1 and high levels of LDH-4 and LDH-5. In conclusion, the LDH isoenzyme pattern may be of clinical diagnostic value in meningitis, particularly when culture results are pending.
Garcia, I; Fainstein, V; McLaughlin, P
After placement of an Ommaya reservoir, meningitis and bacteremia due to Bacillus cereus occurred in a patient with stage IV lymphoblastic lymphoma and meningeal involvement. Bacillus species have been implicated as meningeal pathogens after lumbar punctures. These organisms have become an important cause of severe infection, especially in immunologically compromised patients.
McNeil, Hannah C; Jefferies, Johanna M C; Clarke, Stuart C
Worldwide bacterial meningitis accounts for more than one million cases and 135,000 deaths annually. Profound, lasting neurological complications occur in 9-25% of cases. This review confirms the greatest risk from bacterial meningitis is in early life in Malaysia. Much of the disease burden can be avoided by immunization, particularly against Haemophilus influenzae type b (Hib) and Streptococcus pneumoniae. Despite inclusion of the Hib vaccine in the National Immunisation Programme and the licensure of pneumococcal vaccines, these two species are the main contributors to bacterial meningitis in Malaysia, with Neisseria meningitidis and Mycobacterium tuberculosis, causing a smaller proportion of disease. The high Hib prevalence may partly be due to dated, small-scale studies limiting the understanding of the current epidemiological situation. This highlights the need for larger, better quality surveillance from Malaysia to evaluate the success of Hib immunization and to help guide immunization policy for vaccines against S. pneumoniae and N. meningitidis.
Pinto Jr, Vitor Laerte; Curi, André Land; Pinto, Adriana da Silva; Nunes, Estevão Portela; Teixeira, Maria de Lourdes Benamor; Rozental, Tatiana; Favacho, Alexsandra Rodrigues; Castro, Elba Lemos de; Bóia, Márcio Neves
Cat scratch disease (CSD) is a self limited condition characterized by fever, lymph node enlargement and less often eye involvement. Central nervous system involvement by Bartonella henselae infection is possibly an important cause of morbidity; its role as an agent of aseptic meningitis is unknown. We report a case of a 40 years-old man with CSD accompanied by aseptic meningitis and neuroretinitis. Serum indirect immmunofluorescence (IFI) assays for B. henselae were positive and the cerebrospinal fluid (CSF) analysis showed mononuclear pleocytosis and increased level of protein. Serological tests for other etiologies were negative. The patient responded well to antibiotic therapy with oral doxycicline plus rifampin and in the 12th day of hospitalization evolved to total regression of the headache and partial regression of the visual loss. Clinicians should consider CSD as a differential diagnosis when assessing previously healthy patients with aseptic meningitis associated with regional lymphadenopathy and epidemiological history of feline contact.
Prais, Dario; Nussinovitch, Moshe; Harel, Liora; Amir, Jacob
Citrobacter infection is commonly reported in neonates and immunocompromised patients. Citrobacter koseri (diversus) is an important cause of neonatal meningitis and brain abscess formation. It adults, however, Citrobacter infection with central nervous system involvement is rare, and is usually associated with an underlying disorder. This report describes a 12-y-old previously healthy girl with Citrobacter koseri meningitis. Intravenous treatment with ceftriaxone for 10 d led to complete recovery. Head computed tomography and brainstem-evoked response audiometry were normal. On follow-up, the patient was completely healthy. Previously reported cases of C. koseri meningitis in the adult population were associated with underlying predisposing factors. In this case a normal, healthy adolescent was treated with intravenous ceftriaxone without any of the known neurological complications observed in the neonatal cases.
Okada, Hiroshi; Yoshioka, Keiji
A 73-year-old woman was admitted to our hospital because of persistent fever, headache and fatigue for several weeks. On admission, she was diagnosed as having meningitis due to Mycobacterium intracellulare (M. intracellulare) detected in her cerebrospinal fluid (CSF) by polymerase chain reaction. Even though anti-tuberculous therapy improved her CSF findings, her condition was not restored. Brain MRI showed multifocal and asymmetrical increases in T2 signals involving white matter and cortical gray-white junction of cerebral hemispheres, cerebellum and brainstem. Based on the progression of clinical symptoms and radiological features, we diagnosed her illness as acute disseminated encephalomyelitis (ADEM) associated with meningitis due to M. intracellulare. Steroid therapy dramatically improved her condition. This is the first report of ADEM following meningitis due to M. intracellulare in a non-immunocompromized host.
Boogerd, W; Moffie, D; Smets, L A
A 35-year-old woman was treated with intraventricular methotrexate (MTX) with a total dose of 70 mg followed by cytosine arabinoside (Ara-C) with a total dose of 80 mg for meningeal metastasis of breast carcinoma. Radiation therapy was not given. Despite a response of the meningeal tumor the patient developed in the third week of MTX treatment a progressive visual loss and loss of consciousness which worsened during subsequent Ara-C treatment and led to death within 3 weeks. Postmortem examination revealed only minimal neoplastic infiltration of the meninges. Multiple foci of axonal degeneration and demyelination were found in the optic nerves and chiasm, the superficial layers of the brainstem, and spinal cord and to some extent in other cranial nerves and spinal nerve roots. The possible causes of this previously unreported early complication are discussed.
de Boer, M G J; Lambregts, P C L A; van Dam, A P; van 't Wout, J W
In this article we review the available data concerning meningitis caused by Capnocytophaga canimorsus. The clinical presentation of this rare condition is described with the emphasis on associated conditions and management issues. Two additional cases, illustrating the difficulties in recognizing this rare disease, are presented. Reviewing a total of 28 reported cases, a preceding bite-incident by a cat or dog, or close contact with these animals, was described in the majority of cases (89%). Patients had a median age of 58 years; splenectomy and alcohol abuse were noted in, respectively, 18% and 25% of patients. Only in one case immune suppressive drug use was reported. The diagnosis C. canimorsus meningitis should be considered in healthy and immunocompromised adults, especially after splenectomy, who present with symptoms attributable to meningitis and a history of recent exposure to dogs or cats. The possibility of this condition has implications for both the diagnostic work-up and the treatment of the patient.
Huang, Mingwei; Botts, Michael R.; Hull, Christina M.; Huttenlocher, Anna
Cryptococcal meningoencephalitis is a fungal infection that predominantly affects immunocompromised patients and is uniformly fatal if left untreated. Timely diagnosis is difficult, and screening or prophylactic measures have generally not been successful. Thus, we need a better understanding of early, asymptomatic pathogenesis. Inhaled cryptococci must survive the host immune response, escape the lung, and persist within the bloodstream in order to reach and invade the brain. Here we took advantage of the zebrafish larval infection model to assess the process of cryptococcal infection and disease development sequentially in a single host. Using yeast or spores as infecting particles, we discovered that both cell types survived and replicated intracellularly and that both ultimately established a sustained, low-level fungemia. We propose that the establishment and maintenance of this sustained fungemia is an important stage of disease progression that has been difficult to study in other model systems. Our data suggest that sustained fungemia resulted from a pattern of repeated escape from, and reuptake by, macrophages, but endothelial cells were also seen to play a role as a niche for cryptococcal survival. Circulating yeast collected preferentially in the brain vasculature and eventually invaded the central nervous system (CNS). As suggested previously in a mouse model, we show here that neutrophils can play a valuable role in limiting the sustained fungemia, which can lead to meningoencephalitis. This early stage of pathogenesis—a balanced interaction between cryptococcal cells, macrophages, endothelial cells, and neutrophils—could represent a window for timely detection and intervention strategies for cryptococcal meningoencephalitis. PMID:27481252
Tiffay, Kathleen; Jodar, Luis; Kieny, Marie-Paule; Socquet, Muriel; LaForce, F. Marc
Background. In 2001, the Meningitis Vaccine Project (MVP) was tasked to develop, test, license, and introduce a group A meningococcal (MenA) conjugate vaccine for sub-Saharan Africa. African public health officials emphasized that a vaccine price of less than US$0.50 per dose was necessary to ensure introduction and sustained use of this new vaccine. Methods. Initially, MVP envisioned partnering with a multinational vaccine manufacturer, but the target price and opportunity costs were problematic and formal negotiations ended in 2002. MVP chose to become a “virtual vaccine company,” and over the next decade managed a network of public–private and public–public partnerships for pharmaceutical development, clinical development, and regulatory submission. MVP supported the transfer of key know-how for the production of group A polysaccharide and a new conjugation method to the Serum Institute of India, Ltd, based in Pune, India. A robust staff structure supported by technical consultants and overseen by advisory groups in Europe and Africa ensured that the MenA conjugate vaccine would meet all international standards. Results. A robust project structure including a team of technical consultants and 3 advisory groups in Europe and Africa ensured that the MenA conjugate vaccine (PsA-TT, MenAfriVac) was licensed by the Drug Controller General of India and prequalified by the World Health Organization in June 2010. The vaccine was introduced in Burkina Faso, Mali, and Niger in December 2010. Conclusions. The development, through a public–private partnership, of a safe, effective, and affordable vaccine for sub-Saharan Africa, PsA-TT, offers a new paradigm for the development of vaccines specifically targeting populations in resource-poor countries. PMID:26553666
Scalco, Renata Siciliani; Chatfield, Sherryl; Junejo, Muhammad Hyder; Booth, Suzanne; Pattni, Jatin; Godfrey, Richard; Quinlivan, Ros
Patient: Female, 44 Final Diagnosis: McArdle disease Symptoms: Exercise intolerance • muscle contracture • myalgia • myoglobinuria • recurrent rhabdomyolysis Medication: — Clinical Procedure: — Specialty: Neurology Objective: Rare disease Background: McArdle disease is a glycogen storage disorder mainly characterized by exercise intolerance. Prolonged muscle contracture is also a feature of this condition and may lead to rhabdomyolysis (RM), which is a serious event characterized by acute skeletal muscle damage. Case Report: A 44-year-old female patient presented with an acute contracture of the posterior neck muscles, causing severe nuchal rigidity. The contracture was induced during a dental extraction as she held her mouth open for a prolonged period, with her neck in a rigid position. She presented with severe pain in her ear and head, as well as fever, vomiting, and confusion. Based on her symptoms, she was initially misdiagnosed with bacterial meningitis and experienced an acute allergic reaction to the systemic penicillin she was subsequently administered. Lumbar puncture results were normal. High serum creatine kinase (CK) levels, recurrent exercise-related muscle symptoms, and a previous history of recurrent myoglobinuria raised the suspicion of an underlying neuromuscular condition. McArdle disease was confirmed by muscle biopsy and a genetic test, which revealed that the patient was homozygous for the R50X mutation in the PYGM gene. Conclusions: This case illustrates that even seemingly innocuous movements, if rapid isotonic or prolonged isometric in nature, can elicit a muscle contracture in McArdle disease patients. Here, we highlight the need for careful management in this patient population even during routine healthcare procedures. The allergic reaction to antibiotics emphasises that misdiagnoses may result in iatrogenic harm. PMID:27899787
Karsen, Hasan; Karahocagil, Mustafa Kasim; Irmak, Hasan; Demiröz, Ali Pekcan
Turkey is located at an endemic area for brusellosis and tuberculosis which are both important public health problems. Meningitis caused by Brucella and Mycobacterium spp. may be confused since the clinical and laboratory findings are similar. In this report, a meningitis case with Brucella and tuberculosis co-infection has been presented. A 19-years-old woman was admitted to our clinic with severe headache, fever, vomiting, meningeal irritation symptoms, confusion and diplopia. The patient was initially diagnosed as Brucella meningitis based on her history (stockbreeding, consuming raw milk products, clinical symptoms concordant to brucellosis lasting for 4-5 months), physical examination and laboratory findings of cerebrospinal fluid (CSF). Standard tube agglutination test for brucellosis was positive at 1/80 titer in CSF and at 1/640 titer in serum, whereas no growth of Brucella spp. was detected in CSF and blood cultures. Antibiotic therapy with ceftriaxone, rifampicin and doxycyclin was started, however, there was no clinical improvement and agitation and confusion of the patient continued by the end of second day of treatment. Repeated CSF examination yielded acid-fast bacteria. The patient was then diagnosed as meningitis with double etiology and the therapy was changed to ceftriaxone, streptomycin, morphozinamide, rifampicin and isoniazid for thirty days. Tuberculosis meningitis was confirmed with the growth of Mycobacterium tuberculosis on the 14th day of cultivation (BACTEC, Becton Dickinson, USA) of the CSF sample. On the 30th day of treatment she was discharged on anti-tuberculous treatment with isoniazid and rifampicin for 12 months. The follow-up of the patient on the first and third months of treatment revealed clinical and laboratory improvement. Since this was a rare case of Brucella and tuberculosis co-infection, this report emphasizes that such co-infections should be kept in mind especially in the endemic areas for tuberculosis and brucellosis.
Kloek, Anne T.; van Setten, Jessica; van der Ende, Arie; Bots, Michiel L.; Asselbergs, Folkert W.; Serón, Mercedes Valls; Brouwer, Matthijs C.; van de Beek, Diederik; Ferwerda, Bart
Host genetic variability may contribute to susceptibility of bacterial meningitis, but which genes contribute to the susceptibility to this complex disease remains undefined. We performed a genetic association study in 469 community-acquired pneumococcal meningitis cases and 2072 population-based controls from the Utrecht Health Project in order to find genetic variants associated with pneumococcal meningitis susceptibility. A HumanExome BeadChip was used to genotype 102,097 SNPs in the collected DNA samples. Associations were tested with the Fisher exact test. None of the genetic variants tested reached Bonferroni corrected significance (p-value <5 × 10−7). Our strongest signals associated with susceptibility to pneumococcal meningitis were rs139064549 on chromosome 1 in the COL11A1 gene (p = 1.51 × 10−6; G allele OR 3.21 [95% CI 2.05–5.02]) and rs9309464 in the EXOC6B gene on chromosome 2 (p = 6.01 × 10−5; G allele OR 0.66 [95% CI 0.54–0.81]). The sequence kernel association test (SKAT) tests for associations between multiple variants in a gene region and pneumococcal meningitis susceptibility yielded one significant associated gene namely COL11A1 (p = 1.03 × 10−7). Replication studies are needed to validate these results. If replicated, the functionality of these genetic variations should be further studied to identify by which means they influence the pathophysiology of pneumococcal meningitis. PMID:27389768
Kurapati, Kesava Rao V.; Atluri, Venkata S.; Samikkannu, Thangavel; Garcia, Gabriella; Nair, Madhavan P. N.
As the threat of Human Immunodeficiency Virus (HIV)/Acquired Immunodeficiency Syndrome (AIDS) persists to rise, effective drug treatments are required to treat the infected people. Even though combination antiretroviral therapy (cART) provides stable viral suppression, it is not devoid of undesirable side effects, especially in persons undergoing long-term treatment. The present therapy finds its limitations in the emergence of multidrug resistance and accordingly finding new drugs and novel targets is the need of the hour to treat the infected persons and further to attack HIV reservoirs in the body like brain, lymph nodes to achieve the ultimate goal of complete eradication of HIV and AIDS. Natural products such as plant-originated compounds and plant extracts have enormous potential to become drug leads with anti-HIV and neuroprotective activity. Accordingly, many research groups are exploring the biodiversity of the plant kingdom to find new and better anti-HIV drugs with novel mechanisms of action and for HIV-associated neurocognitive disorders (HAND). The basic challenge that still persists is to develop viral replication-targeted therapy using novel anti-HIV compounds with new mode of action, accepted toxicity and less resistance profile. Against this backdrop, the World Health Organization (WHO) suggested the need to evaluate ethno-medicines for the management of HIV/AIDS. Consequently, there is need to evaluate traditional medicine, particularly medicinal plants and other natural products that may yield effective and affordable therapeutic agents. Although there are a good number of reports on traditional uses of plants to treat various diseases, knowledge of herbal remedies used to manage HIV/AIDS and HAND are scanty, vague and not well documented. In this review, plant substances showing a promising action that is anti-HIV and HAND will be explored along with what they interact. Since some plant substances are also known to modulate several cellular
Schrier, Rachel D.; Hong, Suzi; Crescini, Melanie; Ellis, Ronald; Pérez-Santiago, Josué; Spina, Celsa; Letendre, Scott
Background HIV associated neurocognitive disorders (HAND) continue to affect cognition and everyday functioning despite anti-retroviral treatment (ART). Previous studies focused on mechanisms related to monocyte/macrophage mediated inflammation. However, in the ART era, there is increasing evidence for the involvement of CD8+ T-cells in CNS pathogenesis. Methods To investigate the relationship between T-cell responses and neurocognitive impairment (NCI), cerebrospinal fluid (CSF) and peripheral blood CD4+ and CD8+ T-cell intracellular cytokine (IFNγ, IL-2, TNFα) and lytic marker (CD107a) expression were assessed in HIV infected subjects who underwent comprehensive neurocognitive (NC) evaluation and either initiated or changed ART. Results Data were collected from 31 participants at 70 visits. The frequency of cytokine expressing T-cells in CSF was significantly higher than in peripheral blood for CD4+T-cells: TNFα, IL-2, IFNγ and CD8+T-cells: IL-2 and IFNγ. Analysis of T-cell activity and NCI as a function of CSF HIV RNA levels suggested a general association between NCI, high CSF CD8+ (but not CD4+T-cell) cytokine expression and CSF HIV RNA <103 copies/ml (p<0.0001). Specifically, CSF CD8+ T-cell IFNγ expression correlated with severity of NCI (r = 0.57, p = 0.004). Multivariable analyses indicated that CSF CD8+T-cell IFNγ and myeloid activation (CD163) contributed equally and independently to cognitive status and a composite variable produced the strongest correlation with NCI (r = 0.83, p = 0.0001). In contrast, CD8+ cytolytic activity (CD107a expression) was negatively correlated with NCI (p = 0.05) but was dependent on CD4 levels >400/μl and low CSF HIV RNA levels (<103 copies/ml). In our longitudinal analysis of 16 subjects, higher CSF CD8+IFNγ expression at baseline predicted NC decline at follow-up (p = 0.02). Severity of NCI at follow-up correlated with level of residual HIV RNA in CSF. Conclusions Presence of IFNγ expressing CD8+ T
Bourrillon, Antoine; Bingen, Edouard
Given the devastating nature of Neisseria meningitidis disease and emergence of resistant strains prevention through chemoprophylaxis and meningococcal vaccine remains the best approach to control this serious infection. Chemoprophylaxis may limited strictly to the contact subjects. Polysaccharide meningococcal serogroups A, C, Y and W135 should be given less than 10 days to patients with prolonged contact with the index case. Meningococcal C conjugate vaccine constitutes an additional advantage in the prevention of meningococcal meningitis in children < 2 years. High Haemophilus serotype B coverage level led to near-disappearance of H. influenzae serotype b meningitis but chemoprophylaxis remains indicated.
Ibáñez, J; Weil, B; Ayala, A; Jimenez, A; Acedo, C; Rodrigo, I
We report a case of meningeal melanocytoma in the thoracic spinal cord of a 44-year-old woman and review previously documented cases. Our patient experienced numbness and tingling in her left leg for 8 years, and low back pains with intermittent claudication for the previous 2 months. A histologically benign 20-mm tumour was totally resected. Radiation therapy was not given. The tumour showed the histological, immunohistochemical and ultrastructural features of a meningeal melanocytoma. The patient is alive without recurrence 4.5 years after surgery.
Okokhere, Peter O; Bankole, Idowu A; Iruolagbe, Christopher O; Muoebonam, Benard E; Okonofua, Martha O; Dawodu, Simeon O; Akpede, George O
The Lassa virus is known to cause disease in different organ systems of the human body, with varying clinical manifestations. The features of severe clinical disease may include bleeding and/or central nervous system manifestations. Whereas Lassa fever encephalopathy and encephalitis are well described in the literature, there is paucity of data on Lassa virus meningitis. We present the clinical description, laboratory diagnosis, and management of 4 consecutive cases of aseptic meningitis associated with Lassa virus infection without bleeding seen in a region of Nigeria known to be endemic for both the reservoir rodent and Lassa fever. The 4 patients recovered fully following intravenous ribavirin treatment and suffered no neurologic complications.
Sánchez, J M; Zurro, F J; Ferreiro, D; Llana, R; Uría, D F
We present 2 cases of Haemophilus influenzae meningitis. The first is a patient with atypical simptomatology: abdominal pain, fever and two days later pain in the back of his legs. Abdominal pathology was not found. The cerebrospinal fluid (CSF) showed polymorphonuclear cells, hyperproteinorachia and lowered glucose. CSF culture revealed Haemophilus influenzae, blood culture was sterile. The second had suffered surgery at maxilar and ethmoid sinuses four years before, and unknown germ meningitis 6 months before. Haemophilus influenzae was isolated from CSF cultures and CSF rhinorrhea was detected by isotopic cisternography.
Runge, V.M.; Wells, J.W.; Williams, N.M.
The ability of high-field (1.5 T) magnetic resonance imaging (MRI) to detect early brain meningitis was evaluated in a canine model. Contrast dose, timing postinjection, and imaging technique (specifically the use of magnetization transfer) were assessed. Imaging of five canines was performed at 1.5 T 24 hours after injection of Cowans staphylococcus into the cisterna magna. Two control animals also were imaged using the same protocol. Contrast doses of 0.1, 0.3, and 0.8 mmol/kg gadoteridol were compared. Scans were performed at 2, 13, and 22 minutes after an initial injection of 0.1 mmol/kg. Thirty minutes after the initial injection of contrast, a supplemental dose of 0.2 mmol/kg was given. Scans were then repeated at 2, 12, and 22 minutes after this dose was administered. A second supplemental contrast injection of 0.5 mmol/kg was given at 70 minutes, and immediate postinjection scans with and without MT were acquired. Results. In the animals receiving a cisternal injection of bacteria, the degree of meningeal enhancement was greatest at 0.8 mmol/kg, intermediate at 0.3 mmol/kg, and least at 0.1 mmol/kg. Scans in control studies did not demonstrate abnormal meningeal enhancement. High-contrast dose, MT, and acquisition of immediate postcontrast scans all resulted in statistically significant improvement. On masked film review, abnormal meningeal enhancement was noted in only 2 of 5 experimental dogs at a dose of 0.1 mmol/kg (regardless of the use of MT) compared with all animals at a dose of 0.3 mmol/kg. In 18 of 37 dogs (paired scans with and without MT), when abnormal enhancement was noted, the use of MT improved the visualization of abnormal meningeal enhancement. In early brain meningitis, high-contrast dose (0.3 mmol/kg), MT, and scanning immediately after injection improve detection of abnormal meningeal enhancement, thus facilitating the diagnosis of meningitis. Of these factors, contrast dose is the most important. 14 refs., 9 figs., 2 tabs.
Rodrigues, Joana; Rocha, Dalila; Santos, Fátima; João, Anabela
Citrobacter koseri is a rare cause of neonatal meningitis with predisposal for brain abscesses, and therefore responsible for high mortality and serious neurologic sequelae in this age group. We present the evolution and outcome of four cases of C. koseri meningitis. One of them developed brain abscesses and another one died. The cases show the bacteria's propensity for serious brain damage, despite early and adequate treatment, and the high risk of long-term neurologic complications in survivors, which imposes a close follow-up. PMID:24716069
Singh, Jitendra; Himanshu, Dandu; Nim, Ranjit Kumar; Gupta, Kamlesh Kumar
Meningococcal infection is an important public health concern. Neisseria meningitidis usually colonizes the nasopharynx of healthy adolescents and adults and remains as asymptomatic colonizer, while in rare cases it may present as invasive disease as either meningitis or septicemia or both. Most of the cases have typical presentation of rashes. We hereby present a case of a 40-year-old male who presented with meningococcal meningitis and peripheral digital gangrene but without development of typical rashes. He improved by early institution of appropriate intravenous antibiotics with supportive care. PMID:28208911
Rodrigues, Joana; Rocha, Dalila; Santos, Fátima; João, Anabela
Citrobacter koseri is a rare cause of neonatal meningitis with predisposal for brain abscesses, and therefore responsible for high mortality and serious neurologic sequelae in this age group. We present the evolution and outcome of four cases of C. koseri meningitis. One of them developed brain abscesses and another one died. The cases show the bacteria's propensity for serious brain damage, despite early and adequate treatment, and the high risk of long-term neurologic complications in survivors, which imposes a close follow-up.
Raper, Daniel; Louveau, Antoine; Kipnis, Jonathan
The many interactions between the nervous and the immune systems, which are active in both physiological and pathological states, have recently become more clearly delineated with the discovery of a meningeal lymphatic system capable of carrying fluid, immune cells, and macromolecules from the central nervous system (CNS) to the draining deep cervical lymph nodes. However, the exact localization of the meningeal lymphatic vasculature and the path of drainage from the cerebrospinal fluid (CSF) to the lymphatics remain poorly understood. Here, we discuss the potential differences between peripheral and CNS lymphatic vessels and examine the purported mechanisms of CNS lymphatic drainage, along with how these may fit into established patterns of CSF flow.
Establishing a cost-per-result of laboratory-based, reflex Cryptococcal antigenaemia screening (CrAg) in HIV+ patients with CD4 counts less than 100 cells/μl using a Lateral Flow Assay (LFA) at a typical busy CD4 laboratory in South Africa
Cassim, Naseem; Schnippel, Kathryn; Coetzee, Lindi Marie
Introduction Cryptococcal meningitis is a major cause of mortality and morbidity in countries with high HIV prevalence, primarily affecting patients whose CD4 are < = 100 cells/μl. Routine Cryptococcal Antigen (CrAg) screening is thus recommended in the South African HIV treatment guidelines for all patients with CD4 counts < = 100 cells/μl, followed by pre-emptive anti-fungal therapy where CrAg results are positive. A laboratory-based reflexed CrAg screening approach, using a Lateral Flow Assay (LFA) on remnant EDTA CD4 blood samples, was piloted at three CD4 laboratories. Objectives This study aimed to assess the cost-per-result of laboratory-based reflexed CrAg screening at one pilot CD4 referral laboratory. Methods CD4 test volumes from 2014 were extracted to estimate percentage of CD4 < = 100 cells/μl. Daily average volumes were derived, assuming 12 months per/year and 21.73 working days per/month. Costing analyses were undertaken using Microsoft Excel and Stata with a provider prospective. The cost-per-result was estimated using a bottom-up method, inclusive of test kits and consumables (reagents), laboratory equipment and technical effort costs. The ZAR/$ exchange of 14.696/$1 was used, where applicable. One-way sensitivity analyses on the cost-per-result were conducted for possible error rates (3%– 8%, reductions or increases in reagent costs as well as test volumes (ranging from -60% to +60%). Results The pilot CD4 laboratory performed 267000 CD4 tests in 2014; ~ 9.3% (27500) reported CD4< = 100 cells/μl, equivalent to 106 CrAg tests performed daily. A batch of 30-tests could be performed in 1.6 hours, including preparation and analysis time. A cost-per-result of $4.28 was reported, with reagents contributing $3.11 (72.8%), while technical effort and laboratory equipment overheads contributed $1.17 (27.2%) and $0.03 (<1%) respectively. One-way sensitivity analyses including increasing or decreasing test volumes by 60% revealed a cost-per-result range
Kawakami, Sayoko; Kawamura, Yasuyosi; Nishiyama, Kyouhei; Hatanaka, Hiroki; Fujisaki, Ryuichi; Ono, Yasuo; Miyazawa, Yukihisa; Nishiya, Hajime
A 32-year-old man was admitted to our hospital because of fever, headache, and loss of consciousness. Four days before admission, he had had difficulty speaking. On the day of admission, his colleague had found him to be unconscious and lying on his back. He was admitted to our hospital. The temperature at the eardrum was 35.2°C. Neurologic evaluation was negative. Computed tomography (CT) scan of the brain showed slight ventricular enlargement bilaterally. An X-ray film of the chest showed no abnormality. On the second hospital day, neck stiffness was noted. The cerebrospinal fluid (CSF) contained 870 white cells/μl, most of which were neutrophils; the glucose level in the CSF was 10 mg/dl, and the protein level was 140 mg/dl. Stained smears of the CSF, including Gram staining and India-ink preparations, disclosed no microorganisms. Capsular antigen tests for several bacteria were negative. Antimicrobial agents were started. However, by changing the microscope focus slightly while viewing Gram stains of the CSF, we could see brightened and Gram-positive bacilli that had been phagocytosed by neutrophils. This finding suggested the presence of Mycobacterium tuberculosis. Ziehl-Neelsen staining of the CSF and gastric juice revealed anti-acid bacilli. Polymerase chain reaction for M. tuberculosis in the gastric juice was positive. This case showed that Gram staining could be useful as an initial adjunct for the diagnosis of tuberculous meningitis, particularly when the CSF shows predominantly neutrocytic pleocytosis, but no other evidence of bacterial meningitis.
Pandya, R. E.; Adams-Forgor, A.; Akweogno, P.; Awine, T.; Dalaba, M.; Dukic, V.; Dumont, A.; Hayden, M.; Hodgson, A.; Hopson, T. M.; Hugonnet, S.; Yoksas, T. C.
Meningitis epidemics in the Sahel occur quasi-regularly and with devastating impact. In 2008, for example, eighty-eight thousand people contracted meningitis and over five thousand died. Until very recently, the protection provided by the only available vaccine was so limited and short-lived that the only practical strategy for vaccination was reactive: waiting until an epidemic occurred in the region and then vaccinating in that region to prevent the epidemic's further growth. Even with that strategy, there were still times when demand outpaced available vaccine. While a new vaccine has recently been developed that is effective and inexpensive enough to be used more broadly and proactively, it is only effective against the strain of bacteria that causes the most common kind of bacterial meningitis. As a result, there will likely be continued need for reactive vaccination strategies. It is widely known that meningitis epidemics in the Sahel occur only in the dry season. Our project investigated this relationship, and several independent lines of evidence demonstrate a robust relationship between the onset of the rainy season, as marked by weekly average relative humidity above 40%, and the end of meningitis epidemics. These lines of evidence include statistical analysis of two years of weekly meningitis and weather data across the Sahel, cross-correlation of ten years of meningitis and weather data in the Upper East region of northern Ghana, and high-resolution weather simulations of past meningitis seasons to interpolate available weather data. We also adapted two techniques that have been successfully used in public health studies: generalized additive models, which have been used to relate air quality and health, and a linearized version of the compartmental epidemics model that has been used to understand MRSA. Based on these multiple lines of evidence, average weekly relative humidity forecast two weeks in advance appears consistently and strongly related to
Tlali, Mpho; Fielding, Katherine L.; Charalambous, Salome; Chihota, Violet N.; Churchyard, Gavin J.; Hanifa, Yasmeen; Johnson, Suzanne; McCarthy, Kerrigan; Martinson, Neil A.; Omar, Tanvier; Kahn, Kathleen; Chandramohan, Daniel; Grant, Alison D.
Background The World Health Organization (WHO) aims to reduce tuberculosis (TB) deaths by 95% by 2035; tracking progress requires accurate measurement of TB mortality. International Classification of Diseases (ICD) codes do not differentiate between HIV-associated TB and HIV more generally. Verbal autopsy (VA) is used to estimate cause of death (CoD) patterns but has mostly been validated against a suboptimal gold standard for HIV and TB. This study, conducted among HIV-positive adults, aimed to estimate the accuracy of VA in ascertaining TB and HIV CoD when compared to a reference standard derived from a variety of clinical sources including, in some, minimally-invasive autopsy (MIA). Methods and findings Decedents were enrolled into a trial of empirical TB treatment or a cohort exploring diagnostic algorithms for TB in South Africa. The WHO 2012 instrument was used; VA CoD were assigned using physician-certified VA (PCVA), InterVA-4, and SmartVA-Analyze. Reference CoD were assigned using MIA, research, and health facility data, as available. 259 VAs were completed: 147 (57%) decedents were female; median age was 39 (interquartile range [IQR] 33–47) years and CD4 count 51 (IQR 22–102) cells/μL. Compared to reference CoD that included MIA (n = 34), VA underestimated mortality due to HIV/AIDS (94% reference, 74% PCVA, 47% InterVA-4, and 41% SmartVA-Analyze; chance-corrected concordance [CCC] 0.71, 0.42, and 0.31, respectively) and HIV-associated TB (41% reference, 32% PCVA; CCC 0.23). For individual decedents, all VA methods agreed poorly with reference CoD that did not include MIA (n = 259; overall CCC 0.14, 0.06, and 0.15 for PCVA, InterVA-4, and SmartVA-Analyze); agreement was better at population level (cause-specific mortality fraction accuracy 0.78, 0.61, and 0.57, for the three methods, respectively). Conclusions Current VA methods underestimate mortality due to HIV-associated TB. ICD and VA methods need modifications that allow for more specific
Vehapoglu, Aysel; Ozgurhan, Gamze; Demir, Aysegul Dogan; Uzuner, Selcuk; Nursoy, Mustafa Atilla; Turkmen, Serdar
Recurrent meningitis is an uncommon life-threatening condition. Here, the case of a 6-year-old boy is reported who had two episodes of meningitis with an IgG3 subclass deficiency. The boy had aseptic meningitis at the age of 3 years, followed by bacterial meningitis at the age of 4 years. Primary immunoglobulin deficiencies are a group of disorders associated with an increased incidence and/or severity of infection. Recurrent infections, sinusitis, bronchitis, and pneumonia are the most frequently observed illnesses in patients with IgG subclass deficiencies, of which an IgG3 subclass deficiency is the most common, especially in adults. Although cases of recurrent viral or bacterial meningitis have been reported, herein a patient is presented with recurrence of aseptic and bacterial meningitis 1 year after the initial episode. Some researchers recommend that all children with episodes of recurrent meningitis should be screened for primary immunoglobulin or complement deficiencies.
Siegenthaler, Julie A; Pleasure, Samuel J
The meninges have traditionally been viewed as specialized membranes surrounding and protecting the adult brain from injury. However, there is increasing evidence that the fetal meninges play important roles during brain development. Through the release of diffusible factors, the meninges influence the proliferative and migratory behaviors of neural progenitors and neurons in the forebrain and hindbrain. Meningeal cells also secrete and organize the pial basement membrane (BM), a critical anchor point for the radially oriented fibers of neuroepithelial stem cells. With its emerging role in brain development, the potential that defects in meningeal development may underlie certain congenital brain abnormalities in humans should be considered. In this review, we will discuss what is known about assembly of the fetal meninges and review the role of meningeal-derived proteins in mouse and human brain development.
Jadeja, L.; Kantarjian, H.; Bolivar, R.
We describe the first patient with simultaneous S bovis septicemia and meningitis associated with chronic radiation enterocolitis. This case underlines the value of a thorough gastrointestinal evaluation of all patients with S bovis infection, and the need for a neurologic investigation even with minor neurologic manifestations.