Lazzarotto, Tiziana; Gabrielli, Liliana; Guerra, Brunella; Cervi, Francesca; Piccirilli, Giulia; Simonazzi, Giuliana; Chiereghin, Angela; Bellini, Francesca; Landini, Maria Paola
Congenital cytomegalovirus (CMV) infection is the leading non-genetic cause of sensori-neural hearing loss and neurodevelopmental sequelae. Despite these alarming facts, the general public healthcare system is often not aware of CMV and not enough is done to prevent congenital CMV infection.We describe the clinical and laboratory monitoring of a case with primary CMV infection occurring before the first trimester of gestation. Specific literature review is included in order to point out major goals achieved in the diagnosis and prognosis of congenital CMV infection and the many questions still unanswered. Serological diagnosis of primary CMV infection was performed based on serum-CMV specific-IgM antibodies, combined with low avidity anti-CMV IgG antibodies. The maternal infection was asymptomatic, as it is for most infections in immunocompetent patients. Therefore, disclosing primary infection depended on specific serological tests during the initial period of pregnancy (before weeks 12-16 of gestation). The invasive (amniocentesis) and non-invasive (ultrasonographic examination) prenatal tests, carried out at 21 weeks gestation, revealed a severe CMV infection in a fetus small for gestational age with ventriculomegaly. The presence of overt ultrasound abnormalities combined with high viral load in the amniotic fluid sampled at the appropriate times was highly suggestive of an unfavourable prognosis. The autopsy performed on the fetus confirmed severe disseminated CMV infection with histological brain damage.
Engman, Mona-Lisa; Malm, Gunilla; Engstrom, Lotta; Petersson, Karin; Karltorp, Eva; Tear Fahnehjelm, Kristina; Uhlen, Inger; Guthenberg, Claes; Lewensohn-Fuchs, Ilona
Congenital cytomegalovirus (CMV) infection is asymptomatic in 90% of infected newborns but approximately 10-20% of these infants are at risk of developing sequelae later, mostly hearing deficit. The aims of the study were to investigate the prevalence of congenital CMV infection in a Swedish population of newborns and investigate the relative risk of hearing deficit in newborns with congenital CMV infection. The dried blood spot (DBS) samples of 6060 newborns in southern Stockholm during 12 months (October 2003-June 2004; August 2004-October 2004) were analysed for CMV DNA by TaqMan based real-time PCR. Hearing deficit was assessed by otoacoustic emission (OAE) within a newborn screening programme. 12 infants out of 6060 or 0.2% (95% CI 0.1-0.3%) had congenital CMV infection. One boy among the 12 infected infants had unilateral hearing loss, indicating that the risk of hearing loss is greatly increased (about 20 times) in CMV infected infants. No child developed ocular complications such as chorioretinopathy during 3 y of follow-up. Congenital CMV has an impact on child health but can easily be overlooked due to lack of signs in the neonatal period. Surveillance for congenital CMV is important in addition to programmes for prevention and treatment.
Ikuta, Kazufumi; Minematsu, Toshio; Inoue, Naoki; Kubo, Takahiko; Asano, Kimisato; Ishibashi, Kei; Imamura, Takashi; Nakai, Hidetaka; Yoshikawa, Tetsushi; Moriuchi, Hiroyuki; Fujiwara, Shigeyoshi; Koyano, Shin; Suzutani, Tatsuo
Congenital cytomegalovirus (CMV) infection is caused by maternal primary infection as well as CMV reinfection or reactivation during pregnancy, although differences in the clinical impact between these modes of infection remain to be clarified. To investigate the latest prevalence and risk of multiple CMV infection in healthy pregnant women, as well as the types of maternal CMV infection associated with congenital CMV infection. Seroprevalence against CMV and IgG subclasses were determined in 344 serum samples from healthy pregnant women in Japan. CMV genotype and serotype were also determined in 18 pairs of mothers and neonates with congenital CMV infection identified in our CMV screening program. Thirty-two percent of the pregnant women were seronegative, while 66% of CMV seropositive women had IgG3 antibodies against one epitope on glycoprotein H (gH) as the major subclass, and 52% had IgG1 antibodies against one epitope on glycoprotein B (gB). Only a single genotype determined by CMV gH neutralizing epitope was found in the urine from the 18 neonates with congenital CMV infection, even though one case possessed antibodies against multiple CMV strains. In that case, the antibodies against the strain not detected in the urine from the infant disappeared within one month after birth, whereas the antibodies against the infecting CMV strain continued to be detected at 12 months after birth. Two (11%) of 18 cases of congenital CMV infection occurred via maternal CMV reinfection. Maternal humoral immunity did not prevent congenital CMV infection with another gH subtype. Copyright © 2013 Elsevier B.V. All rights reserved.
Furutate, Sakiko; Iwasaki, Satoshi; Nishio, Shin-ya; Moteki, Hideaki; Usami, Shin-ichi
Congenital cytomegalovirus (CMV) infection is a major cause of bilateral and unilateral sensorineural hearing loss (SNHL) in children, accounting for 9.0% of SNHL cases. The diagnostic rate using combined genetic deafness test and CMV DNA detection test was determined to be 46.4% in bilateral profound SNHL. The present study investigated the prevalence of congenital CMV infection diagnosed retrospectively by detection of CMV DNA in dried umbilical cord specimens from children with unilateral or bilateral SNHL up to the age of 12 years. Preserved dried umbilical cords were collected from 134 children with bilateral (46 children) or unilateral (88 children) SNHL. DNA was extracted from the dried umbilical cords and CMV DNA was detected by quantitative PCR. Genetic deafness tests based on the invader assay were performed in children with bilateral SNHL. CMV DNA from the dried umbilical cords was detected in 8.7% of the bilateral SNHL and 9.1% of unilateral SNHL. Deafness gene mutations were identified in 21.7% (10/46) of children with bilateral SNHL.
Marin, Lauro Juliano; Santos de Carvalho Cardoso, Emanuelle; Bispo Sousa, Sandra Mara; Debortoli de Carvalho, Luciana; Marques Filho, Marcílio F; Raiol, Mônica Regina; Gadelha, Sandra Rocha
CMV is the most common cause of congenital infection in the whole world (0.2 to 2.2 %). That infection may be symptomatic or asymptomatic at birth and, although asymptomatic cases at birth are more common, some children may develop late sequelae, and require medical intervention. This study aimed to determine the prevalence of CMV congenital infections in children who were born in a public hospital in Ilhéus, Brazil, and to evaluate the clinical progression in infected newborns. CMV congenital infection was determined by detecting viral DNA through nested PCR. The viral DNA was detected in 25 newborns, showing a prevalence of 1.19 % (25/2100) of CMV congenital infection. In regards to the risk factors from mothers, only the variables: age of mothers (p = 0.003), number of children (p = 0.011), and use of medications (p < 0.001) were associated with the congenital infection. Approximately 12 % of children presented symptoms. One death and two auditory alterations were detected during the monitored period. Only 50 % of children diagnosed attended their medical follow. The prevalence found confirms the findings from other studies which involved other poor populations. Two children presented impaired hearing during the monitored period; that was one of the main sequelae from the infection. It is noteworthy that there was low adherence to medical follow-up which may underestimate data on complications of the infection CMV. Late symptoms can be mistaken for other diseases or even go unnoticed.
Cannon, Michael J; Griffiths, Paul D; Aston, Van; Rawlinson, William D
Congenital CMV infection is a leading cause of childhood disability. Many children born with congenital CMV infection are asymptomatic or have nonspecific symptoms and therefore are typically not diagnosed. A strategy of newborn CMV screening could allow for early detection and intervention to improve clinical outcomes. Interventions might include antiviral drugs or nonpharmaceutical therapies such as speech-language therapy or cochlear implants. Using published data from developed countries, we analyzed existing evidence of potential benefit that could result from newborn CMV screening. We first estimated the numbers of children with the most important CMV-related disabilities (i.e. hearing loss, cognitive deficit, and vision impairment), including the age at which the disabilities occur. Then, for each of the disabilities, we examined the existing evidence for the effectiveness of various interventions. We concluded that there is good evidence of potential benefit from nonpharmaceutical interventions for children with delayed hearing loss that occurs by 9 months of age. Similarly, we concluded that there is fair evidence of potential benefit from antiviral therapy for children with hearing loss at birth and from nonpharmaceutical interventions for children with delayed hearing loss occurring between 9 and 24 months of age and for children with CMV-related cognitive deficits. We found poor evidence of potential benefit for children with delayed hearing loss occurring after 24 months of age and for children with vision impairment. Overall, we estimated that in the United States, several thousand children with congenital CMV could benefit each year from newborn CMV screening, early detection, and interventions.
Cannon, Michael J.; Griffiths, Paul D.; Aston, Van; Rawlinson, William D.
SUMMARY Congenital CMV infection is a leading cause of childhood disability. Many children born with congenital CMV infection are asymptomatic or have nonspecific symptoms and therefore are typically not diagnosed. A strategy of newborn CMV screening could allow for early detection and intervention to improve clinical outcomes. Interventions might include antiviral drugs or nonpharmaceutical therapies such as speech-language therapy or cochlear implants. Using published data from developed countries, we analyzed existing evidence of potential benefit that could result from newborn CMV screening. We first estimated the numbers of children with the most important CMV-related disabilities (i.e. hearing loss, cognitive deficit, and vision impairment), including the age at which the disabilities occur. Then, for each of the disabilities, we examined the existing evidence for the effectiveness of various interventions. We concluded that there is good evidence of potential benefit from nonpharmaceutical interventions for children with delayed hearing loss that occurs by 9 months of age. Similarly, we concluded that there is fair evidence of potential benefit from antiviral therapy for children with hearing loss at birth and from nonpharmaceutical interventions for children with delayed hearing loss occurring between 9 and 24 months of age and for children with CMV-related cognitive deficits. We found poor evidence of potential benefit for children with delayed hearing loss occurring after 24 months of age and for children with vision impairment. Overall, we estimated that in the United States, several thousand children with congenital CMV could benefit each year from newborn CMV screening, early detection, and interventions. Copyright © 2014 John Wiley & Sons, Ltd. PMID:24760655
CMV mononucleosis; Cytomegalovirus; CMV; Human cytomegalovirus; HCMV ... infection is spread by: Blood transfusions Organ transplants ... viruses remain in your body for the rest of your life. If your ...
Schleiss, Mark R
Congenital human cytomegalovirus (HCMV) infection can lead to long-term neurodevelopmental sequelae, including mental retardation and sensorineural hearing loss. Unfortunately, CMVs are highly adapted to their specific species, precluding the evaluation of HCMV vaccines in animal models prior to clinical trials. Several species-specific CMVs have been characterized and developed in models of pathogenesis and vaccine-mediated protection against disease. These include the murine CMV (MCMV), the porcine CMV (PCMV), the rhesus macaque CMV (RhCMV), the rat CMV (RCMV), and the guinea pig CMV (GPCMV). Because of the propensity of the GPCMV to cross the placenta, infecting the fetus in utero, it has emerged as a model of particular interest in studying vaccine-mediated protection of the fetus. In this paper, a review of these various models, with particular emphasis on the value of the model in the testing and evaluation of vaccines against congenital CMV, is provided. Recent exciting developments and advances in these various models are summarized, and recommendations offered for high-priority areas for future study.
Schleiss, Mark R.
Summary Congenital human cytomegalovirus (HCMV) infection can lead to long-term neurodevelopmental sequelae, including mental retardation and sensorineural hearing loss. Unfortunately, CMVs are highly adapted to their specific species, precluding the evaluation of HCMV vaccines in animal models prior to clinical trials. Several species-specific CMVs have been characterized and developed in models of pathogenesis and vaccine-mediated protection against disease. These include the murine CMV (MCMV), the porcine CMV (PCMV), the rhesus macaque CMV (RhCMV), the rat CMV (RCMV), and the guinea pig CMV (GPCMV). Because of the propensity of the GPCMV to cross the placenta, infecting the fetus in utero, it has emerged as a model of particular interest in studying vaccine-mediated protection of the fetus. In this paper, a review of these various models, with particular emphasis on the value of the model in the testing and evaluation of vaccines against congenital CMV, is provided. Recent exciting developments and advances in these various models are summarized, and recommendations offered for high-priority areas for future study. PMID:24523827
Hearing impairment in children with congenital cytomegalovirus (CMV) infection based on distortion product otoacoustic emissions (DPOAE) and brain evoked response audiometry stimulus click (BERA Click) examinations
Airlangga, T. J.; Mangunatmadja, I.; Prihartono, J.; Zizlavsky, S.
Congenital cytomegalovirus (congenital CMV) infection is a leading factor of nongenetic sensorineural hearing loss in children. Hearing loss caused by CMV infection does not have a pathognomonic configuration hence further research is needed. The development of knowledge on hearing loss caused by congenital CMV infection is progressing in many countries. Due to a lack of research in the context of Indonesia, this study assesses hearing impairment in children with congenital CMV infection in Indonesia, more specifically in the Cipto Mangunkusumo Hospital. Our objective was to profile hearing impairment in children 0-5 years of age with congenital CMV infection using Distortion Product Otoacoustic Emissions (DPOAE) and Brain Evoked Response Audiometry Stimulus Click (BERA Click) examinations. This cross-sectional study was conducted in the Cipto Mangunkusum Hospital from November, 2015 to May 2016 with 27 children 0-5 years of age with congenital CMV infection. Of individual ears studied, 58.0% exhibited sensorineural hearing loss. There was a significant relationship between developmental delay and incidence of sensorineural hearing loss. Subjects with a developmental delay were 6.57 times more likely (CI 95%; 1.88-22.87) to experience sensorineural hearing loss. Congenital CMV infection has an important role in causing sensorineural hearing loss in children.
Auerbach, Marcy R.; Yan, Donghong; Vij, Rajesh; Hongo, Jo-Anne; Nakamura, Gerald; Vernes, Jean-Michel; Meng, Y. Gloria; Lein, Samantha; Chan, Pamela; Ross, Jed; Carano, Richard; Deng, Rong; Lewin-Koh, Nicholas; Xu, Min; Feierbach, Becket
Human cytomegalovirus (HCMV) is the most common cause of congenital virus infection. Congenital HCMV infection occurs in 0.2–1% of all births, and causes birth defects and developmental abnormalities, including sensorineural hearing loss and developmental delay. Several key studies have established the guinea pig as a tractable model for the study of congenital HCMV infection and have shown that polyclonal antibodies can be protective –. In this study, we demonstrate that an anti-guinea pig CMV (GPCMV) glycoprotein H/glycoprotein L neutralizing monoclonal antibody protects against fetal infection and loss in the guinea pig. Furthermore, we have delineated the kinetics of GPCMV congenital infection, from maternal infection (salivary glands, seroconversion, placenta) to fetal infection (fetus and amniotic fluid). Our studies support the hypothesis that a neutralizing monoclonal antibody targeting an envelope GPCMV glycoprotein can protect the fetus from infection and may shed light on the therapeutic intervention of HCMV congenital infection in humans. PMID:24722349
... of antiviral drugs. Antiviral drugs slow the virus reproduction, but can't cure it. Researchers are studying ... saliva. Practice safe sex. Wear a condom during sexual contact to prevent spreading the CMV virus through ...
Nelson, C T; Istas, A S; Wilkerson, M K; Demmler, G J
PCR detected cytomegalovirus (CMV) DNA in the serum of 18 of 18 infants with symptomatic congenital CMV infection, 1 of 2 infants with asymptomatic congenital CMV infection, and 0 of 32 controls. Serum CMV PCR provided a rapid, sensitive, and specific method for diagnosis of congenital CMV infection in infants who were symptomatic at birth. PMID:8586726
Muldoon, Kathleen M; Armstrong-Heimsoth, Amy; Thomas, Jodi
Congenital cytomegalovirus (cCMV) infections cause more children to have permanent disabilities than Down Syndrome, Fetal Alcohol Syndrome, Spina Bifida, and pediatric HIV/AIDS combined. The risk of infection during pregnancy can be significantly decreased using universal precautions, such as thorough handwashing and cleansing of surfaces and objects that have come into contact with infected body fluids. Children under 3 years of age are commonly asymptomatic excretors of CMV, with the highest viral loads present in saliva. Pediatric therapists have regular close contact with young children, and are thus likely at elevated occupational risk of acquiring CMV. Our objective was to evaluate therapist knowledge of cCMV and its transmission. We recruited American Occupational Therapy Association (AOTA) and American Physical Therapy Association (APTA) members via electronic newsletters and printed flyers from April to September 2015. Participants completed an online, anonymous 24-question survey using Survey Monkey. We compared responses between groups and previously published CMV awareness data using binomial tests of difference of proportions and multiple logistic regression. Our study identified both a low level of therapist awareness and poor demonstrated understanding of cCMV. Self-reported cCMV awareness amongst therapists was greater than awareness in the general population, and equivalent to awareness amongst health care professionals. Whereas 52% of participants self-reported awareness of cCMV, only 18% demonstrated understanding of the behavioral modes of CMV transmission. Fewer therapists reported awareness of cCMV than other, less prevalent conditions. Higher levels of health risk knowledge were associated with greater contact with children. Most participants reported learning about cCMV from the workplace. The knowledge gaps between self-reported awareness of cCMV and demonstrated understanding of modes of transmission described by our results emphasize the
Ganz, W.I.; Cohen, D.; Mallin, W.
Due to extensive use of prophylactic therapy for Pneumonitis Carinii Pneumonia (PCP), Cytomegalic Viral (CMV) infection may now be the most common lung infection in AIDS patients. This study was performed to determine Gallium-67 patterns in AIDS patients with CMV. Pathology reports were reviewed in AIDS patients who had a dose of 5 to 10 mCi of Gallium-67 citrate. Analysis of images were obtained 48-72 hours later of the entire body was performed. Gallium-67 scans in 14 AIDS patients with biopsy proven CMV, were evaluated for eye, colon, adrenal, lung and renal uptake. These were compared to 40 AIDS patients without CMV. These controls had infections including PCP, Mycobacterial infections, and lymphocytic interstitial pneumonitis. 100% of CMV patients had bowel uptake greater than or equal to liver. Similar bowel activity was seen in 50% of AIDS patients without CMV. 71% had intense eye uptake which was seen in only 10% of patients without CMV. 50% of CMV patients had renal uptake compared to 5% of non-CMV cases. Adrenal uptake was suggested in 50%, however, SPECT imaging is needed for confirmation. 85% had low grade lung uptake. The low grade lung had perihilar prominence. The remaining 15% had high grade lung uptake (greater than sternum) due to superimposed PCP infection. Colon uptake is very sensitive indicator for CMV infection. However, observing eye, renal, and or adrenal uptake improved the diagnostic specificity. SPECT imaging is needed to confirm renal or adrenal abnormalities due to intense bowel activity present in 100% of cases. When high grade lung uptake is seen superimposed PCP is suggested.
... is rarely done. Antibody testing and viral CMV detection may be used to help diagnose primary CMV ... to distinguish between active and latent CMV. Direct detection of CMV Viral detection involves determining the presence ...
The immune response to cytomegalovirus (CMV) infection is highly complex, including humoral, cellular, innate, and adaptive immune responses. Detection of CMV by the innate immune system triggers production of type I IFNs and inflammatory cytokines which initiate cellular and humoral responses that are critical during the early viremic phase of CMV infection. Sustained control of CMV infection is largely accounted for by cellular immunity, involving various T-cell and B-cell subsets. In solid organ transplant patients, global suppression of innate and adaptive immunities by immunosuppressive agents limits immunological defense, including inhibition of natural killer cell activity with ongoing lowering of Ig levels and CMV-specific antibody titers. This is coupled with a short-term suppression of CMV-specific T cells, the extent and duration of which can predict risk of progression to CMV viremia. CMV immunoglobulin (CMVIG) preparations have the potential to exert immunomodulatory effects as well as providing passive immunization. Specific CMVIG antibodies and virus neutralization might be enhanced by modulation of dendritic cell activity and by a decrease in T-cell activation, effects which are of importance during the initial phase of infection. In summary, the role of CMVIG in reconstituting specific anti-CMV antibodies may be enhanced by some degree of modulation of the innate and adaptive immune responses, which could help to control some of the direct and indirect effects of CMV infection.
Abstract The immune response to cytomegalovirus (CMV) infection is highly complex, including humoral, cellular, innate, and adaptive immune responses. Detection of CMV by the innate immune system triggers production of type I IFNs and inflammatory cytokines which initiate cellular and humoral responses that are critical during the early viremic phase of CMV infection. Sustained control of CMV infection is largely accounted for by cellular immunity, involving various T-cell and B-cell subsets. In solid organ transplant patients, global suppression of innate and adaptive immunities by immunosuppressive agents limits immunological defense, including inhibition of natural killer cell activity with ongoing lowering of Ig levels and CMV-specific antibody titers. This is coupled with a short-term suppression of CMV-specific T cells, the extent and duration of which can predict risk of progression to CMV viremia. CMV immunoglobulin (CMVIG) preparations have the potential to exert immunomodulatory effects as well as providing passive immunization. Specific CMVIG antibodies and virus neutralization might be enhanced by modulation of dendritic cell activity and by a decrease in T-cell activation, effects which are of importance during the initial phase of infection. In summary, the role of CMVIG in reconstituting specific anti-CMV antibodies may be enhanced by some degree of modulation of the innate and adaptive immune responses, which could help to control some of the direct and indirect effects of CMV infection. PMID:26900990
The risk of intrauterine transmission of cytomegalovirus (CMV) during pregnancy is much greater for women who contract primary CMV infection after conception than for women with evidence of infection (circulating CMV antibodies) before conception. Thus, laboratory tests that aid in the identification of recent primary CMV infection are important tools for managing the care of pregnant women suspected of having been exposed to CMV. CMV IgM detection is a sensitive marker of primary CMV infection, but its specificity is poor because CMV IgM is also produced during viral reactivation and persists following primary infection in some individuals. Studies conducted over the last 20 years convincingly demonstrate that measurement of CMV IgG avidity is both a sensitive and a specific method for identifying pregnant women with recent primary CMV infection and thus at increased risk for vertical CMV transmission. IgG avidity is defined as the strength with which IgG binds to antigenic epitopes expressed by a given protein; it matures gradually during the 6 months following primary infection. Low CMV IgG avidity is an accurate indicator of primary infection within the preceding 3 to 4 months, whereas high avidity excludes primary infection within the preceding 3 months. In this minireview, we summarize published data demonstrating the clinical utility of CMV IgG avidity results for estimating time since primary infection in pregnant women, describe commercially available CMV IgG avidity assays, and discuss some of the issues and controversies surrounding CMV IgG avidity testing during pregnancy. PMID:25165026
Enders, Gisela; Daiminger, Anja; Bäder, Ursula; Exler, Simone; Schimpf, Yvonne; Enders, Martin
Primary CMV infections in pregnancy are usually asymptomatic and only detected by serology. Estimating the onset of infection is a major diagnostic goal, since primary infections around conception and in early gestation hold a higher risk for congenital disease than those in later pregnancy. To assess the ability of serological supplementary CMV assays to date the onset of primary infection. From our routine diagnosis we identified 61 pregnant women (n=188 serum samples) with precisely determined onset of CMV primary infection either by IgG seroconversion (n=24) or by significant IgG antibody rise (n=37). One hundred and forty-seven sera were investigated using the VIDAS(®) CMV IgG avidity EIA (BioMèrieux) and 83 sera using the recomBlot CMV IgG with avidity (Mikrogen). Both assays proofed to be reliable in terms of timing the onset of CMV primary infection. An avidity index (AI) in the VIDAS avidity EIA of <40% indicated primary infection within the last 20 weeks (positive predictive value 93.4%; 99/106), whereas an intermediate AI excluded primary infection within the last 12 weeks (negative predictive value 88.2%; 15/17). The recomBlot showed high reliability (PPV 96.9%; 31/33) for timing the onset of infection within the last 14 weeks. Avidity testing by blot however could not be interpreted in 11 of 47 sera (23.4%). For timing the onset of infection (before or in early pregnancy) CMV avidity testing is most helpful if carried out within the first trimester up to the beginning of second trimester. Copyright © 2012 Elsevier B.V. All rights reserved.
Johnson, Julie; Anderson, Brenna; Pass, Robert F.
Congenital cytomegalovirus (CMV) infection is an important cause of hearing impairment, mental retardation and cerebral palsy. Principal sources of infection during pregnancy are young children and intimate contacts. Prevention of maternal and congenital CMV infection depends on counseling women regarding the sources of infection and hygienic measures that might prevent infection. There is currently insufficient evidence to support use of antiviral treatment or passive immunization for post-exposure prophylaxis of pregnant women or as a maternal treatment aimed at preventing fetal infection. Vaccines for CMV are under development but it will be a number of years before one is licensed. PMID:22510635
Boos, Vinzenz; Feiterna-Sperling, Cornelia; Sarpong, Akosua; Garten, Lars; Cremer, Malte; von Weizsäcker, Katharina; Bührer, Christoph; Dame, Christof
We report on a late-preterm neonate with severe congenital cytomegalovirus (CMV) infection, refractory to antiviral therapy with ganciclovir. Subsequent immune diagnostics led to the finding of HIV infection at day 69, even though the mother tested negative for HIV in early pregnancy. Thus, in congenital CMV infection, HIV testing should be performed to elucidate maternal HIV seroconversion during late pregnancy. Our case strongly supports third trimester screening of HIV infection acquired during pregnancy, yet recommended only for women with traditional risk factors for HIV or living in an area of high HIV prevalence.
Schulz, Uwe; Solidoro, Paolo; Müller, Veronika; Szabo, Attila; Gottlieb, Jens; Wilkens, Heinrike; Enseleit, Frank
Intravenous ganciclovir and, increasingly, oral valganciclovir are now considered the mainstay of treatment for cytomegalovirus (CMV) infection or CMV disease. Under certain circumstances, CMV immunoglobulin (CMVIG) may be an appropriate addition or, indeed, alternative. Data on monotherapy with CMVIG are limited, but encouraging, for example in cases of ganciclovir intolerance. In cases of recurrent CMV in thoracic transplant patients after a disease- and drug-free period, adjunctive CMVIG can be considered in patients with hypogammaglobulinemia. Antiviral-resistant CMV, which is more common among thoracic organ recipients than in other types of transplant, can be an indication for introduction of CMVIG, particularly in view of the toxicity associated with other options, such as foscarnet. Due to a lack of controlled trials, decision-making is based on clinical experience. In the absence of a robust evidence base, it seems reasonable to consider the use of CMVIG to treat CMV in adult or pediatric thoracic transplant patients with ganciclovir-resistant infection, or in serious or complicated cases. The latter can potentially include (i) treatment of severe clinical manifestations, such as pneumonitis or eye complications; (ii) patients with a positive biopsy in end organs, such as the lung or stomach; (iii) symptomatic cases with rising polymerase chain reaction values (for example, higher than 5.0 log10) despite antiviral treatment; (iv) CMV disease or CMV infection or risk factors, such as CMV-IgG-negative serostatus; (vi) ganciclovir intolerance; (vii) patients with hypogammaglobulinemia.
Aichelburg, Maximilian C; Weseslindtner, Lukas; Mandorfer, Mattias; Strassl, Robert; Rieger, Armin; Reiberger, Thomas; Puchhammer-Stöckl, Elisabeth; Grabmeier-Pfistershammer, Katharina
Among HIV-1-infected individuals, cytomegalovirus (CMV) reactivation and disease occur in the setting of advanced immunosuppression. The value of a standardized assessment of CMV-specific T-cell mediated immunity by the CMV QuantiFERON assay (CMV-QFT) has not yet been thoroughly investigated in HIV-1-infected subjects. Prospective, longitudinal study in 153 HIV-1-infected subjects with a CD4+ T cell count < 350/μL who simultaneously underwent CMV-QFT, CMV serology testing and CMV-DNA quantification. Factors associated with CMV-QFT were evaluated. Clinical screening for CMV manifestations was then performed every 3 months. Among the 141 CMV IgG-seropositive individuals the CMV-QFT assay yielded reactive results in 84% (118/141), negative results in 15% (21/141) and indeterminate (negative mitogen IFN-gamma response) results in 1% (2/141) of subjects. The mean actual CD4+ T cell count was significantly higher in CMV-QFT reactive subjects, when compared to CMV-QFT non-reactive individuals (183 ± 102 vs. 126 ± 104 cells/μL, P = 0.015). A significantly lower proportion of CMV-QFT reactive vs. non-reactive patients displayed CMV DNAemia > 100 copies/mL (23% (27/118) vs. 48% (11/23), P = 0.02). Furthermore, a statistically significant inverse association between mitogen IFN-gamma response and CMV-DNAemia > 1000 copies/mL was observed (P < 0.001). During the observational period, 5 CMV end-organ manifestations were observed. In three of the CMV cases the CMV-QFT yielded indeterminate results. While CMV-QFT reactivity indicates CMV-specific immunity, indeterminate results due to negative mitogen IFN-gamma response might reflect HIV-1-induced immunodeficiency. Thus, dependency upon CD4+ T cell count should be considered when interpreting CMV-QFT results.
Gibson, Laura; Dooley, Sheryl; Trzmielina, Sonia; Somasundaran, Mohan; Fisher, Donna; Revello, Maria Grazia; Luzuriaga, Katherine
Cytomegalovirus (CMV) infection remains a significant cause of morbidity and mortality in young children. We have previously shown that CD8+ T cell responses to CMV pp65 or IE1 protein were readily detectable in children with congenital or postnatal CMV infection. Here, we have further characterized the evolution of the peptide specificity of these responses in 7 infants<6 months of age at the start of the study. Thirteen pp65 and 15 IE1 peptides (median, 5 peptides/infant) were targeted, and most (61%) represented sequences not previously reported. Peptide specificity remained stable or broadened over time despite the clearance of CMV viremia. Loss of peptide recognition was not observed. Responses with the highest functional peptide avidity were not necessarily detected earliest. These data provide additional evidence that young infants can generate diverse CMV-specific CD8+ T cell responses but show that early responses may exhibit relatively focused peptide specificity and lower peptide avidity.
Pirillo, Maria Franca; Liotta, Giuseppe; Andreotti, Mauro; Jere, Haswel; Sagno, Jean-Baptiste; Scarcella, Paola; Mancinelli, Sandro; Buonomo, Ersilia; Amici, Roberta; Marazzi, Maria Cristina; Vella, Stefano; Palombi, Leonardo; Giuliano, Marina
Antiretroviral therapy has been shown to reduce rates of congenital CMV infection. Little information is available on the possible impact of antiretroviral therapy on postnatal breastfeeding-associated CMV infection acquisition. A cohort of 89 HIV-infected mothers and their children was studied. Women received antiretroviral therapy from week 25 of gestation until 6 months postpartum or indefinitely if meeting the criteria for treatment. All women were evaluated for CMV IgG presence and CMV DNA in breast milk. Children were tested for CMV infection by either the presence of IgM or the presence of CMV DNA in plasma at 1, 6 and 12 months and by the presence of IgG at 24 months. All mothers had high titers of CMV DNA in breast milk (5.7 log at Month 1 and 5.1 log at Month 6). Cumulative CMV infection rates were 60.3 % at Month 6, 69 % at Month 12 and 96.4 % at Month 24. There was a significant negative correlation between the duration of antiretroviral treatment during pregnancy and levels of CMV DNA in breast milk at Month 1 (P = 0.033). There was a trend for a correlation between high titers of CMV DNA in breast milk at 6 months and CMV infection at 6 months (P = 0.069). In this cohort, more than 95 % of the children had acquired CMV infection by 2 years of age. Besides breastfeeding, which played a major role, also horizontal transmission between 1 and 2 years was certainly relevant in determining CMV infection acquisition.
The wide spectrum of congenital cytomegalovirus (CMV) disease and known differences in the biology and in vitro growth of CMV strains continue to drive studies in search for specific viral genetic determinants that may predict severity of congenital CMV disease. Several CMV genes have been studied in detail in congenitally infected children, but the complexity of the viral genome and differences in the definition of symptomatic disease versus asymptomatic CMV infection continue to raise questions related to what constitutes a pathogenic CMV strain. Copyright © 2015 Elsevier Inc. All rights reserved.
Williams, Eleri J; Kadambari, Seilesh; Berrington, Janet E; Luck, Suzanne; Atkinson, Claire; Walter, Simone; Embleton, Nicholas D; James, Peter; Griffiths, Paul; Davis, Adrian; Sharland, Mike; Clark, Julia E
Congenital cytomegalovirus (cCMV) is the most common non-genetic cause of sensorineural hearing loss (SNHL) in children. Ganciclovir has been shown to prevent the continued deterioration in hearing of children with symptomatic cCMV, but some children with cCMV-related SNHL are unidentified in the neonatal treatment period. Neonatal cCMV screening provides an opportunity to identify infants with cCMV-related SNHL who might benefit from early treatment. To assess the feasibility (ability to take samples before 3 weeks of age and clinical assessment by 30 days of age) and acceptability (maternal anxiety) of targeted CMV testing of infants who are 'referred' for further audiological testing after routine newborn hearing screening programme (NHSP). Parents of infants who have 'no clear responses' on routine NHSP before 22 days of life in London and North East England were approached. Salivary and urine samples were tested by CMV PCR. At recruitment and 3 months, the short form Spielberger State-Trait Anxiety Inventory measured maternal anxiety. 411 infants were recruited. 99% (407/411) returned a sample; 98% (404/411) successfully yielded a CMV result, 6 had cCMV, all diagnosed on salivary samples taken <22 days of age (1.5%; 95% CI 0.6% to 3.2%). Only 50% returned urine samples compared with 99% returning salivary samples (p<0.001). Using saliva swabs 98% were successfully screened for CMV within 3 weeks. All positive screening CMV results were known by day 23, and 5/6 infants with cCMV were assessed within 31 days. Anxiety was not increased in mothers of infants screened for cCMV. Targeted salivary screening for cCMV within the NHSP is feasible, acceptable and detects infants with cCMV-related SNHL who could benefit from early treatment.
Nuñez-Ramos, Raquel; Becerril, Jesús; Blázquez, Daniel; Rojo, Pablo; de Vergas, Joaquín; Folgueira, Dolores
Cytomegalovirus (CMV) infection is the most common congenital infection in Europe. Symptoms are present at birth in 10% of infected children, and up to 30-40% have some degree of hearing loss after the newborn period. A retrospective study was performed over a period of 4 years and included all patients with congenital CMV infection diagnosed after the neonatal period using the dried blood spots from neonatal metabolic screening. We present 5 patients diagnosed with congenital CMV infection outside the neonatal period. The main reasons for consultation were hearing loss and/or neurological impairment in the first few months of life. Congenital CMV infection may be mildly symptomatic at birth, and present as hearing loss and/or neurological impairment in infancy. Therefore, a high degree of suspicion is necessary in order to make an accurate diagnosis and start specific treatment to improve the outcome. Copyright © 2012 Elsevier España, S.L. All rights reserved.
Lanzieri, Tatiana M.; Bialek, Stephanie R.; Ortega-Sanchez, Ismael R.; Gambhir, Manoj
Background Understanding the potential for vaccination to change cytomegalovirus (CMV) epidemiology is important for developing CMV vaccines and designing clinical trials. Methods We constructed a deterministic, age-specific and time-dependent mathematical model of pathogen transmission, parameterized using CMV seroprevalence from the United States and Brazil, to predict the impact of vaccination on congenital CMV infection. Findings Concurrent vaccination of young children and adolescents would result in the greatest reductions in congenital CMV infections in populations with moderate and high baseline maternal seroprevalence. Such a vaccination strategy, assuming 70% vaccine efficacy, 90% coverage and 5-year duration of protection, could ultimately prevent 30%-50% of congenital CMV infections. At equilibrium, this strategy could result in a 30% reduction in congenital CMV infections due to primary maternal infection in the United States but a 3% increase in Brazil. The potential for an increase in congenital CMV infections due to primary maternal infections in Brazil was not predicted with use of a vaccine that confers protection for greater than 5 years. Interpretation Modeling suggests that vaccination strategies that include young children will result in greater declines in congenital CMV infection than those restricted to adolescents or women of reproductive age. Our study highlights the critical need for better understanding of the relative contribution of type of maternal infection to congenital CMV infection and disease, the main focus of vaccine prevention. PMID:24837782
Dayan, K; Neufeld, D M; Lang, R; Novis, B; Bernheim, J; Freund, U
A 53-year-old man is reported who developed a widespread gastrointestinal infection due to cytomegalic (CMV) virus and was found to be suffering from AIDS. He died of overwhelming pulmonary infection. There is need for awareness of the rapid increase of AIDS in our local population, particularly in groups not regarded as at high risk. It is imperative to keep this diagnosis in mind when dealing with patients with gastroenterocolitis not responding to standard treatments. CMV has a broad spectrum of clinical manifestations, from carrier state to life-threatening infection. In the gastrointestinal system it causes inflammation and ulcers in the mucosa that may bleed or perforate. There are increasing numbers of reports of CMV ileocolitis in homosexuals with AIDS. The rate of sero-positive CMV in healthy homosexual populations is 94-100% and in 14% there is active infection. CMV is the main infective agent in patients suffering from AIDS; 90% will develop an infection with this virus and in most cases it will be fatal.
Chen, Sharon F; Holmes, Tyson H; Slifer, Teri; Ramachandran, Vasavi; Mackey, Sally; Hebson, Cathleen; Arvin, Ann M; Lewis, David B; Dekker, Cornelia L
Congenital cytomegalovirus (CMV) is reported to affect up to 1% of all live births in the United States. T-cell immunity may be important for controlling CMV replication in congenital CMV-infected infants. We describe the natural history of CMV-specific T-cell evolution and CMV replication in infants with congenital CMV infection. Cytomegalovirus viral load, CMV urine culture, and CMV-specific CD4 and CD8 T-cell responses were assessed in a prospective longitudinal cohort of 51 infants with congenital CMV infection who were observed from birth to 3 years of age. We found a kinetic pattern of decreasing urinary CMV replication and increasing CMV-specific CD4 and CD8 T-cell responses during the first 3 years of life. We also found higher CMV-specific CD8 T-cell responses were associated with subsequent reduction of urine CMV viral load. For infants with congenital CMV infection, our data suggest an age-related maturation of both CMV-specific CD4 and CD8 T-cell immunity that is associated with an age-related decline in urinary CMV replication. © The Author 2014. Published by Oxford University Press on behalf of the Pediatric Infectious Diseases Society. All rights reserved. For Permissions, please e-mail: firstname.lastname@example.org.
Krause, Philip R; Bialek, Stephanie R; Boppana, Suresh B; Griffiths, Paul D; Laughlin, Catherine A; Ljungman, Per; Mocarski, Edward S; Pass, Robert F; Read, Jennifer S; Schleiss, Mark R; Plotkin, Stanley A
A multidisciplinary meeting addressed priorities related to development of vaccines against cytomegalovirus (CMV), the cause of congenital CMV (cCMV) disease and of serious disease in the immunocompromised. Participants discussed optimal uses of a CMV vaccine, aspects of clinical study design, and the value of additional research. A universal childhood CMV vaccine could potentially rapidly reduce cCMV disease, as infected children are sources of viral transmission to seronegative and seropositive mothers. A vaccine administered to adolescents or adult women could also reduce cCMV disease by making them immune prior to pregnancy. Clinical trials of CMV vaccines in women should evaluate protection against cCMV infection, an essential precursor of cCMV disease, which is a more practical and acceptable endpoint for assessing vaccine effects on maternal-fetal transmission. Clinical trials of vaccines to evaluate prevention of CMV disease in stem cell transplant recipients could use CMV viremia at a level triggering pre-emptive antiviral therapy as an endpoint, because widespread use of pre-emptive and prophylactic antivirals has rendered CMV-induced disease too rare to be a practical endpoint for clinical trials. In solid organ transplant patients, CMV-associated disease is sufficiently common for use as a primary endpoint. Additional research to advance CMV vaccine development should include identifying factors that predict fetal loss due to CMV, determining age-specific incidence and transmission rates, defining the mechanism and relative contributions of maternal reactivation and re-infection to cCMV disease, developing assays that can distinguish between reactivation and re-infection in seropositive vaccinees, further defining predictors of sequelae from cCMV infection, and identifying clinically relevant immune response parameters to CMV (including developing validated assays that could assess CMV antibody avidity) that could lead to the establishment of immune
Mikulska, Małgorzata; Raiola, Anna Maria; Bruzzi, Paolo; Varaldo, Riccardo; Annunziata, Silvana; Lamparelli, Teresa; Frassoni, Francesco; Tedone, Elisabetta; Galano, Barbara; Bacigalupo, Andrea; Viscoli, Claudio
Cytomegalovirus (CMV) infection and disease are important complications after hematopoietic stem cell transplant, particularly after transplant from alternative donors. Allogeneic cord blood transplantation (CBT) is being increasingly used, but immune recovery may be delayed. The aim of this study was to compare CMV infection in CBT with transplants from unrelated or mismatched related donors, from now on defined as alternative donors. A total of 165 consecutive transplants were divided in 2 groups: (1) alternative donors transplants (n = 85) and (2) CBT recipients (n = 80). Donor and recipient (D/R) CMV serostatus were recorded. The incidence of CMV infection, its severity, timing, and outcome were compared. Median follow-up was 257 days (1-1328). CMV infection was monitored by CMV antigenemia and expressed as CMV Ag positive cell/2 × 10(5) polymorphonuclear blood cells. There was a trend toward a higher cumulative incidence of CMV infection among CBT than alternative donor transplant recipients (64% vs 51%, P = .12). The median time to CMV reactivation was 35 days, and was comparable in the 2 groups (P = .8). The maximum number of CMV-positive cells was similar in the 2 groups (11 versus 16, P = .2). The time interval between the first and the last positive CMV antigenemia was almost 4 times longer in CBT compared with alternative donor transplants (109 vs 29 days, respectively, P = .008). The incidence of late CMV infection was also higher in CBT (62% vs 24%, P < .001). The incidence of early and late CMV infection in CBT was similar to D-/R+ alternative transplants, and higher than in D+/R+ alternative transplants: early infection, 72% in CBT versus 69% in D-/R+ alternative versus 55% in D+/R+ alternative (P = .21); and late infection, 67% in CBT versus 60% in D-/R+ alternative versus 7% in D+/R+ alternative (P < .001). Transplant-related mortality and overall survival were similar between the groups: 34% versus 36% (P = .6) and 54% versus 46% (P = .3) for
Ogawa, Hiroshi; Matsui, Takamichi; Baba, Yoko; Yamada, Naoko; Suzuki, Yukie; Suzutani, Tatsuo
Not all patients diagnosed with congenital infection using umbilical cord assay were found to be positive for CMV-DNA by perilymphatic fluid assay. In addition, a CMV-DNA-positive result was observed in one patient who had not been diagnosed with congenital infection. Sampling of perilymphatic fluid from a large population of patients with congenital SNHL caused by congenital CMV infection or of unknown etiology is required to determine the prevalence of CMV-related profound HL. Sensorineural hearing loss (SNHL) is one of the most frequent manifestations in patients with congenital cytomegalovirus (CMV) infection. Using dried umbilical cord, a PCR-based assay was recently developed for the retrospective detection of congenital CMV infection. This study analyzed the presence of CMV in the perilymphatic fluid and evaluated differences in the effect of cochlear implantation between CMV-positive and -negative groups. Perilymphatic fluid was collected from each patient at the time of cochlear implantation and analyzed for the presence of CMV using a PCR method. The perilymphatic fluid in two of the five patients suffering from congenital CMV infection and in one of the 17 patients without congenital CMV infection was found to be positive for CMV.
Melero-Ferrer, Josep; Sanchez-Lazaro, Ignacio J.; Navea-Tejerina, Amparo; Almenar-Bonet, Luis; Blanes-Julia, Marino; Martinez-Dolz, Luis; Salvador-Sanz, Antonio
Infections are one of the leading causes of morbidity and mortality in heart transplantation (HTx). Cytomegalovirus (CMV) is the most common viral infection during the first year after HTx, but it is more unusual after this time. We present the case of a patient who underwent an HTx due to a severe ischemic heart disease. Although the patient did not have a high risk for CMV, infection, he suffered a reactivation during the first year and then up to six more episodes, especially in his eyes. The patient received different treatments against CMV and the immunosuppression was changed several times. Finally, everolimus was introduced instead of cyclosporine, and mycophenolate mofetil was withdrawn. The presented case provides an example of how the immunosupresion plays a key role in some infections in spite of being a suitable antiviral treatment. PMID:23213610
Cohen, L; Yeshurun, M; Shpilberg, O; Ram, R
We aimed to study the risk factors for first and subsequent cytomegalovirus (CMV) infection among patients who are CMV seropositive and underwent allogeneic hematopoietic cell transplantation (HCT). We performed an historical cohort study of all sequential CMV-seropositive patients who underwent allogeneic HCT at a single center. Between May 2007 and December 2012, 121 patients fulfilled inclusion criteria. Multivariate model identified myeloablative preparative regimen (hazard ratio [HR] = 4.297, P = 0.033) and acute graft-versus-host disease (GVHD) prior to infection (HR = 5.091, P = 0.021) as risk factors for first CMV infection. The cumulative incidences of first CMV infection for patients with 0, 1, and 2 risk factors were 52%, 71%, and 91%, respectively. Multivariate analysis identified the diagnosis of lymphoma/myeloma (HR = 3.5, P = 0.049) and GVHD (HR = 1.280, P = 0.045) as risk factors for subsequent CMV infection. High graft CD3 stem cell dose was associated with a trend of lower rate of subsequent CMV infection (HR = 0.543, P = 0.056). The cumulative incidences for subsequent CMV infection in patients with 0, 1, and 2-3 risk factors were 11%, 41%, and 77%, respectively. In conclusion, in CMV-seropositive patients, myeloablative conditioning and acute GVHD are risk factors for first CMV infection, while lymphoma/myeloma, ongoing GVHD, and low CD3 graft content are risk factors for subsequent infection. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.
Pass, Robert F; Anderson, Brenna
Mother-to-child transmission (MTCT) of cytomegalovirus (CMV) occurs transplacentally (congenital infection), during birth and through breast milk, although the latter 2 modes of transmission are not associated with the central nervous system sequelae that occur with congenital infection. CMV persists indefinitely in its human host, and MTCT can occur if the mother was infected in the past or during the current pregnancy. The goal of efforts to prevent MTCT of CMV is to prevent congenital infection, an important cause of disability due to hearing loss, impaired vision, cognitive impairment, and neuromotor deficits. Vaccines for prevention of maternal and congenital CMV infection are being developed but will not likely be available for at least a decade. Rather than waiting for an effective vaccine to solve the problem, more effort must be devoted to defining the potential for public health measures to prevent congenital CMV infection by reducing rates of maternal infection during pregnancy.
Pass, Robert F.; Anderson, Brenna
Mother-to-child transmission (MTCT) of cytomegalovirus (CMV) occurs transplacentally (congenital infection), during birth and through breast milk, although the latter 2 modes of transmission are not associated with the central nervous system sequelae that occur with congenital infection. CMV persists indefinitely in its human host, and MTCT can occur if the mother was infected in the past or during the current pregnancy. The goal of efforts to prevent MTCT of CMV is to prevent congenital infection, an important cause of disability due to hearing loss, impaired vision, cognitive impairment, and neuromotor deficits. Vaccines for prevention of maternal and congenital CMV infection are being developed but will not likely be available for at least a decade. Rather than waiting for an effective vaccine to solve the problem, more effort must be devoted to defining the potential for public health measures to prevent congenital CMV infection by reducing rates of maternal infection during pregnancy. PMID:25232473
Yilmaz Çiftdogan, Dilek; Vardar, Fadil
Congenital cytomegalovirus (CMV) infection is the leading nongenetic cause of congenital sensorineural hearing loss (SNHL). Hearing loss due to congenital CMV infection either has onset after the newborn period or shows progressive decline in auditory thresholds. Although 90% of the congenitally infected infants are asymptomatic at birth, evidence is accumulating that these infants are at risk for audiologic, neurologic and developmental sequelae. In symptomatically infected infants, ganciclovir therapy administered in the neonatal period prevents hearing deterioration. However, preventative therapy of asymptomatic congenital CMV disease is controversial. Here in, we reported a male newborn with asymptomatic congenital CMV with bilateral SNHL. Oral treatment with valganciclovir in patient resulted in progressive improvement of SNHL, which effectively reduced the CMV viral load and was well tolerated without apparent adverse effects.
Garofoli, Francesca; Lombardi, Giuseppina; Orcesi, Simona; Pisoni, Camilla; Mazzucchelli, Iolanda; Angelini, Micol; Balottin, Umberto; Stronati, Mauro
The aim of this retrospective study, with prospective data collection, was to correlate congenital cytomegalovirus (CMV) infection with autism spectrum disorder (ASD) and to define its prevalence. Seventy proven congenitally-infected infants, born between 2007 and 2012, were referred to our centre for CMV diagnosis and follow-up, which consisted…
Stranzinger, Johanna; Kindel, Jutta; Henning, Melanie; Wendeler, Dana; Nienhaus, Albert
Background: Staff in children’s hospitals may run an increased risk of cytomegalovirus (CMV) contact infection leading to a congenital CMV fetopathy during pregnancy. The main risk factor is close contact with inapparent carriers of CMV among infants (<3 years). We therefore examined CMV seroprevalence (SP) and possible risk factors for CMV infection among staff at a children’s hospital. Method: In 2014, staff at a metropolitan children’s hospital were offered a CMV antibody test in the context of occupational health screening. Besides of anti-CMV immunoglobulin G (anti-CMV IgG) gender, age, profession, number of children and migration background were assessed and used as independent variables in multiple logistic regression. Women without a migration background (MIG) were considered as a separate group. Results: The study included 219 employees. Women showed a significant higher risk than men of being CMV-positive (adjusted odds ratio [aOR] 3.0; 95% CI 1.1–7.8). The risk among age groups of 30 and over was double that of the under-30s (aOR 2.0; 95% CI 1.0–3.9); among those aged 40-plus it was aOR 2.3 (95% CI 1.1–4.7). Staff with an MIG tested more often positive than those without an MIG (95.5% versus 45.7%). CMV SP was 47.7% among women without an MIG. In this subgroup the probability of CMV infection increased with age (p=0.08) as well. Conclusion: In the staff group as a whole there was a significant correlation between CMV SP, country of origin and age. We found no significant differences between occupational groups; perhaps our random sample was too small. Given the low CMV SP particularly in those without MIG, women who want to have children in particular must be protected from CMV infection. Follow-up studies should be undertaken to test whether good workplace hygiene offers sufficient protection for pregnant women and could be an alternative to prohibiting certain activities. PMID:27730028
Moienafshari, R.; Bar-Oz, B.; Ford-Jones, L.; Koren, G.
QUESTION: One of my patients contracted a primary cytomegalovirus (CMV) infection. What is the recommended waiting time between primary CMV infection and conception, and which tests are valid for determining whether infectivity is over? ANSWER: Although no data on the proper waiting period between primary CMV infection and conception are available, we suggest waiting until CMV-specific immunoglobulin G antibodies are present (at least 6 months). PMID:9839051
Romanelli, Roberta Maia de Castro; Magny, Jean François; Jacquemard, François
The objective of this research was to identify maternal and fetal characteristics as prognostic markers of congenital cytomegalovirus (CMV) infection. This is a descriptive study of 13 cases of congenital CMV infection referred to Institute de Puericulture et Perinatologie de Paris (IPP) from January 2005 to October 2006. Amniotic fluid puncture was performed to research CMV polimerase chain reaction (PCR). Cordocentesis and cord blood samples at delivery were also analyzed to determinate fetal platelets count, GGT, ASAT, ALAT, CMV-DNA and IgM antibody. Variables of symptomatic and asymptomatic infants were then compared. Data were analyzed by SPSS--15.0. Mean gestational age of amniocentesis was 24.6 weeks and there was no difference of mean viral load in amniotic fluid considering infant features. Mean gestational age of cordocentesis was 26.1 weeks. There were no statistical differences of fetal viral load, IgM, platelets, GGT, ASAT and ALAT analyzed at cordocentesis samples, but at delivery, mean values of IgM and ASAT of fetal blood were increased in symptomatic ones (p= 0.03 for both parameters). When considering groups with normal and abnormal parameters, ASAT of cordon samples was also increased in symptomatic infants (p= 0.02). Sensibility, specificity, positive and negative predictive value of fetal ultrasound anomalies to detect symptomatic infants were, respectively, 80%, 62.5%, 57.1% and 83.3%. Thus, identification of markers of CMV symptomatic infants should be aimed. Prenatal diagnosis, identification and follow up of congenital CMV infected infants are important to consider treatment for symptomatic infants, trying to avoid or reducing some possible sequels.
Kadambari, S; Luck, S; Davis, A; Williams, Ej; Berrington, J; Griffiths, Pd; Sharland, M
Screening for a condition should only be undertaken if certain strict criteria are met. Congenital CMV (cCMV) is a leading cause of sensorineuronal hearing loss (SNHL) and meets many of these criteria, but is not currently screened for in the UK. Ganciclovir reduces CMV-induced progressive SNHL if treatment is begun in the first month of life. The Newborn Hearing Screening Programme (NHSP) has been shown to identify SNHL at the earliest possible age. The potential of integrating screening for cCMV into the NHSP is discussed to consolidate the link between screening, early diagnosis and management. The early diagnosis and treatment of cCMV may prevent a small proportion of late SNHL. In the absence of any screening programme, we provide evidence that clinically targeted screening through the NHSP is a potential option in the UK, enhancing the diagnostic pathway and enabling appropriate early treatment to reduce long-term morbidity. ©2013 Foundation Acta Paediatrica. Published by John Wiley & Sons Ltd.
Ross, Danielle S; Dollard, Sheila C; Victor, Marcia; Sumartojo, Esther; Cannon, Michael J
Perhaps no single cause of birth defects and developmental disabilities in the United States currently provides greater opportunity for improved outcomes in more children than congenital cytomegalovirus (CMV). --Cannon and Davis. BMC Public Health 2005;5:70 Each year in the United States, thousands of children and their families are affected by congenital cytomegalovirus (CMV) infection. More children may be affected by congenital CMV than by other, better known childhood conditions, such as Down syndrome, fetal alcohol syndrome, and spina bifida. The Centers for Disease Control and Prevention (CDC) has formed a Workgroup on Congenital CMV, led by the National Center on Birth Defects and Developmental Disabilities and the National Center on Infectious Diseases. This report provides background on congenital CMV infection and describes the goals and activities of the workgroup for reducing the burden of sequelae of congenital CMV infection.
... Infection: A Guide for Patients and Families after Stem Cell Transplant What is cytomegalovirus (CMV)? Cytomegalovirus (CMV), a ... weakened by medicines that you must take after stem cell transplant and by the transplant itself. Your body ...
Kimani, Jane W; Buchman, Craig A; Booker, Jessica K; Huang, Benjamin Y; Castillo, Mauricio; Powell, Cynthia M; Weck, Karen E
To examine the incidence of congenital cytomegalovirus (CMV) infection relative to common genetic etiologies of hearing loss in a pediatric population with sensorineural hearing loss (SNHL), and to characterize intracranial radiological abnormalities in patients with CMV-associated hearing loss. Retrospective study. Academic tertiary care center. A total of 112 pediatric patients with confirmed SNHL. The association of congenital CMV infection status with abnormal brain magnetic resonance imaging (MRI) scans and the frequencies of congenital CMV infection, gap junction β-2 (GJB2) mutations, and the mitochondrial DNA (mtDNA) 1555A>G mutation in children with SNHL. Of 109 patients, 11 (10%) had positive results for CMV DNA; 10 of the 11 had normal GJB2 sequence and had negative test results for the mtDNA 1555A>G mutation. Brain MRI scans for 97 patients demonstrated a higher proportion of abnormalities in patients with positive CMV test results (80%) compared with those with no detectable CMV DNA (33%) (P = .006). GJB2 mutations and the mtDNA 1555A>G mutation were seen in 10 of 88 patients (11%) and 1 of 97 patients (1%) with SNHL, respectively. The presence of brain abnormalities in most patients with congenital CMV infection suggests that neurological damage in otherwise asymptomatic patients may not be limited to SNHL. Congenital CMV infection accounted for a significant proportion of patients with SNHL, with an incidence rate comparable with that of GJB2-related SNHL.
Uematsu, Mitsugu; Haginoya, Kazuhiro; Kikuchi, Atsuo; Hino-Fukuyo, Naomi; Ishii, Keiko; Shiihara, Takashi; Kato, Mitsuhiro; Kamei, Atsushi; Kure, Shigeo
Congenital cytomegalovirus (CMV) infection causes various neurological sequelae. However, most infected infants are asymptomatic at birth, and retrospective diagnosis is difficult beyond the neonatal period. This study aimed to investigate the aspects of neurological sequelae associated with asymptomatic congenital CMV infection. We retrospectively analyzed 182 patients who were suspected of having asymptomatic congenital CMV infection with neurological symptoms in Japan. Congenital CMV infection was diagnosed by quantitative polymerase chain reaction amplification of CMV from dried umbilical cord DNA. Fifty-nine patients (32.4%) who tested positive for CMV were confirmed as having congenital CMV infection. Among 54 congenital CMV patients, major neurological symptoms included intellectual disability (n=51, 94.4%), hearing impairment (n=36, 66.7%) and cerebral palsy (n=21, 38.9%), while microcephaly (n=16, 29.6%) and epilepsy (n=14, 25.9%) were less common. In a brain magnetic resonance imaging (MRI) study, cortical dysplasia was observed in 27 CMV-positive patients (50.0%), and all patients (100%) had cerebral white matter (WM) abnormality. Intracranial calcification was detected by CT in 16 (48.5%) of 33 CMV-positive patients. Cerebral palsy, cortical dysplasia and a WM abnormality with a diffuse pattern were associated with marked intellectual disability. Brain MRI investigations are important for making a diagnosis and formulating an intellectual prognosis. Analysis of umbilical cord tissue represents a unique and useful way to retrospectively diagnose congenital CMV infection. Copyright © 2016 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.
Somsouk, Ma; Hunt, Peter W.
Although invasive cytomegalovirus (CMV) disease is uncommon in the era of antiretroviral therapy (ART), asymptomatic CMV coinfection is nearly ubiquitous in HIV infected individuals. While microbial translocation and gut epithelial barrier dysfunction may promote persistent immune activation in treated HIV infection, potentially contributing to morbidity and mortality, it has been unclear whether CMV replication in individuals with no symptoms of CMV disease might play a role in this process. We hypothesized that persistent CMV replication in the intestinal epithelium of HIV/CMV-coinfected individuals impairs gut epithelial barrier function. Using a combination of state-of-the-art in situ hybridization technology (RNAscope) and immunohistochemistry, we detected CMV DNA and proteins and evidence of intestinal damage in rectosigmoid samples from CMV-positive individuals with both untreated and ART-suppressed HIV infection. Two different model systems, primary human intestinal cells differentiated in vitro to form polarized monolayers and a humanized mouse model of human gut, together demonstrated that intestinal epithelial cells are fully permissive to CMV replication. Independent of HIV, CMV disrupted tight junctions of polarized intestinal cells, significantly reducing transepithelial electrical resistance, a measure of monolayer integrity, and enhancing transepithelial permeability. The effect of CMV infection on the intestinal epithelium is mediated, at least in part, by the CMV-induced proinflammatory cytokine IL-6. Furthermore, letermovir, a novel anti-CMV drug, dampened the effects of CMV on the epithelium. Together, our data strongly suggest that CMV can disrupt epithelial junctions, leading to bacterial translocation and chronic inflammation in the gut and that CMV could serve as a target for therapeutic intervention to prevent or treat gut epithelial barrier dysfunction during HIV infection. PMID:28241080
Wang, Shiwen; Wang, Tongzhan; Zhang, Wenqiang; Liu, Xiaolin; Wang, Xiaofang; Wang, Haiyan; He, Xiaozhou; Zhang, Shunxian; Xu, Shuhui; Yu, Yang; Jia, Xingbing; Wang, Maolin; Xu, Aiqiang; Ma, Wei; Amin, Minal M.; Bialek, Stephanie R.; Dollard, Sheila C.; Wang, Chengbin
Abstract Congenital cytomegalovirus (CMV) infection is the leading viral cause of birth defects and developmental disabilities in developed countries. However, CMV seroprevalence and burden of congenital CMV infection are not well defined in China. Cohort of newborns from 5 birthing hospitals in 2 counties of Shandong Province, China, were enrolled from March 2011 to August 2013. Dried blood spots (DBS) and saliva were collected within 4 days after birth for IgG testing for maternal seroprevalence and real-time PCR testing for congenital CMV infection, respectively. Among 5020 newborns tested for CMV IgG, 4827 were seropositive, resulting in CMV maternal seroprevalence of 96.2% (95% confidence interval [CI]:95.6%–96.7%). Of the 10,933 newborns screened for congenital CMV infection, 75 had CMV detected, resulting in an overall prevalence of 0.7% (95% CI: 0.5%–0.9%), with prevalences of 0.4% (14/3995), 0.6% (66/10,857), and 0.7% (52/7761) for DBS, wet saliva, and dried saliva specimens screened, respectively. Prevalence of congenital CMV infection decreased with increasing maternal age (0.9%, 0.6%, and 0.3% among newborns delivered from mothers aged 16–25, 26–35, and >35 years, respectively; P = 0.03), and was higher among preterm infants than full term infants (1.3% vs 0.6%, P = 0.04), infants with intrauterine growth restriction (IUGR) than those without (1.8% vs 0.7%, P = 0.03), and twins or triplets than singleton pregnancies (2.8% vs 0.7%, P = 0.04). None of the 75 newborns exhibited symptomatic congenital CMV infection, and there was no difference in clinical characteristics and newborn hearing screening results between infants with and without congenital CMV infection at birth. Congenital CMV infection prevalence was lower and the clinical manifestations were milder in this relatively developed region of China compared to populations from other countries with similarly high maternal seroprevalence. Follow-up on children with congenital
Wang, Shiwen; Wang, Tongzhan; Zhang, Wenqiang; Liu, Xiaolin; Wang, Xiaofang; Wang, Haiyan; He, Xiaozhou; Zhang, Shunxian; Xu, Shuhui; Yu, Yang; Jia, Xingbing; Wang, Maolin; Xu, Aiqiang; Ma, Wei; Amin, Minal M; Bialek, Stephanie R; Dollard, Sheila C; Wang, Chengbin
Congenital cytomegalovirus (CMV) infection is the leading viral cause of birth defects and developmental disabilities in developed countries. However, CMV seroprevalence and burden of congenital CMV infection are not well defined in China.Cohort of newborns from 5 birthing hospitals in 2 counties of Shandong Province, China, were enrolled from March 2011 to August 2013. Dried blood spots (DBS) and saliva were collected within 4 days after birth for IgG testing for maternal seroprevalence and real-time PCR testing for congenital CMV infection, respectively.Among 5020 newborns tested for CMV IgG, 4827 were seropositive, resulting in CMV maternal seroprevalence of 96.2% (95% confidence interval [CI]:95.6%-96.7%). Of the 10,933 newborns screened for congenital CMV infection, 75 had CMV detected, resulting in an overall prevalence of 0.7% (95% CI: 0.5%-0.9%), with prevalences of 0.4% (14/3995), 0.6% (66/10,857), and 0.7% (52/7761) for DBS, wet saliva, and dried saliva specimens screened, respectively. Prevalence of congenital CMV infection decreased with increasing maternal age (0.9%, 0.6%, and 0.3% among newborns delivered from mothers aged 16-25, 26-35, and >35 years, respectively; P = 0.03), and was higher among preterm infants than full term infants (1.3% vs 0.6%, P = 0.04), infants with intrauterine growth restriction (IUGR) than those without (1.8% vs 0.7%, P = 0.03), and twins or triplets than singleton pregnancies (2.8% vs 0.7%, P = 0.04). None of the 75 newborns exhibited symptomatic congenital CMV infection, and there was no difference in clinical characteristics and newborn hearing screening results between infants with and without congenital CMV infection at birth.Congenital CMV infection prevalence was lower and the clinical manifestations were milder in this relatively developed region of China compared to populations from other countries with similarly high maternal seroprevalence. Follow-up on children with congenital CMV infection will
Liu, J; Kong, J; Chang, Y J; Chen, H; Chen, Y H; Han, W; Wang, Y; Yan, C H; Wang, J Z; Wang, F R; Chen, Y; Zhang, X H; Xu, L P; Liu, K Y; Huang, X J
Pre-emptive therapy is an effective approach for cytomegalovirus (CMV) control; however, refractory CMV still occurs in a considerable group of recipients after allogeneic haematopoietic stem cell transplantation (allo-HSCT). Until now, hardly any data have been available about the clinical characteristics and risk factors of refractory CMV, or its potential harmful impact on the clinical outcome following allo-HSCT. We studied transplant factors affecting refractory CMV in the 100 days after allo-HSCT, and the impact of refractory CMV on the risk of CMV disease and non-relapse mortality (NRM). We retrospectively studied 488 consecutive patients with CMV infection after allo-HSCT. Patients with refractory CMV in the 100 days after allo-HSCT had a higher incidence of CMV disease and NRM than those without refractory CMV (11.9% vs. 0.8% and 17.1% vs. 8.3%, respectively). Multivariate analysis showed that refractory CMV infection in the 100 days after allo-HSCT was an independent risk factor for CMV disease (hazard ratio (HR) 10.539, 95% CI 2.467-45.015, p 0.001), and that refractory CMV infection within 60-100 days after allo-HSCT was an independent risk factor for NRM (HR 8.435, 95% CI 1.511-47.099, p 0.015). Clinical factors impacting on the risk of refractory CMV infection included receiving transplants from human leukocyte antigen-mismatched family donors (HR 2.012, 95% CI 1.603-2.546, p <0.001) and acute graft-versus-host disease (HR 1.905, 95% CI 1.352-2.686, p <0.001). We conclude that patients with refractory CMV infection during the early stage after allo-HSCT are at high risk for both CMV disease and NRM. Copyright © 2015 European Society of Clinical Microbiology and Infectious Diseases. Published by Elsevier Ltd. All rights reserved.
Schleiss, Mark R.
Human cytomegalovirus (CMV) is responsible for approximately 40,000 congenital infections in the United States each year. Congenital CMV disease frequently produces serious neurodevelopmental disability, as well as vision impairment and sensorineural hearing loss. Development of a CMV vaccine is therefore considered to be a major public health priority. The mechanisms by which CMV injures the fetus are complex and likely include a combination of direct fetal injury induced by pathologic virally-encoded gene products, an inability of the maternal immune response to control infection, and the direct impact of infection on placental function. CMV encodes gene products that function, both at the RNA and the protein level, to interfere with many cellular processes. These include gene products that modify the cell cycle; interfere with apoptosis; induce an inflammatory response; mediate vascular injury; induce site-specific breakage of chromosomes; promote oncogenesis; dysregulate cellular proliferation; and facilitate evasion of host immune responses. This minireview summarizes current concepts regarding these aspects of the molecular virology of CMV and the potential pathogenic impact of viral gene expression on the developing fetus. Areas for potential development of novel therapeutic intervention are suggested for improving the outcome of this disabling congenital infection. PMID:21827434
Li, Lu-Quan; Tan, Jun-Jie; Zhou, Yuan; Yu, Jia-Lin
Congenital cytomegalovirus (CMV) infection and mutation of the gap junction β-2 (GJB2) gene are important causes of sensorineural hearing loss (SNHL). This study aims to determine if congenital CMV infection leads to deafness by inducing GJB2 mutation. GJB2 gene sequencing and auditory brainstem response testing were performed in 159 neonates (63 with and 96 without CMV infection) from August 2008 to August 2011. For neonates with GJB2 mutation, their parents were further screened for GJB2 sequence. The incidence of SNHL was 12.7% in CMV-infected but 0% in uninfected children aged 1-1.5 y (P = 0.000). Similar mutation rates of the GJB2 gene were observed in neonates with or without CMV infection (34.9 vs. 32.3%, respectively, P = 0.734). No significant difference in the mutation rate of GJB2 was found among neonates with CMV infection and SNHL, those with CMV infection and normal hearing, and uninfected newborns with normal hearing (P = 0.438). Mutations 79G>A, 109G>A, 341A>G, and 608T>C were found in neonates with and without CMV infection. All of the above mutations were also found in both or one of the corresponding parents. Congenital CMV infections may cause deafness in neonates, but this might be independent of GJB2 gene mutation.
Sakamoto, Ayako; Moriuchi, Hiroyuki; Matsuzaki, Junko; Motoyama, Kazunori; Moriuchi, Masako
Congenital cytomegalovirus (CMV) infection can cause a variety of neurological deficits of delayed onset in infants who are asymptomatic at birth. The aim of this study was to investigate the prevalence of congenital CMV infection among children with autism spectrum disorder (ASD) in Nagasaki, Japan. Twenty-nine children with ASD who were born in Nagasaki and had no other major neurological deficits were recruited. Two of the patients were excluded due to significant perinatal events. The remaining 27 children were investigated retrospectively for congenital CMV infection by analyzing dried blood spot samples or dried umbilical cords for CMV DNA using real-time PCR. CMV DNA was detected in two (7.4%) of the 27 children. Neither of the patients had perinatal histories suggestive of congenital CMV disease or other neurological deficits, including hearing impairment and epilepsy. The severity of their autistic disorders varied considerably. The rate of congenital CMV infection in this study (two of 27 children with ASD), which was significantly (p=0.004) higher than the incidence of congenital CMV infection in Nagasaki (0.31%, 10/3230 live births), suggests the involvement of congenital CMV infection in a portion of children with ASD, although definite diagnosis was not obtained due to limited clinical data of the study subjects. Copyright © 2014 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.
Cannon, Michael J.; Hyde, Terri B.; Schmid, D. Scott
SUMMARY Congenital cytomegalovirus (CMV) infections are a leading cause of sensorineural hearing loss (SNHL) and neurological impairment. Congenital transmission of CMV can occur with maternal primary infection, reactivation, or reinfection during pregnancy. We reviewed studies of CMV shedding in bodily fluids (defined as CMV detected by culture or CMV DNA detected by polymerase chain reaction). Following diagnosis at birth, children with congenital CMV infection exhibited the highest prevalences of CMV shedding (median = 80%, number of sample population prevalences [N] = 6) and duration of shedding, with a steep decline by age five. Healthy children attending day care shed more frequently (median = 23%, N = 24) than healthy children not attending day care (median = 12%, N = 11). Peak shedding prevalences in children occurred at 1–2 years of age, confirming that young children are the key transmission risk for pregnant women. CMV shedding among children was more prevalent in urine specimens than in oral secretions (median prevalence difference = 11.5%, N = 12). Adults with risk factors such as STD clinic attendance had higher shedding prevalences (median = 22%, N = 20) than adults without risk factors (median = 7%, N = 44). In adults with risk factors, CMV was shed more frequently in urine; in adults without risk factors genital shedding was most common. The prevalence of CMV shedding in nine sample populations of pregnant women increased with advancing gestation. In seven sample populations of children with congenital CMV infection, higher viral load at birth was consistently associated with an elevated risk of SNHL. Higher CMV viral load at birth also consistently correlated with the presence of symptoms of congenital CMV at birth. Published 2011. This article is a US Government work and is in the public domain in the USA. PMID:21674676
Kawada, Jun-ichi; Torii, Yuka; Kawano, Yoshihiko; Suzuki, Michio; Kamiya, Yasuko; Kotani, Tomomi; Kikkawa, Fumitaka; Kimura, Hiroshi; Ito, Yoshinori
Congenital cytomegalovirus (CMV) infection is the most common non-genetic cause of sensorineural hearing loss (SNHL) in children. However, congenital SNHL without other clinical abnormalities is rarely diagnosed as CMV-related in early infancy. The aim of this study was to identify and treat patients with congenital CMV-related SNHL or CMV-related clinical abnormalities other than SNHL. The association between CMV load and SNHL was also evaluated. Newborns who had abnormal hearing screening results or other clinical abnormalities were screened for congenital CMV infection by PCR of saliva or urine specimens, and identified infected patients were treated with valganciclovir (VGCV) for 6 weeks. The CMV load of patients with or without SNHL was compared at regular intervals during as well as after VGCV treatment. Of 127 infants with abnormal hearing screening results, and 31 infants with other clinical abnormalities, CMV infection was identified in 6 and 3 infants, respectively. After VGCV treatment, 1 case had improved hearing but the other 5 SNHL cases had little or no improvement. Among these 9 patients with or without SNHL at 1 year of age, there was no significant difference in CMV blood or urine load at diagnosis, but both were significantly higher in patients with SNHL during VGCV treatment. Selective CMV screening of newborns having an abnormal hearing screening result would be a reasonable strategy for identification of symptomatic congenital CMV infection. Prolonged detection of CMV in blood could be a risk factor for SNHL. Copyright © 2015 Elsevier B.V. All rights reserved.
Gunkel, Julia; van der Knoop, Bloeme J; Nijman, Joppe; de Vries, Linda S; Manten, Gwendolyn T R; Nikkels, Peter G J; Murk, Jean-Luc; de Vries, Johanna I P; Wolfs, Tom F W
Congenital cytomegalovirus (cCMV) infections are the most prevalent intrauterine infections worldwide and are the result of maternal primary or non-primary infections. Early maternal primary infections are thought to carry the highest risk of fetal developmental abnormalities as seen by ultrasound; however, non-primary infections may prove equally detrimental. This case series presents 5 cases with fetal abnormalities detected in the second and third trimester, in which cCMV infection was ruled out due to negative maternal CMV-IgM. This series highlights the possible pitfalls in serology interpretation and fetal diagnosis necessary for appropriate parental counseling. Once fetal abnormalities have been confirmed and cCMV is suspected, maternal CMV serostatus and fetal infection should be determined. Maternal CMV serology may be ambiguous; therefore, caution should be exercised when interpreting the results. © 2017 The Author(s) Published by S. Karger AG, Basel.
Arbelaez, Andres; Restrepo, Feliza; Davila, Jorge; Castillo, Mauricio
Pediatric congenital intracranial infections are a group of different and important entities that constitute a small percentage of all pediatric infections. The causal factors and clinical presentations are different in children compared with adults. They require early recognition because delay diagnosis and initiation of treatment may have catastrophic consequences. Despite improvements in prenatal screening, vaccine safety, and antibiotics, infections of the central nervous system remain an important cause of neurological disabilities worldwide. This article reviews the most common congenital infections and their imaging findings.
Yaghini, Omid; Nasr Azadani, Hossein; Mohammadizadeh, Majid; Arabzadeh, Seyed Ali Mohammad; Adibi, Atosa
Introduction. Need of neonatal screening for Cytomegalovirus (CMV) infection is under debate, in part because of limited data on importance of the disease regarding the prevalence of congenital CMV (cCMV) infection and associated morbidity and mortality. We aimed to evaluate the prevalence and prognosis of cCMV infection in Iran, where there is high maternal seroprevalence of CMV. Methodology. This prospective study was conducted in Isfahan city, Iran, from 2014 to 2016. CMV was investigated in urine specimens by using the real-time polymerase chain reaction (RT-PCR) method. CMV-infected infants were examined for clinical and laboratory findings attributed to CMV infection and followed up for one year. Results. Among 1617 studied neonates, eight (0.49%) were positive for CMV infection. CMV-infected neonates were more likely to be preterm than noninfected ones (25% versus 4.5%, p = 0.0508), and they had lower birth weight. Three out of the eight CMV-infected neonates had transient symptoms at birth. At follow-up, one case had mild hearing loss. Most patients had impaired growth during the one-year follow-up. Conclusions. The primary object of this study was determination of prevalence of cCMV infection in Iran as a developing country, which was at the lower range compared with other such countries. cCMV infection may result in short-term impairment in growth. PMID:28070187
Lanzieri, Tatiana M.; Dollard, Sheila C.; Bialek, Stephanie R.; Grosse, Scott D.
Summary Background Congenital cytomegalovirus (CMV) infection is the leading infectious cause of congenital hearing loss and neurodevelopmental disability in developed countries. Information on congenital CMV infection in developing countries appears to be lacking. Methods We conducted a systematic literature review to identify studies from developing countries with population-based samples of at least 300 infants that used laboratory methods established as reliable for the diagnosis of congenital CMV infection. Results Most studies were excluded due to biased samples or inadequate diagnostic methods; consequently the search identified just 11 studies that were from Africa, Asia, and Latin America. The number of newborns tested ranged from 317 to 12 195. Maternal CMV seroprevalence ranged from 84% to 100%. CMV birth prevalence varied from 0.6% to 6.1%. CMV-associated impairments were not documented in most studies. Conclusions Birth prevalence ranges were higher than for Europe and North America, as expected based on the higher maternal CMV seroprevalence. With very limited data available on sequelae, the disease burden of congenital CMV in developing countries remains largely unknown at this time. PMID:24631522
Lanzieri, Tatiana M; Dollard, Sheila C; Bialek, Stephanie R; Grosse, Scott D
Congenital cytomegalovirus (CMV) infection is the leading infectious cause of congenital hearing loss and neurodevelopmental disability in developed countries. Information on congenital CMV infection in developing countries appears to be lacking. We conducted a systematic literature review to identify studies from developing countries with population-based samples of at least 300 infants that used laboratory methods established as reliable for the diagnosis of congenital CMV infection. Most studies were excluded due to biased samples or inadequate diagnostic methods; consequently the search identified just 11 studies that were from Africa, Asia, and Latin America. The number of newborns tested ranged from 317 to 12 195. Maternal CMV seroprevalence ranged from 84% to 100%. CMV birth prevalence varied from 0.6% to 6.1%. CMV-associated impairments were not documented in most studies. Birth prevalence ranges were higher than for Europe and North America, as expected based on the higher maternal CMV seroprevalence. With very limited data available on sequelae, the disease burden of congenital CMV in developing countries remains largely unknown at this time. Published by Elsevier Ltd.
Mussi-Pinhata, Marisa Márcia; Yamamoto, Aparecida Yulie; do Carmo Rego, Maria Aparecida; Pinto, Patrícia Cristina Gomes; da Motta, Márcia Soares Freitas; Calixto, Cristina
In a prospective study, we evaluated the frequency, correlates, and clinical significance of perinatal or early-postnatal cytomegalovirus (CMV) infection in <34-week-gestation infants (n=95) born to CMV-seropositive mothers. None had congenital CMV infection. Overall, 21 (22.1%; 95% CI=14.2-31.8) infants were found to be infected; 10 excreted CMV at <60 days, and 11 had later excretion. Blood transfusion, birth weight, and vaginal delivery were not associated factors. Receiving natural breast milk within the first 30 days (OR=4.5, P=.02) or for >30 days (OR=7.9, P <.01) was associated with infection. Only one (4.8%) of the infected infants was symptomatic. For <34-week-gestation infants, frequency of perinatal and early-postnatal CMV infection is high. Early or prolonged exposure to breast milk is an associated factor. However, most infections are asymptomatic, indicating that CMV infection in preterm infants within such a population is a serious problem infrequently.
Wilkens, Heinrike; Sester, Martina
Cytomegalovirus (CMV) infection after lung transplantation is associated with increased risk for pneumonitis and bronchiolitis obliterans as well as allograft rejection and opportunistic infections. Ganciclovir is the mainstay of prophylaxis and treatment but CMV infections can be unresponsive. Apart from direct antiviral drugs, CMV immunoglobulin (CMVIG) preparations may be considered but are only licensed for prophylaxis. A CMV-seronegative 42-year-old man with cystic fibrosis received a lung from a CMV-seropositive donor. Intravenous ganciclovir prophylaxis was delayed until day 12 due to acute postoperative renal failure and was accompanied by five doses of CMVIG (10 g). By day 16, CMV-DNA was detectable and rising; CMV-specific T-cells were undetectable. Switch from ganciclovir to foscarnet prompted a transient decrease in CMV viral load, but after increasing again to reach 3600 copies/mL foscarnet was changed to intravenous cidofovir and CMVIG was restarted. CMV load continued to fluctuate and declined slowly, whereas CMV-specific T-cells were detected five months later and increased thereafter. At last follow-up, the patient was in very good clinical condition with no evidence of bronchiolitis obliterans. No side effects of this treatment were observed. In this hard-to-treat case, the combination of cidofovir with off-label use of CMVIG contributed to a successful outcome.
Cortés, A; Peña, E; Vega, R; Reyes, G; Bautista, E
Alveolar hemorrhage may be a complication of diseases with local and systemic manifestations. Both share the same pathophysiological concept: damage to the alveolar microcirculation. It is a clinical entity that generates a diagnostic challenge for the physician. Early recognition favors aggressive treatment, which can improve the outcome. Despite the technological advances in its diagnosis and treatment, it is still a condition having high morbidity and mortality. We present the case of a 42-year old woman diagnosed of massive alveolar hemorrhage induced by cytomegalovirus (CMV) and HIV infection. Its presentation is atypical because most reported cases have occurred as a pneumonic process, episodes of massive hemorrhage being uncommon. The diagnosis was documented by bronchoscopy with bronchoalveolar lavage and etiological diagnosis with molecular techniques using reverse transcription polymerase chain reaction. Copyright © 2009 Elsevier España, S.L. y SEMICYUC. All rights reserved.
Puhakka, Laura; Renko, Marjo; Helminen, Merja; Peltola, Ville; Heiskanen-Kosma, Tarja; Lappalainen, Maija; Surcel, Heljä-Marja; Lönnqvist, Tuula; Saxen, Harri
Both primary and non-primary maternal cytomegalovirus (CMV) infection during pregnancy can lead to vertical transmission. We evaluated the proportion of maternal primary/non-primary infections among 26 babies with symptomatic congenital CMV infection born in Finland from 2000 to 2012. We executed a database search on hospital records from all five university hospitals in Finland to identify infants with congenital CMV infection. The preserved maternal serum samples drawn at the end of the first trimester were analysed for CMV antibodies. Maternal infection was classified to be non-primary, if there was high avidity CMV immunoglobulin G (IgG) in the early pregnancy samples. Infection was considered primary in the case of either low avidity IgG (primary infection in the first trimester or near conception) or absent CMV IgG at the end of the first trimester (primary infection in the second or third trimester). The majority of the symptomatic congenital CMV infections (54%) were due to maternal non-primary infection, 27% due to maternal primary infection in the first trimester or near conception, and 19% during the second or third trimester. Long-term sequelae occurred in 59% of patients: in 6/7 after primary infection in the first trimester, in 0/5 after primary infection in the second or third trimester, and in 9/14 after non-primary infection. In this register-based cohort, non-primary infections caused the majority of symptomatic congenital CMV infections, and resulted in significant morbidity.
Dioverti, M Veronica; Lahr, Brian D; Germer, Jeffrey J; Yao, Joseph D; Gartner, Michelle L; Razonable, Raymund R
Quantification of cytomegalovirus (CMV) deoxyribonucleic acid (DNA) has important diagnostic, prognostic, and therapeutic implications in the management of transplant recipients. We aimed to assess a viral load in plasma and whole blood that distinguishes CMV disease from asymptomatic infection in a cohort of solid organ and hematopoietic stem cell transplantation. We prospectively measured and compared CMV viral load in paired plasma and whole blood samples collected from transplant recipients with CMV infection and disease. Cytomegalovirus viral loads were determined by a commercially available US Food and Drug Administration-approved quantitative assay (COBAS AmpliPrep/COBAS TaqMan CMV Test [CAP/CTM CMV]) calibrated to the first World Health Organization International Standard for CMV DNA quantification. Moderate agreement of CMV viral load was observed between plasma and whole blood, with 31% of samples having discordant findings, particularly among samples with low DNA levels. Among the subset of samples where both paired samples had quantifiable levels, we observed a systematic bias that reflected higher viral load in whole blood compared with plasma. Based on receiver operating curve analysis, an initial plasma CMV viral load threshold of 1700 IU/mL in solid organ transplant recipients (sensitivity 80%, specificity 74%) and 1350 IU/mL in allogeneic hematopoietic stem cell transplant recipients (sensitivity 87%, specificity 87%) distinguished CMV disease and asymptomatic infection. This study identifies standardized viral load thresholds that distinguish CMV disease from asymptomatic infection using CAP/CTM CMV assay. We propose these thresholds as potential triggers to be evaluated in prospective studies of preemptive therapy. Plasma was better than whole blood for measuring viral load using the CAP/CTM CMV assay.
Dioverti, M Veronica; Lahr, Brian D; Germer, Jeffrey J; Yao, Joseph D; Gartner, Michelle L
Abstract Background Quantification of cytomegalovirus (CMV) deoxyribonucleic acid (DNA) has important diagnostic, prognostic, and therapeutic implications in the management of transplant recipients. We aimed to assess a viral load in plasma and whole blood that distinguishes CMV disease from asymptomatic infection in a cohort of solid organ and hematopoietic stem cell transplantation. Methods We prospectively measured and compared CMV viral load in paired plasma and whole blood samples collected from transplant recipients with CMV infection and disease. Cytomegalovirus viral loads were determined by a commercially available US Food and Drug Administration-approved quantitative assay (COBAS AmpliPrep/COBAS TaqMan CMV Test [CAP/CTM CMV]) calibrated to the first World Health Organization International Standard for CMV DNA quantification. Results Moderate agreement of CMV viral load was observed between plasma and whole blood, with 31% of samples having discordant findings, particularly among samples with low DNA levels. Among the subset of samples where both paired samples had quantifiable levels, we observed a systematic bias that reflected higher viral load in whole blood compared with plasma. Based on receiver operating curve analysis, an initial plasma CMV viral load threshold of 1700 IU/mL in solid organ transplant recipients (sensitivity 80%, specificity 74%) and 1350 IU/mL in allogeneic hematopoietic stem cell transplant recipients (sensitivity 87%, specificity 87%) distinguished CMV disease and asymptomatic infection. Conclusions This study identifies standardized viral load thresholds that distinguish CMV disease from asymptomatic infection using CAP/CTM CMV assay. We propose these thresholds as potential triggers to be evaluated in prospective studies of preemptive therapy. Plasma was better than whole blood for measuring viral load using the CAP/CTM CMV assay. PMID:28852681
Background Congenital cytomegalovirus (CMV) infection is a leading cause of sensorineural hearing loss (SNHL). The mechanisms of pathogenesis of CMV-related SNHL are still unclear. The aim is to study congenital CMV-related damage in the fetal inner ear, in order to better understand the underlying pathophysiology behind CMV-SNHL. Results We studied inner ears and brains of 20 human fetuses, all at 21 week gestational age, with a high viral load in the amniotic fluid, with and without ultrasound (US) brain abnormalities. We evaluated histological brain damage, inner ear infection, local inflammatory response and tissue viral load. Immunohistochemistry revealed that CMV was positive in 14/20 brains (70%) and in the inner ears of 9/20 fetuses (45%). In the cases with inner ear infection, the marginal cell layer of the stria vascularis was always infected, followed by infection in the Reissner’s membrane. The highest tissue viral load was observed in the inner ear with infected Organ of Corti. Vestibular labyrinth showed CMV infection of sensory cells in the utricle and in the crista ampullaris. US cerebral anomalies were detected in 6 cases, and in all those cases, the inner ear was always involved. In the other 14 cases with normal brain scan, histological brain damage was present in 8 fetuses and 3 of them presented inner ear infection. Conclusions CMV-infection of the marginal cell layer of the stria vascularis may alter potassium and ion circulation, dissipating the endocochlear potential with consequent SNHL. Although abnormal cerebral US is highly predictive of brain and inner ear damage, normal US findings cannot exclude them either. PMID:24252374
Sahiner, Fatih; Cekmez, Ferhat; Cetinkaya, Merih; Kaya, Guven; Kalayci, Tugce; Gunes, Omer; Sener, Kenan; Yapar, Mehmet; Tunc, Turan; Ecemis, Tolga; Cekmez, Yasemin; Kubar, Ayhan
Cytomegalovirus (CMV) infections are the leading cause of infectious hearing loss and central nervous system disease among children worldwide. In this study, we aimed to determine the birth prevalence of congenital CMV infection in live-born infants in Turkey. In total, 944 consecutive live-born infants born from 926 pregnant women were included in this study. CMV-DNA was investigated in saliva samples of all newborns within the first 3 days after birth using TaqMan-based real-time PCR. The birth prevalence of congenital CMV infection in live-born infants was 1.91% (18/944), and all congenitally infected infants were asymptomatic at birth. The prevalence of congenital CMV infection was 16.7% (3/18) in twin pregnancies and 1.32% (12/908) in single pregnancies (p = 0.002). Genotyping analysis showed glycoprotein B-1 (gB1) to be the most frequently detected genotype at 83.3%. The study results suggest that the majority of congenital CMV infection in Turkey occurs following nonprimary maternal infection. We believe that congenital CMV infection and its long-term effects have been underestimated in our country, as infected infants are usually asymptomatic at birth.
Dar, Lalit; Namdeo, Divya; Kumar, Pankaj; Thakar, Alok; Kant, Shashi; Rai, Sanjay; Singh, Pawan K; Kabra, Madhulika; Fowler, Karen B; Boppana, Suresh B
Congenital cytomegalovirus infection (cCMV) is a leading nongenetic cause of permanent congenital or early-onset hearing loss (PCEHL). Although cCMV rates are high despite near-universal seroimmunity, the contribution of cCMV to PCEHL in the developing world is unclear. Neonates at a rural North Indian hospital were screened for cCMV by saliva polymerase chain reaction and hearing by distortion-product otoacoustic emission testing. Cytomegalovirus (CMV)-positive infants and those not passing newborn hearing screening (NHS) were evaluated by auditory brainstem response to confirm PCEHL. Infants with cCMV and those with PCEHL were tested for mutations within the GJB2 gene. Of the 1720 infants screened, 40 (2.3%) did not pass NHS and 20 (1.2%) were CMV positive. Auditory brainstem evoked response testing confirmed unilateral or bilateral PCEHL in 11 (0.64%) children who either did not pass NHS or CMV positive. PCEHL was 20-fold higher in neonates with cCMV (2/20, 10%) than those without (9/1700, 0.5%; P < 0.01). None of 11 infants with PCEHL had connexin 26 mutations. PCEHL incidence is high in India, with cCMV contributing significantly despite near-universal seroimmunity. Our findings also demonstrate the feasibility and the utility of simultaneous newborn screening for both cCMV and hearing loss in a resource-limited setting.
Nabi, Shahzaib; Kahlon, Pushpinderdeep; Goggins, Mariella; Patel, Anita
A 73-year-old woman with a history of deceased donor kidney transplantation and a recent cytomegalovirus (CMV) infection, presented to the emergency department with an altered mental status. She was found to have varicella zoster virus VZV encephalitis based on cerebrospinal fluid analysis and was treated successfully with intravenous valaciclovir with an improvement in her mental status. A review of the literature shows very few case reports on patients with kidney transplantation developing VZV encephalitis. A few case reports and studies report an association between CMV and VZV infection. In these patients, CMV infection can cause a marked decline in immunity and this predisposes them to other infections. Such associations have also been reported between other types of virus infections from the Herpesviridae family. The risk of disseminated VZV infection increases in the presence of CMV infection. 2014 BMJ Publishing Group Ltd.
Collinet, P; Subtil, D; Houfflin-Debarge, V; Kacet, N; Dewilde, A; Puech, F
Cytomegalovirus (CMV) screening during pregnancy has been widely discussed for several years, but still no consensus has been agreed. With a number of live births of 750,000 per year in France, we would expect 7500 infected infants at birth per year (rate of congenital infection of 1%). Among infected infants at birth, the number of severely infected foetuses would be approximately 75, the number of infants with severe sequelae would be 480, 675 approximately would present with hearing loss and the number of asymptomatic infants would be 6270. Five different preventive methods for congenital CMV infection are possible: (1) Routine CMV screening at the beginning of pregnancy for primary prevention. (2) Secondary prevention by antenatal diagnosis of congenital CMV infection complications. (3) Tertiary prevention by serological testing during pregnancy. (4) Tertiary prevention by serological screening at birth. (5) Tertiary prevention: Hearing loss screening at birth. The aims of this review are to define the advantages and disadvantages of these different methods of CMV screening during pregnancy and to determine if the current available information would make systematic testing acceptable.
Colitis - cytomegalovirus; Gastroenteritis - cytomegalovirus; Gastrointestinal CMV disease ... or after bone marrow or organ transplant Ulcerative colitis or Crohn disease Rarely, serious CMV infection involving ...
Meer, Shabnum; Coleman, Hedley; Altini, Mario; Alexander, Terence
Herpes zoster is a common viral infection, the oral soft tissue manifestations of which are widely known and recognized. Reports of spontaneous tooth exfoliation and jaw osteonecrosis following herpes zoster infection in the distribution of the trigeminal nerve are extremely infrequent and sporadic, with only 39 cases being reported in the literature. We report an additional case of mandibular osteomyelitis and spontaneous tooth exfoliation following herpes zoster infection, which occurred in the left mandible of a 70-year-old diabetic man; however, our case also showed CMV co-infection. The role of CMV in the pathogenesis of the osteonecrosis remains uncertain. Awareness of the possibility of CMV co-infection in various oral diseases including oral ulcers, Kaposi's sarcoma, and herpes zoster infections especially in immunocompromised patients is important, since spread of the CMV can easily occur to other sites with potentially fatal consequences. Early diagnosis can lead to effective treatment and prevention of complications.
Ogawa, Hiroshi; Suzutani, Tatsuo; Baba, Yohko; Koyano, Shin; Nozawa, Naoki; Ishibashi, Kei; Fujieda, Kenji; Inoue, Naoki; Omori, Koichi
Sensorineural hearing loss (SNHL) is the most common congenital disease. Longitudinal studies of infants with congenital cytomegalovirus (CMV) infection have demonstrated an association between CMV and SNHL. However, because of the lack of suitable neonatally collected specimens, the proportion of CMV-associated SNHL has not been defined, nor has the relationship between CMV and the major genetic causes of SNHL, such as mutations in the GJB2 gene. Sixty-seven children with severe SNHL were analyzed for CMV and human herpesvirus 6 (HHV-6) infections and for GJB2 mutations. DNA specimens were prepared from dried umbilical cords, which are available for everyone born in Japan. Four children with typical symptomatic infection at birth served as positive control subjects. Congenital CMV infection and GJB2 mutations were identified in 15% and 24% of the patients, respectively. HHV-6 was not detected. All children with CMV-associated cases developed SNHL before they were 2 years old. Most children with CMV-associated SNHL had no obvious clinical abnormality at birth, and their viral loads were lower than those of symptomatic children. Congenital CMV infection is an important cause of severe SNHL, and it has an incidence comparable to that of GJB2-associated SNHL.
Neuenhahn, M; Albrecht, J; Odendahl, M; Schlott, F; Dössinger, G; Schiemann, M; Lakshmipathi, S; Martin, K; Bunjes, D; Harsdorf, S; Weissinger, E M; Menzel, H; Verbeek, M; Uharek, L; Kröger, N; Wagner, E; Kobbe, G; Schroeder, T; Schmitt, M; Held, G; Herr, W; Germeroth, L; Bonig, H; Tonn, T; Einsele, H; Busch, D H; Grigoleit, G U
Cytomegalovirus (CMV) infection is a common, potentially life-threatening complication following allogeneic hematopoietic stem cell transplantation (allo-HSCT). We assessed prospectively the safety and efficacy of stem cell-donor- or third-party-donor-derived CMV-specific T cells for the treatment of persistent CMV infections after allo-HSCT in a phase I/IIa trial. Allo-HSCT patients with drug-refractory CMV infection and lacking virus-specific T cells were treated with a single dose of ex vivo major histocompatibility complex-Streptamer-isolated CMV epitope-specific donor T cells. Forty-four allo-HSCT patients receiving a T-cell-replete (D(+) repl; n=28) or T-cell-depleted (D(+) depl; n=16) graft from a CMV-seropositive donor were screened for CMV-specific T-cell immunity. Eight D(+) depl recipients received adoptive T-cell therapy from their stem cell donor. CMV epitope-specific T cells were well supported and became detectable in all treated patients. Complete and partial virological response rates were 62.5% and 25%, respectively. Owing to longsome third-party donor (TPD) identification, only 8 of the 57 CMV patients transplanted from CMV-seronegative donors (D(-)) received antigen-specific T cells from partially human leukocyte antigen (HLA)-matched TPDs. In all but one, TPD-derived CMV-specific T cells remained undetectable. In summary, adoptive transfer correlated with functional virus-specific T-cell reconstitution in D(+) depl patients. Suboptimal HLA match may counteract expansion of TPD-derived virus-specific T cells in D(-) patients.Leukemia advance online publication, 17 February 2017; doi:10.1038/leu.2017.16.
Naing, Zin W; Scott, Gillian M; Shand, Antonia; Hamilton, Stuart T; van Zuylen, Wendy J; Basha, James; Hall, Beverly; Craig, Maria E; Rawlinson, William D
Human cytomegalovirus (CMV) is under-recognised, despite being the leading infectious cause of congenital malformation, affecting ~0.3% of Australian live births. Approximately 11% of infants born with congenital CMV infection are symptomatic, resulting in clinical manifestations, including jaundice, hepatosplenomegaly, petechiae, microcephaly, intrauterine growth restriction and death. Congenital CMV infection may cause severe long-term sequelae, including progressive sensorineural hearing loss and developmental delay in 40-58% of symptomatic neonates, and ~14% of initially asymptomatic infected neonates. Up to 50% of maternal CMV infections have nonspecific clinical manifestations, and most remain undetected unless specific serological testing is undertaken. The combination of serology tests for CMV-specific IgM, IgG and IgG avidity provide improved distinction between primary and secondary maternal infections. In pregnancies with confirmed primary maternal CMV infection, amniocentesis with CMV-PCR performed on amniotic fluid, undertaken after 21-22 weeks gestation, may determine whether maternofetal virus transmission has occurred. Ultrasound and, to a lesser extent, magnetic resonance imaging are valuable tools to assess fetal structural and growth abnormalities, although the absence of fetal abnormalities does not exclude fetal damage. Diagnosis of congenital CMV infection at birth or in the first 3 weeks of an infant's life is crucial, as this should prompt interventions for prevention of delayed-onset hearing loss and neurodevelopmental delay in affected infants. Prevention strategies should also target mothers because increased awareness and hygiene measures may reduce maternal infection. Recognition of the importance of CMV in pregnancy and in neonates is increasingly needed, particularly as therapeutic and preventive interventions expand for this serious problem.
Li, J M; Zhang, H F; Zhang, X Q; Huang, G L; Huang, H Z; Yu, W W
We aimed to compare the diagnostic value of various detection methods for cytomegalovirus (CMV) infection, to investigate the genetic mechanism associated with CMV infection in pregnant women, and to analyze the risk of sequelae development in fetuses with CMV infection. A total of 300 participants who had the same immunosuppressive regimen and received preemptive therapy for CMV infection were prospectively enrolled in this study; they included 289 vaccine trial participants. The gB-absorbed CMV IgG assay was performed for each vaccine trial participant. The healthy women were divided into 2 groups, and amniotic fluids were collected from them at 15-18 weeks of gestation to test for CMV seropositivity before conception by using IgM specific antibodies, CMV-DNA, and IgG analysis. In 104 cases, cord blood sera and urine specimens were also collected from the infants and examined. The sensitivity and specificity of immediate-early messenger RNA and pp67 (late) messenger RNA detection by the nucleic acid sequence-based amplification technique was comparable to those of virus isolation and PCR. Furthermore, an association between single nucleotide polymorphisms in the TLR-2 gene and congenital CMV infection was observed and confirmed. Moreover, CMV infection during early pregnancy has been shown to have a much more severe effect on the pregnancy outcome compared to infection during later stages of pregnancy.
Goderis, Julie; Keymeulen, Annelies; Smets, Koenraad; Van Hoecke, Helen; De Leenheer, Els; Boudewyns, An; Desloovere, Christian; Kuhweide, Rudolf; Muylle, Marie; Royackers, Liesbeth; Schatteman, Isabelle; Dhooge, Ingeborg
To evaluate hearing outcome, to characterize the nature of symptomatic and asymptomatic congenital cytomegalovirus (cCMV) infection and associated hearing loss, and to compare results with data from previous studies. A prospective multicenter registry was set up in 2007. Six centers participated in the development of a standardized protocol for diagnosis, treatment, and follow-up. Data were gathered in an online registry. Children (n = 379) with a documented cCMV infection and at least 2 separate audiologic evaluations were included. Audiometric results from a multicenter cohort study of children with cCMV infection with longitudinal observation were examined. Results from 123 children with a symptomatic and 256 children with an asymptomatic cCMV infection were analyzed. In the group with symptomatic cCMV, 63% had hearing loss, compared with 8% in the group with asymptomatic cCMV. Delayed-onset hearing loss occurred in 10.6% of symptomatic cCMV and in 7.8% of asymptomatic cCMV. In the group with symptomatic cCMV, 29.3% of children used some kind of hearing amplification; 1.6% in the group with asymptomatic cCMV used hearing amplification. Symptomatic and asymptomatic cCMV infections are a major cause of hearing loss in childhood. Reliable estimates of the long-term outcome of cCMV infection are mandatory to increase vigilance, especially among pregnant women and to draw attention to preventive measures, vaccine development, and prenatal and postnatal therapy. Universal screening of newborns for cCMV infection should be initiated and combined with longitudinal audiometric follow-up. Copyright © 2016 Elsevier Inc. All rights reserved.
Teär Fahnehjelm, Kristina; Olsson, Monica; Fahnehjelm, Cecilia; Lewensohn-Fuchs, Ilona; Karltorp, Eva
The aim of this study was to compare visual function and ocular characteristics in children with cochlear implants, due to severe hearing impairment caused by the congenital cytomegalovirus (CMV) infection, with control children fitted with cochlear implants due to connexin 26 mutations (Cx26), a genetic cause of hearing impairment. We carried out ophthalmological assessments, including visual acuity, ocular alignment, Ocular Motor Score, biomicroscopy and fundus photography, on 26 children with congenital CMV (median age 8.3 years, range 1.4-16.7) and 13 Cx26 controls (median age 5.6 years, range 1.7-12.5). We found unilateral chorioretinal macular scars that reduced best-corrected visual acuity ≤0.3 in five (19%) of the children with congenital CMV, but in none of the children with Cx26 (p = 0.15). Ocular motility problems were more common among children with congenital CMV, but the difference was not significant (p = 0.20). The vestibulo-ocular reflex was more frequently pathological in children with congenital CMV (p = 0.011). Ocular complications with central chorioretinal scars and ocular motility disturbances were common in children treated with cochlear implants due to severe hearing impairment caused by the congenital CMV infection. Ophthalmological assessments are advisable in such children for early identification, intervention and follow-up. ©2015 Foundation Acta Paediatrica. Published by John Wiley & Sons Ltd.
Mena-Romo, Juan Damián; Pérez Romero, Pilar; Martín-Gandul, Cecilia; Gentil, Miguel Ángel; Suárez-Artacho, Gonzalo; Lage, Ernesto; Sánchez, Magdalena; Cordero, Elisa
To characterize whether the CMV-specific cellular immune response can be used as a predictor of the control of CMV infection and disease and determine thresholds in solid organ transplant (SOT) recipients seropositive for CMV (R+). The CMV-specific T-cell response was characterized using intracellular cytokine staining and the evolution of clinical and virological parameters were recorded during the first year after transplantation. Besides having positive CMV serology, only 28.4% patients had positive immunity (CD8(+)CD69(+)IFN-γ(+) ≥0.25%) at 2 weeks after transplantation. These patients had less indication of preemptive treatment (p = 0.025) and developed less high grade (≥2000 IU/ml) CMV replication episodes (p = 0.006) than patients with no immunity. Of the 49 patients with a pretransplant sample, only 22.4% had positive immunity, and had a detectable immune response early after transplantation (median of 3.7 weeks). However, only 50% of patients with negative pretransplant immunity acquired a positive immune response and it was significantly later, at a median of 11 weeks (p < 0.001). Patients that developed CMV disease had no CMV-specific immunity. Having CMV-specific CD8(+)IFN-γ(+) cells ≥0.25% before transplant; 0.15% at two weeks or 0.25% at four weeks after transplantation, identifies patients that may spontaneously control CMV infection and may require less monitoring. Copyright © 2017 The British Infection Association. Published by Elsevier Ltd. All rights reserved.
Swanson, Elizabeth C.; Schleiss, Mark R.
SYNOPSIS Cytomegalovirus (CMV) is the most common congenital viral infection in the developed world, with an overall birth prevalence of approximately 0.6%. Approximately 10% of congenitally infected infants have signs and symptoms of disease at birth, and these symptomatic infants have a high risk for demonstration of subsequent neurologic sequelae, including sensorineural hearing loss (SNHL), mental retardation, microcephaly, development delay, seizure disorders, and cerebral palsy. Antiviral therapy of children with symptomatic central nervous system (CNS) congenital CMV infection is effective at reducing the risk of long-term disabilities and should be offered to families with affected newborns. An effective pre-conceptual vaccine against CMV could, by preventing congenital infection, protect against long-term neurological sequelae and other disabilities. A variety of active and passive immunization strategies are in clinical trials and are likely to be licensed in the next few years. Until a vaccine is licensed, preventive strategies aimed at reducing transmission should be emphasized and public awareness increased, particularly among women of child-bearing age. PMID:23481104
Freeman, Michael L; Lederman, Michael M; Gianella, Sara
In the current era of combination antiretroviral therapy (ART), human immunodeficiency virus (HIV)-infected individuals are living longer and healthier lives. Nevertheless, HIV-infected persons are at greater risk for age-related disorders, which have been linked to residual immune dysfunction and inflammation. HIV-infected individuals are almost universally co-infected with cytomegalovirus (CMV) and both viruses are associated with inflammation-related morbidities. Therefore, a detailed investigation of the relationship between CMV and aging-related morbidities emerging during chronic HIV infection is warranted. Here, we review the literature on how CMV co-infection affects HIV infection and host immunity and we discuss the gaps in our knowledge that need elucidation.
Cheeran, Maxim C.-J.; Lokensgard, James R.; Schleiss, Mark R.
Congenital cytomegalovirus (CMV) infection is the leading infectious cause of mental retardation and hearing loss in the developed world. In recent years, there has been an improved understanding of the epidemiology, pathogenesis, and long-term disabilities associated with CMV infection. In this review, current concepts regarding the pathogenesis of neurological injury caused by CMV infections acquired by the developing fetus are summarized. The pathogenesis of CMV-induced disabilities is considered in the context of the epidemiology of CMV infection in pregnant women and newborn infants, and the clinical manifestations of brain injury are reviewed. The prospects for intervention, including antiviral therapies and vaccines, are summarized. Priorities for future research are suggested to improve the understanding of this common and disabling illness of infancy. PMID:19136436
Matsui, Takamichi; Ogawa, Hiroshi; Yamada, Naoko; Baba, Yoko; Suzuki, Yukie; Nomoto, Mika; Suzutani, Tatsuo; Inoue, Naoki; Omori, Koichi
Outcomes following cochlear implantation in children with congenital cytomegalovirus (CMV) infection were almost equivalent to those of children with GJB2 mutation-related sensorineural hearing loss (SNHL). Although our patients with developmental disorder showed poor auditory performance and speech and language skills after cochlear implantation, SNHL with developmental disorder should not be a contraindication for the procedure. Congenital CMV infection accounts for approximately 20% of all cases of neonatal hearing loss, while the GJB2 mutation accounts for 30-50% of all cases of profound nonsyndromic hearing loss. Here, outcomes for auditory behavior and speech and language skills were compared in children with congenital CMV infection or GJB2 mutation who received cochlear implantation for profound SNHL. Five children with asymptomatic congenital CMV infection and seven children with GJB2 mutation-related SNHL, with and without developmental disorder, underwent cochlear implantation. Hearing level and speech and language development were evaluated post-implantation using IT-MAIS, MUSS, and S-S method. The IT-MAIS and MUSS scores of the congenital CMV infection group and the GJB2 mutation group continued to increase for 4 years after implantation. The S-S method score in both groups gradually increased, although the scores for children with mental retardation were low.
Karltorp, Eva; Hellström, Sten; Lewensohn-Fuchs, Ilona; Carlsson-Hansén, Eva; Carlsson, Per-Inge; Engman, Mona-Lisa
The aim of this study was to investigate the role of congenital cytomegalovirus (CMV) infection as a cause of various types of sensorineural hearing loss (SNHL) in a group of nonsyndromic children with otherwise unknown aetiology of hearing loss. Furthermore, the occurrence of combined congenital CMV infection and connexin 26 (Cx26) mutations was investigated. The dried blood spot (DBS) cards of 45 children with various degrees of hearing deficits and 46 children with severe/profound hearing loss were tested for CMV DNA with polymerase chain reaction (PCR) technique. The DBS cards of the 46 children with severe/profound hearing loss were also analysed for Cx26 mutations. Of the 45 children with various degrees of hearing loss, nine were positive for CMV DNA (20%). The nine children represented severe/profound, mild and unilateral hearing loss. From the 46 children with severe/profound hearing loss, nine of 46 (20%) were positive for CMV DNA. In addition, three of the CMV DNA-positive children were carriers of mutations of Cx26. Congenital CMV infection is a high risk factor in hearing impairment among children. © 2012 The Author(s)/Acta Paediatrica © 2012 Foundation Acta Paediatrica.
Kasztelewicz, B; Czech-Kowalska, J; Lipka, B; Milewska-Bobula, B; Borszewska-Kornacka, M K; Romańska, J; Dzierżanowska-Fangrat, K
Cytomegalovirus (CMV) is the most common viral agent of congenital infections and a leading nongenetic cause of sensorineural hearing loss (SNHL). The host immunologic factors that render a developing foetus prone to intrauterine CMV infection and development of hearing loss are unknown. The aim of this study was to assess the potential associations between the polymorphisms within cytokine and cytokine receptors genes, and the risk of congenital CMV infection, and the hearing outcome. A panel of 11 candidate single nucleotide polymorphisms (SNPs): TNF rs1799964, TNF rs1800629, TNFRSF1A rs4149570, IL1B rs16944, IL1B rs1143634, IL10 rs1800896, IL10RA rs4252279, IL12B rs3212227, CCL2 rs1024611, CCL2 rs13900, CCR5 rs333 was genotyped in 470 infants (72 with confirmed intrauterine CMV infection and 398 uninfected controls), and related to congenital CMV infection, and the outcome. In multivariate analysis, the IL1B rs16944 TT and TNF rs1799964 TC genotypes were significantly associated with intrauterine CMV infection (aOR = 2.32; 95% CI, 1.11-4.89; p = 0.032, and aOR = 2.17, 95% CI, 1.25-3.77; p = 0.007, respectively). Twenty-two out of 72 congenitally infected newborns had confirmed SNHL. Carriers of CT or TT genotype of CCL2 rs13900 had increased risk of hearing loss at birth and at 6 months of age (aOR = 3.59; p = 0.028 and aOR = 4.10; p = 0.039, respectively). This is the first study to report an association between SNPs in IL1B, TNF, and CCL2, and susceptibility to congenital CMV infection (IL1B and TNF) and SNHL (CCL2).
... Close contact includes activities like changing diapers and kissing. What is congenital cytomegalovirus (congenital CMV)? Pregnant women ... or saliva. Try to avoid mouth-to-mouth kissing with children in day-care. Do not share ...
Lautenschlager, Irmeli; Loginov, Raisa; Mäkisalo, Heikki; Höckerstedt, Krister
Cytomegalovirus (CMV) can cause severe infections in transplanted patients. To prevent CMV infection, most liver centers use prophylaxis for CMV-seronegative recipients receiving an organ from a seropositive donor (D+/R-). Valganciclovir is mostly given for 3-6 months after transplantation. However, the patients may develop primary CMV infection after the cessation of prophylaxis and late-onset CMV disease may occur. A prospective long-term follow-up of CMV (D+/R-) adult liver transplant recipients after 3 months valganciclovir prophylaxis was investigated. Of 154 consecutive adult liver recipients transplanted from 2006 to 2009, 20 (13%) were CMV D+/R- and received antiviral prophylaxis up to 3 months after transplantation. After excluding the recipients with incomplete prophylaxis or monitoring, 13 (D+/R-) patients with follow-up of >4 years after the 3-month period of valganciclovir prophylaxis were included in the study.The patients were monitored for CMV by real-time quantitative plasma PCR. No break-through CMV infections were recorded during the prophylaxis period. After cessation of valganciclovir prophylaxis 12/13 (90%) patients demonstrated CMV-DNAemia following a post transplantation mean interval of 165 days (range 95-320). Ten patients with high viral loads (peak viral load mean 81,510, range 1900-648950cps/ml) were successfully treated, 6 with valganciclovir, and 4 with ganciclovir. Two patients with low level CMV-DNAemia (<1000cps/ml) were asymptomatic and not treated. No intragraft infection was seen, but one patient developed gastrointestinal CMV infection verified from ileum biopsy. During long-term follow-up, 3 patients demonstrated low-level viral replication, but no symptomatic recurrences occurred. One patient died of bacterial sepsis, but no patient or graft was lost due to CMV. Primary CMV infections after cessation of prophylaxis were common, but were successfully treated with valganciclovir or ganciclovir. Copyright © 2015 Elsevier B
Pati, Sunil; Pinninti, Swetha; Novak, Zdenek; Chowdhury, Nazma; Patro, Raj; Fowler, Karen; Ross, Shannon; Boppana, Suresh
Background Congenital cytomegalovirus (cCMV) is a common congenital infection and a leading non-genetic cause of sensorineural hearing loss (SNHL). CMV exhibits extensive genetic variability and infection with multiple CMV strains (mixed infection) was shown to be common in cCMV. The role of mixed infections in disease and outcome remains to be defined. Methods Genotyping of envelope glycoproteins, UL55 (gB), UL73 (gN) and UL75 (gH) was performed on saliva specimens from 79 infants from the ongoing CMV and Hearing Multicenter Screening Study (CHIMES) and on blood and urine specimens from 52 infants who participated in natural history studies at the University of Alabama at Birmingham. Genotyping of UL144 and US28 was also performed in the CHIMES cohort. The association of individual genotypes and mixed infection with clinical findings at birth and SNHL was examined. Results Thirty seven of 131 infants (28%) were symptomatic at birth and 26 (20%) had SNHL at birth. All known genotypes of UL55, UL75, UL73, and US28 were represented and no particular genotype was associated with symptomatic infection or SNHL. UL144 subtype C was more common in symptomatic babies but not associated with SNHL. Mixed infection was observed in 59 infants (45%) and not associated with symptoms (p = 0.43) or SNHL at birth (p = 0.82). In the cohort of 52 infants with long-term hearing outcome, mixed infection at birth was not predictive of SNHL. Conclusions Mixed infection is common in infants with cCMV but is neither associated with symptomatic infection nor with SNHL. PMID:23694837
Yoshida, Haruo; Takahashi, Haruo; Kanda, Yukihiko; Kitaoka, Kyoko; Hara, Minoru
To investigate the role of the developmental delay often observed in children with congenital cytomegalovirus (CMV) infection on the improvement of language understanding after cochlear implantation (CI). Retrospective chart review. Sixteen children with severe and/or profound hearing loss due to congenital CMV infection (CMV group) and 107 congenitally deaf children (168 ears) without CMV infection as the cause of deafness (non-CMV group). Mean age at which patients underwent CI was 2.9 years in both groups. The mean follow-up period was 7.8 versus 8.2 years, respectively. The Enjoji Scale of Infant Analytical Development was used to evaluate/compare pre- and postoperative hearing level, word recognition score, speech discrimination score, and language production and perception skills. The Picture Vocabulary Test-Revised was used to assess vocabulary understanding skill. Correlation between the final vocabulary understanding skill assessment and several factors was also examined. Improvement in hearing thresholds (mean: 106.0 dB) was greater after the first CI, (27-45 dB; mean: 33.8 dB) compared with hearing aid (48-74 dB; mean: 63.1 dB). Similarly, language perception and production were better in the CMV group. However, in the long term, differences between good and poor cases became prominent, especially in children with motor or cognitive delay and brain abnormalities who performed poorly in the CMV group. Long-term language perception and production after CI were overall satisfactory in congenital CMV-deafened children. CI was effective, particularly in the absence of CMV-induced disorders. However, this effectiveness was limited in those with motor or cognitive delay.
Cytomegalovirus (CMV) is the leading cause of congenital infection in developed countries, affecting 0.3 to 0.6% of all live births in Europe. Primary CMV infection occurs in 1 to 4% of seronegative women during pregnancy and may be transmitted to the fetus in 40% of cases. Up to 10% of intrauterine CMV infections result in symptomatic congenital disease at birth. Half of these children and 13% of those born with asymptomatic infection will develop long-term sequelae, especially neurosensory hearing loss and mental retardation. Accurate diagnosis of primary maternal and fetal infection is now possible using the avidity index of anti-CMV IgG and virological testing to detect the virus in amniotic fluid. Symptomatic congenital infection may be preventable using CMV hyperimmune globulin during pregnancy. The gold standard for diagnosis of congenital CMV infection is the detection of the virus in urine within the first 2 weeks of life by rapid cell culture techniques (shell vial) or nucleic acid amplification of viral DNA (PCR). Retrospective diagnosis can be achieved by detection of viral DNA by PCR in dried blood spots (Guthrie card) collected on filter paper in the first days of life. Currently available drugs for the treatment of congenital CMV include ganciclovir and its oral prodrug valganciclovir. Treatment with intravenous ganciclovir for six weeks may prevent hearing deterioration in children with symptomatic congenital CMV infection and central nervous system involvement. Valganciclovir may be an excellent alternative because of its good bio-availability, providing plasma concentrations similar to those achieved with intravenous ganciclovir.
Frenzel, K; Lehmann, J; Krüger, D H; Martin-Parras, L; Uharek, L; Hofmann, J
Cytomegalovirus (CMV)-specific hyperimmunoglobulin (CMV-HIG) is used to treat and prevent CMV infection in immunocompromised patients, and anti-CD20 monoclonal antibody is successfully used in the treatment for post-transplant lymphoproliferative disease caused by Epstein-Barr virus (EBV). Two immunological approaches have been suggested to further improve the control of viral reproduction in patients with active disease: first, the use of monoclonal antibodies with specificity against viral epitopes and second, coadministration of cells with the capacity to promote antibody-dependent cell-mediated cytotoxicity. Here, we have evaluated the effectiveness of these strategies in vitro (alone and in combination) with neutralization and cytotoxicity assays. Our results indicate that monoclonal antibodies (in particular SM5-1) can be as effective as CMV-HIG in neutralizing-cell-free CMV. Moreover, our data indicate that antibody-mediated elimination (either by moAb or by HIG) of EBV-infected cells can be significantly enhanced by NK cells. Using human NK cells that have been purified, cultured and expanded under GMP conditions, we were able to demonstrate that the combination of NK cells and antibodies could represent a feasible and highly effective clinical approach to achieve control of EBV infections. Especially in leukopenic patients with low numbers of ADCC-promoting cells, the combination of adoptively transferred NK cells and antiviral antibodies offers a promising strategy that should be tested in clinical trials.
Hassan, J; Connell, J
Cytomegalovirus (CMV) is the leading cause of congenital viral infection, with an incidence of 0.5-3% of live births worldwide. Clinical evidence has shown hearing and vision loss, mental retardation and sometimes death in affected newborns. Primary maternal CMV infection during gestation poses a 40% risk of intrauterine transmission in contrast to recurrent infection. European laboratories have made significant progress in the last decade in solving diagnostic problems linked to infection in pregnancy. With the advances in CMV serology, such as detection of anti-CMV IgM by enzyme immunoassays (EIA), confirmed by Western blot, together with seroconversion and anti-CMV IgG avidity evaluation in pregnant mothers, can help to identify recent infection. Preventative measures such as screening for CMV in the routine serological work-up of pregnant women have been introduced in countries such as Spain and Italy. The development of specific T cell-mediated immune responses in mothers, fetus and neonates is now emerging with regard to antigen-specific CD4 and CD8 T cells, differentiation status, proliferative and cytokine responses. A protective vaccine against CMV is a major public health priority and the study of vaccines in animal model systems has identified potential strategies for interrupting transmission and preventing disease in newborns. Congenital CMV infection has a variable outcome and therefore novel diagnostic methods are required to identify those at risk and therapeutic interventions are needed to improve the long-term prognosis of those infected. CMV was first isolated in 1957. We are now 50 years on, so procrastination is not an option.
Role of cytomegalovirus (CMV)-specific polyfunctional CD8+ T-cells and antibodies neutralizing virus epithelial infection in the control of CMV infection in an allogeneic stem-cell transplantation setting.
Giménez, Estela; Blanco-Lobo, Pilar; Muñoz-Cobo, Beatriz; Solano, Carlos; Amat, Paula; Pérez-Romero, Pilar; Navarro, David
The role of cytomegalovirus (CMV)-specific polyfunctional CD8+ T-cells and that of antibodies neutralizing virus epithelial infection (AbNEI) in the control of CMV DNAemia were investigated in 39 CMV-seropositive allogeneic stem-cell transplant (Allo-SCT) recipients with (n = 24) or without (n = 15) CMV DNAemia. AbNEI levels were monitored prospectively by means of a neutralization assay employing retinal epithelial cells (ARPE-19) and the recombinant CMV strain BADrUL131-Y4. Quantification of CMV-specific polyfunctional CD8+ T-cells (expressing two or three of the following markers: IFN-γγ, TNF-α and CD107a) in whole blood was performed by flow cytometry for intracellular cytokine staining. We found no differences in the dynamic pattern of AbNEI in patients with or without subsequent CMV DNAemia. Baseline and peak AbNEI titres were not predictive of the dynamics of CMV replication within episodes. No correlation was found between CMV DNA loads and AbNEI levels during episodes of CMV DNAemia (ρ = 0.09; 95 % confidence interval - 0.52 to 0.64; P = 0.78). The detection of pp65/IE-1 CMV-specific polyfunctional CD8+ T-cells was associated with low-level virus replication within subsequent episodes of CMV DNAemia. Interestingly, the presence of AbNEI titres (inverse) >4.7 log2 was predictive of the occurrence of CMV DNAemia (sensitivity, 83 %; specificity, 80 %). Our findings provide an insight to the role of humoral and cellular immunity in the control of CMV infection in an Allo-SCT setting.
Llorente, Antolin M; Castillo, Christine L
Cytomegalovirus (CMV) is the most ubiquitous member of the herpes virus family and is the leading cause of congenital (vertical) infection in newborns (Fowler, Stagno, & Pass, 2003; Llorente, Steigmeyer, Cooper, Rivers, & Gazley, 2011; Noyola et al., 2000; Steigmeyer & Llorente, 2010). CMV is related to the group of viruses capable of causing more pernicious infectious diseases, such as chicken pox (Santos de Barona, 1998). Although the virus generally remains dormant, individuals whose symptoms are clinically apparent often are dramatically affected. Common symptomatic characteristics of the virus include microcephaly, jaundice, liver-spleen infections, pneumonia, cardiac anomalies, chorioretinitis, vision loss, sensory-neural hearing loss, mental retardation, and mononucleosis (Demmler, 1991; Kashden, Frison, Fowler, Pass, & Boll, 1998; Noyola et al., 2000; Pass, 2005; Santos de Barona). The prognosis of individuals with CMV is highly variable, and the prognosis of individuals with congenital CMV can usually be determined based on the extent of infection at birth. The purpose of this investigation is to present longitudinal results of neuropsychological evaluation of two dizygotic twin sets (one twin of each set is asymptomatic CMV-positive and the other is uninfected) who were reared in the same environment. In addition, the present findings are discussed within the context of emerging murine and other animal analogues of CMV as well as within the extant CMV literature.
Endo, Takeshi; Goto, Kenji; Ito, Koichi; Sugiura, Tokio; Terabe, Koji; Cho, Sangmi; Nishiyama, Masato; Sugiyama, Kohachiro; Togari, Hajime
Easy screening and accurate diagnosis of congenital cytomegalovirus (CMV) infection are needed to predict and treat complications. We report the clinical course of two neonates with congenital CMV infection confirmed by real-time polymerase chain reaction (PCR) for CMV DNA in umbilical cord blood. A total of 1,010 neonates born at Yonaha Clinic from July 2005 to March 2007 were investigated. Umbilical cord blood was collected at birth, and DNA was extracted to screen for CMV DNA by real-time PCR. Head MRI and a developmental test were conducted for two cases (0.2%) in which CMV DNA was detected. Neither case showed clear abnormalities at birth, and head CT conducted at 1 month after birth revealed no abnormalities. Auditory brainstem responses were normal at both 1 and 12 months after birth in both cases. Head MRI at 12 months showed abnormalities in both cases. For both cases, development tests conducted at 12 months revealed mild developmental delays, particularly in posture and movement areas, which might have been caused by congenital CMV infection.
Sousa, Patrícia; Madureira, Gabriel; Moucho, Marina; Rouxinol-Dias, Ana Lídia; Montenegro, Nuno
Currently in Portugal, universal screening of pregnant women for Cytomegalovirus (CMV) infection is not performed. However, it is recommended to screen all women attending preconception care. We aimed to assess women's attendance to preconception care and if their serologic status regarding CMV was known and/or investigated in that consultation. In this cross-sectional study, we interviewed 240 women admitted to the obstetrical ward of a hospital in the Metropolitan Area of Porto (Portugal) about their adherence to preconception care and collected data regarding their CMV serologic status and its investigation. We found that 71.3% of the women who attended preconception care were not screened for CMV infection. Among primigravida, the screening rate was only of 30.4% (upper limit of CI 95%: 44.8%). There were no statistically significant differences between the private and public sectors of healthcare. We observed attendance to preconception care is high (73.1%). For the population subgroup of the metropolitan area of Porto, attendance to preconception care is at least 66%, with a 95% confidence level. Portuguese guidelines stating a woman's serologic status regarding CMV should be investigated in preconception care are not properly implemented. This suggests guidelines should assure the screening of previously non-screened women during pregnancy.
Di Bona, Danilo; Scafidi, Valeria; Plaia, Antonella; Colomba, Claudia; Nuzzo, Domenico; Occhino, Cecilia; Tuttolomondo, Antonino; Giammanco, Giovanni; De Grazia, Simona; Montalto, Giuseppe; Duro, Giovanni; Cippitelli, Marco; Caruso, Calogero
Natural killer (NK) cells provide a major defense against cytomegalovirus (CMV) infection through the interaction of their surface receptors, including the activating and inhibitory killer immunoglobulin-like receptors (KIRs), and human leukocyte antigens (HLA) class I molecules. This study assessed whether the KIR and HLA repertoire may influence the risk of developing symptomatic or asymptomatic disease after primary CMV infection in the immunocompetent host. Sixty immunocompetent patients with primary symptomatic CMV infection were genotyped for KIR and their HLA ligands, along with 60 subjects with a previous asymptomatic infection as controls. The frequency of the homozygous A haplotype (only KIR2DS4 as activating KIR) was higher in symptomatic patients than controls (30% vs 12%, respectively; odds ratio [OR] = 3.24; P = .01). By logistic regression, the risk of developing symptomatic disease was associated with the homozygous A haplotype and the HLABw4(T) allele. Combining the 2 independent variables, we found that 37 out of 60 (62%) symptomatic patients but only 18 out of 60 (30%) of controls possessed the homozygous A haplotype or the HLABw4(T) allele with a highly significant OR (OR = 3.75, P < .0005). Immunocompetent subjects carrying the homozygous A haplotype or the HLABw4(T) allele are at higher risk of developing symptomatic disease after primary CMV infection. © The Author 2014. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: email@example.com.
Carlier, Yves; Truyens, Carine; Deloron, Philippe; Peyron, François
This review defines the concepts of maternal-fetal (congenital) and vertical transmissions (mother-to-child) of pathogens and specifies the human parasites susceptible to be congenitally transferred. It highlights the epidemiological features of this transmission mode for the three main congenital parasitic infections due to Toxoplasma gondii, Trypanosoma cruzi and Plasmodium sp. Information on the possible maternal-fetal routes of transmission, the placental responses to infection and timing of parasite transmission are synthesized and compared. The factors susceptible to be involved in parasite transmission and development of congenital parasitic diseases, such as the parasite genotypes, the maternal co-infections and parasitic load, the immunological features of pregnant women and the capacity of some fetuses/neonates to overcome their immunological immaturity to mount an immune response against the transmitted parasites are also discussed and compared. Analysis of clinical data indicates that parasitic congenital infections are often asymptomatic, whereas symptomatic newborns generally display non-specific symptoms. The long-term consequences of congenital infections are also mentioned, such as the imprinting of neonatal immune system and the possible trans-generational transmission. The detection of infection in pregnant women is mainly based on standard serological or parasitological investigations. Amniocentesis and cordocentesis can be used for the detection of some fetal infections. The neonatal infection can be assessed using parasitological, molecular or immunological methods; the place of PCR in such neonatal diagnosis is discussed. When such laboratory diagnosis is not possible at birth or in the first weeks of life, standard serological investigations can also be performed 8-10 months after birth, to avoid detection of maternal transmitted antibodies. The specific aspects of treatment of T. gondii, T. cruzi and Plasmodium congenital infections are
Goulabchand, Radjiv; Khellaf, Lakhdar; Forestier, Amandine; Costes, Valerie; Foulongne, Vincent; le Quellec, Alain; Guilpain, Philippe
To describe the pathophysiological mechanisms involving cytomegalovirus (CMV) primary infection and natural killer (NK) cell expansion in the development of localized scleroderma. A 43-year-old woman presented acute erythematous discoloration and skin thickening concerning face, neck, trunk, abdomen, and the four limbs, predominantly in proximal areas. Our case did not respond to systemic sclerosis criteria diagnosis. However, skin and muscle biopsy revealed early scleroderma associated with capillary thrombi, and tissue infiltration with NK cells (CD56+/Granzyme B). Scleroderma was attributed to CMV primary infection responsible for cytolytic hepatitis (7-fold over the limit) and circulating NK cell excess. After 6 months of prednisone and a 2-year follow-up, a complete resolution of symptoms was observed. Our observation suggests a potential triggering role of CMV primary infection in the development of scleroderma. Histological features from our observation addresses the role of CMV and NK cells in the development of endothelial damage and fibrotic process. Copyright © 2014 Elsevier B.V. All rights reserved.
Wang, Li; Xu, Xiaoxing; Zhang, Huiping; Qian, Jihong; Zhu, Jianxing
The performance of dried blood spots (DBS) polymerase chain reaction (PCR) assays in screening for congenital cytomegalovirus (cCMV) infection varies between different studies. To determine whether the DBS PCR assay has sufficient accuracy to be used as a screening test for cCMV infection, we performed a meta-analysis of 15 studies (n = 26007 neonates) that evaluated the performance of DBS PCR tests in screening for cCMV infection and that met our inclusion criteria. The pooled sensitivity and specificity were 0.844 (95% CI = 0.812-0.872) and 0.999 (95% CI = 0.998-0.999), respectively, and the diagnostic odds ratio was 1362.10 (95%CI = 566.91-3272.60). As sensitivity analysis showed that the results were robust. In conclusion, the performance of DBS PCR assays for testing cCMV was more suitable for retrospective diagnosis than screening.
Bartlett, Adam W; McMullan, Brendan; Rawlinson, William D; Palasanthiran, Pamela
Congenital CMV is one of the commonest congenital infections and a recognised cause of sensorineural hearing loss and neurodevelopmental impairment. Ninety percent are clinically inapparent at birth but are reported to be at risk of developing such abnormalities throughout childhood, the extent of which requires further elucidation. A systematic literature review was conducted using Medline and Embase databases, manual citation review, and personal libraries for articles reporting primary data on hearing and neurodevelopmental outcomes for children with asymptomatic congenital CMV. PROSPERO registration number CRD42015025407. Thirty-seven of 480 articles identified between 1969 and 2016 met the eligibility criteria. Twenty-nine of these contributed primary data on hearing outcomes and 20 on neurodevelopmental outcomes (12 of the 37 studies contributed data on both). Cumulative incidence of sensorineural hearing loss with follow-up to at least 5 years was 7% to 11%, which is more than healthy controls but less than children with symptomatic congenital CMV (34%-41%). The onset, course, and severity of hearing loss was variable with no reliable virological prognostic marker. In comparison to controls, children with asymptomatic congenital CMV did not perform worse than controls in neurodevelopmental assessments and performed better than children with symptomatic congenital CMV. Studies show children with asymptomatic congenital CMV are at increased risk of developing hearing loss but perform equally well on neurodevelopmental assessments when compared with healthy controls. There is no reliable virological marker to determine which infants will develop sequelae. Regular follow-up until school entry is supported by the literature. Copyright © 2017 John Wiley & Sons, Ltd.
Gantt, Soren; Leister, Erin; Jacobsen, Denise L; Boucoiran, Isabelle; Huang, Meei-Li; Jerome, Keith R; Jourdain, Gonzague; Ngo-Giang-Huong, Nicole; Burchett, Sandra; Frenkel, Lisa
Congenital cytomegalovirus (cCMV) infection is common among infants born to HIV-infected women. Nelfinavir (NFV), an antiretroviral drug that is safe during pregnancy, inhibits CMV replication in vitro at concentrations that standard doses achieve in plasma. We hypothesized that infants born to women receiving NFV for prevention of mother-to-child transmission of HIV (PMTCT) would have a reduced prevalence of cCMV infection. The prevalence of cCMV infection was compared among HIV-uninfected infants whose HIV-infected mothers either received NFV for >4 weeks during pregnancy (NFV-exposed) or did not receive any NFV in pregnancy (NFV-unexposed). CMV PCR was performed on infant blood samples collected at <3 weeks from birth. Of the 1,255 women included, 314 received NFV for >4 weeks during pregnancy and 941 did not receive any NFV during pregnancy. The overall prevalence of cCMV infection in the infants was 2.2%, which did not differ by maternal NFV use. Maternal CD4 T cell counts were inversely correlated with risk of cCMV infection, independent of the time NFV was initiated during gestation. Infants with cCMV infection were born 0.7 weeks earlier (P = 0.010) and weighed 170 g less (P = 0.009) than uninfected infants. Among HIV-exposed uninfected infants, cCMV infection was associated with adverse perinatal outcomes. NFV use in pregnancy was not associated with protection against cCMV. Safe and effective strategies to prevent cCMV infection are needed. © 2015 Wiley Periodicals, Inc.
Gantt, Soren; Leister, Erin; Jacobson, Denise L.; Boucoiran, Isabelle; Huang, Meei-Li; Jerome, Keith R.; Jourdain, Gonzague; Ngo-Giang-Huong, Nicole; Burchett, Sandra; Frenkel, Lisa
Background Congenital cytomegalovirus (cCMV) infection is common among infants born to HIV-infected women. Nelfinavir (NFV), an antiretroviral drug that is safe during pregnancy, inhibits CMV replication in vitro at concentrations that standard doses achieve in plasma. We hypothesized that infants born to women receiving NFV for prevention of mother-to-child transmission of HIV (PMTCT) would have a reduced prevalence of cCMV infection. Methods The prevalence of cCMV infection was compared among HIV-uninfected infants whose HIV-infected mothers either received NFV for ≥4 weeks during pregnancy (NFV-exposed) or did not receive any NFV in pregnancy (NFV-unexposed). CMV PCR was performed on infant blood samples collected at <3 weeks from birth. Results Of the 1,255 women included, 314 received NFV for ≥4 weeks during pregnancy and 941 did not receive any NFV during pregnancy. The overall prevalence of cCMV infection in the infants was 2.2%, which did not differ by maternal NFV use. Maternal CD4 T cell counts were inversely correlated with risk of cCMV infection, independent of the time NFV was initiated during gestation. Infants with cCMV infection were born 0.7 weeks earlier (p=0.010) and weighed 170 grams less (p=0.009) than uninfected infants. Conclusion Among HIV-exposed uninfected infants, cCMV infection was associated with adverse perinatal outcomes. NFV use in pregnancy was not associated with protection against cCMV. Safe and effective strategies to prevent cCMV infection are needed. PMID:26519647
Gantt, Soren; Dionne, Francois; Kozak, Fred K; Goshen, Oran; Goldfarb, David M; Park, Albert H; Boppana, Suresh B; Fowler, Karen
Congenital cytomegalovirus (cCMV) infection is a major cause of childhood deafness. Most cCMV infections are not diagnosed without newborn screening, resulting in missed opportunities for directed care. To estimate the cost-effectiveness of universal and targeted newborn cCMV screening programs compared with no cCMV screening. Models were constructed using rates and outcomes from prospective cohort studies of newborn cCMV screening in US postpartum care and early hearing programs. Costs of laboratory testing, treatment, and hearing loss were drawn from Medicaid data and published estimates. The benefits of cCMV screening were assumed to come from antiviral therapy for affected newborns to reduce hearing loss and from earlier identification of hearing loss with postnatal onset. Analyses were performed from July 2014 to March 2016. Models compared universal or targeted cCMV screening of newborns with a failed hearing screen, with standard care for cCMV infection. The incremental costs of identifying 1 cCMV infection, identifying 1 case of cCMV-related hearing loss, and preventing 1 cochlear implant; the incremental reduction in cases of severe to profound hearing loss; and the differences in costs per infant screened by universal or targeted strategies under different assumptions about the effectiveness of antiviral treatment. Among all infants born in the United States, identification of 1 case of cCMV infection by universal screening was estimated to cost $2000 to $10 000; by targeted screening, $566 to $2832. The cost of identifying 1 case of hearing loss due to cCMV was as little as $27 460 by universal screening or $975 by targeted screening. Assuming a modest benefit of antiviral treatment, screening programs were estimated to reduce severe to profound hearing loss by 4.2% to 13% and result in direct costs of $10.86 per newborn screened. However, savings of up to $37.97 per newborn screened were estimated when costs related to functionality were included
Clari, María A; Aguilar, Gerardo; Benet, Isabel; Belda, Javier; Giménez, Estela; Bravo, Dayana; Carbonell, José A; Henao, Liliana; Navarro, David
The current study was designed to assess the predictive value of the evaluation of cytomegalovirus (CMV)-specific T-cell immunity early following admission to the intensive care unit for inferring the risk of active CMV infection in non-immunosuppressed surgical and trauma patients. A total of 31 CMV-seropositive patients were included. Patients were screened for the presence of CMV DNA in plasma and in tracheal aspirates by real-time PCR. Enumeration of CMV pp65 and IE-1-specific IFN-γ CD8(+) and CD4(+) T cells was performed by flow cytometry for intracellular cytokine staining. Virological and immunological monitoring was conducted once or twice a week. Active CMV infection occurred in 17 out of 31 patients. Undetectable levels of pp65 and IE-1-specific IFN-γ CD8(+) and CD4(+) T-cell subsets cells were observed in 10 patients who developed active CMV infection and in one who did not (at a median of 2 days following ICU admission). Peak CMV DNA loads in both tracheal aspirates and plasma were substantially higher (P = 0.018 and P = 0.091, respectively) in patients with undetectable IFN-γ T-cell responses than in patients with detectable responses. The expansion of both CMV-specific T-cell subsets following detection of active CMV infection was demonstrated in 9 out of 14 patients with active CMV infection. In conclusion, the evaluation of CMV pp65 and IE-1-specific IFN-γ-producing CD8(+) and CD4(+) T cells early following ICU admission may allow the identification of patients most at risk of either having or developing an episode of active CMV infection, particularly those associated with high-level virus replication.
Engman, M-L; Lewensohn-Fuchs, I; Mosskin, M; Malm, G
Cytomegalovirus has been suggested to have a teratogenous influence during the migration of neural cells from the ventricular zones to the cortex during the gestational period. The aim of this study was to investigate the prevalence of congenital cytomegalovirus infections in a cohort of children with neurological disability and cerebral cortical malformations recognized by neuroimaging. Twenty-six children with neurological disability and cerebral cortical malformations were investigated retrospectively for congenital cytomegalovirus infection by analysing the dried blood spot samples for cytomegalovirus deoxynucleic acid using qualitative polymerase chain reaction. CMV DNA in the dried blood spot samples was found in four out of 26 children. Two of these four had severe disabilities with mental retardation, autism, spastic cerebral palsy, epilepsy and deafness. A third child had epilepsy and unilateral cerebral palsy, while the fourth had a mild motor coordination dysfunction and hearing deficit. In our study, the number of congenital cytomegalovirus infections in children with cerebral cortical malformations was higher (4/26) than expected with reference to the birth prevalence (0.2-0.5%) of congenital cytomegalovirus infection in Sweden. We thus conclude that congenital cytomegalovirus infection should be considered in children with cortical malformations of unknown origin. © 2010 The Author(s)/Journal Compilation © 2010 Foundation Acta Paediatrica.
Distéfano, Angélica Lidia; Alonso, Alicia; Martin, Fabián; Pardon, Fabián
Background Human cytomegalovirus (CMV) is one of the most commonly found agents of congenital infections. Primary maternal infection is associated with risk of symptomatic congenital diseases, and high morbidity is frequently associated with very low birth weight. Neonates with asymptomatic infection develop various sequelae during infancy. This is the first Argentine study performed in neonates with congenital and postnatal HCMV infection. The purpose of this study was to evaluate the performance of the polymerase chain reaction (PCR) technique with different pairs of primers, to detect cytomegalovirus isolated in tissue cultures and directly in urine and dried blood spot (DBS) specimens. Results were compared with IgM detection. Methods The study was performed between 1999 and 2001 on routine samples in the Laboratory. A total of 61 urine and 56 serum samples were selected from 61 newborns/infants, 33 patients whose samples were analyzed during the first two to three weeks of life were considered congenital infections; the remaining 28 patients whose samples were taken later than the third week were grouped as perinatal infections, although only in 4 the perinatal transmission of infection was determined unequivocally Cytomegalovirus diagnosis was made by isolating the virus from urine samples in human foreskin fibroblast cells. Three different primer pairs directed to IE, LA and gB genes were used for the HCMV PCR assay in viral isolates. Subsequently, PCR and nested PCR (nPCR) assays with gB primers were performed directly in urine and in 11 samples of dried blood spot (DBS) on Guthrie Card, these results were then compared with serology. Results The main clinical manifestations of the 33 patients with congenital infection were purpura, jaundice, hepatomegaly and anaemia. Three patients presented low birth weight as single symptom, 10, intracranial calcifications, and 2, kidney failure. In the 28 patients grouped as with perinatal infection, anaemia
Zavala-Vega, Sergio; Castro-Escarpulli, Graciela; Hernández-Santos, Hector; Salinas-Lara, Citlatepetl; Palma, Icela; Mejía-Aranguré, Juan Manuel; Gelista-Herrera, Noemí; Rembao-Bojorquez, Daniel; Ochoa, Sara A; Cruz-Córdova, Ariadnna; Xicohtencatl-Cortes, Juan; Uribe-Gutiérrez, Gabriel; Arellano-Galindo, José
Several risk factors are involved in glioblastoma, including cytomegalovirus (CMV). This research was carried out to determine the rate of CMV infection, as well as HSV 1/2 and EBV in brain tissue, in patients with glioblastomamultiforme (GBM). The tissues were tested using immunohistochemistry, PCR, in situ hybridization and real-time PCR. At least, one HHV was detected in 21/29 (72%) patients as follows: single infections with HSV-1/2 in 4/21 (19%), EBV in 6/21 (28.6%) and CMV in 1/21 (4.8%). Mixed viral infection, HSV-1/2 and EBV were detected in 4/21 patients (19%), CMV and EBV in 5/21 (23.8%), and HSV-1/2, EBV, and CMV in 1/21. The CMV viral load ranged from 3×10(2) to 4.33×10(5) genome/100ng of tissue. Genotype based on CMV gB was 3/7 where 2/3 was gB1 and 1/3 gB4. HSV, EBV and CMV were frequently found in brain tissues, more in mix in a population reported as highly seropositive. Copyright © 2017 Elsevier GmbH. All rights reserved.
Yamaguchi, Akira; Oh-ishi, Tsutomu; Arai, Takashi; Sakata, Hideaki; Adachi, Nodoka; Asanuma, Satoshi; Oguma, Eiji; Kimoto, Hirofumi; Matsumoto, Jiro; Fujita, Hidetoshi; Uesato, Tadashi; Fujita, Jutaro; Shirato, Ken; Ohno, Hideki; Kizaki, Takako
Objective Approximately 8–10% of newborns with asymptomatic congenital cytomegalovirus (cCMV) infection develop sensorineural hearing loss (SNHL). However, the relationship between CMV load, SNHL and central nervous system (CNS) damage in cCMV infection remains unclear. This study aimed to examine the relationship between urinary CMV load, SNHL and CNS damage in newborns with cCMV infection. Study design The study included 23 368 newborns from two maternity hospitals in Saitama Prefecture, Japan. Urine screening for cCMV infection (quantitative real-time PCR) and newborn hearing screening (automated auditory brainstem response (AABR) testing) were conducted within 5 days of birth to examine the incidence of cCMV infection and SNHL, respectively. CNS damage was assessed by MRI of cCMV-infected newborns. Results The incidence of cCMV infection was 60/23 368 (0.257%; 95% CI 0.192% to 0.322%). The geometric mean urinary CMV DNA copy number in newborns with cCMV was 1.79×106 copies/mL (95% CI 7.97×105 to 4.02×106). AABR testing revealed abnormalities in 171 of the 22 229 (0.769%) newborns whose parents approved hearing screening. Of these 171 newborns, 22 had SNHL (12.9%), and 5 of these 22 were infected with cCMV (22.7%). Newborns with both cCMV and SNHL had a higher urinary CMV DNA copy number than newborns with cCMV without SNHL (p=0.036). MRI revealed CNS damage, including white matter abnormalities, in 83.0% of newborns with cCMV. Moreover, newborns with CNS damage had a significantly greater urinary CMV load than newborns without CNS damage (p=0.013). Conclusions We determined the incidence of cCMV infection and urinary CMV DNA copy number in seemingly healthy newborns from two hospitals in Saitama Prefecture. SNHL and CNS damage were associated with urinary CMV DNA copy number. Quantification of urinary CMV load may effectively predict the incidence of late-onset SNHL and neurodevelopmental disorders. PMID:28110288
Chris Buck, W.; Kazembe, Peter N.; Phiri, Sam; Andrianarimanana, Diavolana; Weigel, Ralf
Background: Little is known about viral co-infections in African human immunodeficiency virus (HIV)-infected children. We examined the prevalence of seromarkers for cytomegalovirus (CMV), herpes simplex virus type 2 (HSV-2) and hepatitis B virus (HBV) infections among HIV-infected, antiretroviral treatment (ART)-naïve children in Lilongwe, Malawi. Methods: Ninety-one serum samples were tested for IgG and IgM antibodies to CMV, and IgG antibodies to HSV-2 and hepatitis B surface antigen (HBsAg). Baseline demographic, clinical and laboratory data were abstracted from electronic records. Results: CMV IgG was the most common positive result in all age groups (in 73% of children <1 year, and 100% in all other groups). Three patients were CMV IgM positive (3.3%), suggesting acute infection. HSV-2 IgG was positive in four patients (4.4%), and HBsAg in two (2.2%). Conclusions: CMV infection occurred early in life, and few children had specific signs of CMV infection at the time of ART initiation. Unrecognized HBV infection represents opportunities for testing and treatment of HIV/HBV co-infected children. PMID:26884443
Bonaros, Nikolaos; Mayer, Bernd; Schachner, Thomas; Laufer, Günther; Kocher, Alfred
The goal of this meta-analysis was to investigate the impact of cytomegalovirus hyperimmune globulin (CMVIG) on cytomegalovirus (CMV) infection, CMV disease, and mid-term survival in solid organ transplant recipients. Medline, EMBASE, and the Cochrane databases were searched since their inceptions until 2006. Inclusion criteria comprised: prospective randomized trials, in solid organ transplantation which received CMV prophylaxis including CMVIG on one of the treatment arms. Random effects models were used to calculate pooled risk ratios (RR) and meta-regression was employed to explain study heterogeneity. Stratified analyses were conducted and Funnel plot was used to assess publication bias. Literature searches identified 11 randomized trials (698 patients; median follow-up: 12 months, range: 3-22 months) including six randomized trials (302 patients) after kidney transplantation. The analysis demonstrated a beneficial effect of the prophylactic use of CMVIG on total survival [RR (95% confidence interval; CI): 0.67 (0.47-0.95)] and prevention of CMV-associated death [RR (95% CI): 0.45 (0.24-0.84)] in solid organ transplant recipients but not kidney transplant recipients [RR (95% CI): 0.35 (0.12-1.04)]. CMV disease was significantly reduced in all recipients receiving prophylactic CMVIG [RR (95% CI): 0.697 (0.57-0.85)]. CMVIG had no impact on CMV-infections and clinically relevant rejections. Prophylactic administration of CMVIG after solid organ transplantation is associated with improved total survival, reduced CMV disease, and CMV-associated deaths.
Bilavsky, E; Schwarz, M; Bar-Sever, Z; Pardo, J; Amir, J
Congenital cytomegalovirus (cCMV) infection can reside in many organ systems; however, the virus has a particular predilection towards inhabiting the reticuloendothelial system, especially the liver. Specific studies focusing only on hepatic involvement in infants with cCMV are lacking. We report our experience with a large cohort of infants treated in our hospital clinic due to cCMV and hepatic involvement. Hepatic involvement was defined either as hepatitis (elevated alanine transaminases (ALT) >80 units/L without cholestatic disease) or cholestatic disease (elevated ALT >80 units/L combined with direct bilirubin >2 mg/dL). During the study period, 198 infants were diagnosed with symptomatic cCMV in our clinic. Hepatic involvement was observed in 13 infants (6.6%); 7 (3.5%) with hepatitis and 6 (3%) with cholestatic disease. Maternal primary infection with cytomegalovirus during pregnancy was diagnosed in 7 (53.8%) of the 13 infants, nonprimary in 3 (23.1%) and unknown in 3 (23.1%). Among these 13 infants, central nervous system (CNS) involvement was observed in 11 (84.6%) and hearing impairment in 7 (53.8%). Treatment with an antiviral agent was initiated in all cases. Gradual improvement of hepatic enzymes and cholestasis was observed over a prolonged period. We found that the incidence of hepatic involvement in infants with cCMV is much less frequent than previously reported. The hepatic involvement in these infants may manifest in two different ways, and thus, a high index of suspicion and a stepwise approach will help in correctly diagnosing these infants. Antiviral treatment due to CNS involvement is warranted and prognosis is excellent.
Jeitziner, Sanja Mandaric; Walton, Senta M; Torti, Nicole; Oxenius, Annette
Cytomegalovirus (CMV) infects a majority of the human population and establishes a life-long persistence. CMV infection is usually asymptomatic but the virus carries pathogenic potential and causes severe disease in immunocompromised individuals. T-cell-mediated immunity plays an essential role in control of CMV infection and adoptive transfer of CMV-specific CD8(+) T cells restores viral immunity in immunosuppressed patients but a role for CD4(+) T cells remains elusive. Here, we analyzed in adoptive transfer studies the features and antiviral functions of virus-specific CD4(+) T cells during primary murine CMV (MCMV) infection. MCMV-specific CD4(+) T cells expanded upon MCMV infection and displayed an effector phenotype and function. Adoptive transfer of in vivo activated MCMV-specific CD4(+) T cells to immune-compromised mice was protective during pathogenic MCMV infection and IFN-γ was a crucial mediator of this protective capacity. Moreover, co-transfer of low doses of both MCMV-specific CD4(+) T cells and CD8(+) T cells synergized in control of lytic viral replication in immune-compromised mice. Our data reveal a pivotal antiviral role for virus-specific CD4(+) T cells in protection from pathogenic CMV infection and provide evidence for their antiviral therapeutic potential.
Adler, Stuart P; Nigro, Giovanni
A primary maternal infection with cytomegalovirus (CMV) either during or just before pregnancy accounts for the majority of congenital infections where the baby is symptomatic at birth. Following a primary maternal infection, depending on gestational age, between one quarter and three quarters of fetuses will become infected, and approximately one-third of infected fetuses will have symptoms at birth. Experiments using animal models of CMV infection and observational studies in humans indicate that administration of a CMV hyperimmune globulin (HIG) to the pregnant woman with a primary CMV infection should be effective for both the treatment and prevention of fetal infection. The HIG probably acts by reducing placental inflammation, neutralizing virus with high avidity antibodies, and perhaps by reducing cytokine mediated cellular immune responses.
Vauloup-Fellous, C; Lazzarotto, T; Revello, M G; Grangeot-Keros, L
Congenital cytomegalovirus (CMV) infection has potentially severe consequences in newborns. The testing of pregnant women for CMV-specific antibodies may be useful for the identification of women at risk of transmitting the infection to the fetus. The determination of CMV IgG avidity helps to establish the timing of infection as IgG avidity matures during the course of infection. This study examines the performance of the Elecsys CMV IgG Avidity assay using preselected samples from patients at different phases of CMV infection. The Elecsys CMV IgG Avidity assay was tested at three sites using sequential samples from patients with recent primary CMV infection, as well as single samples from patients with recent primary or past CMV infection. The Elecsys assay discriminated well between early (low avidity) and late (high avidity) phases of infection in sequential serum samples. Overall, 98.8% of low-avidity samples corresponded to infection onset <180 days before sampling and 77.8% of all high-avidity results corresponded to infection onset >90 days before sampling. The assay's sensitivity was 90-97%, with specificity ranging from 89 to 100%, depending on the consideration of gray-zone avidity values. Single samples from recent primary or past infection showed similar distributions of avidity results. The Elecsys CMV IgG Avidity assay results are in agreement with preselected samples from patients with primary or past CMV infection, showing that the test is an adequate predictor of the phase of infection.
van Duin, D; Avery, R K; Hemachandra, S; Yen-Lieberman, B; Zhang, A; Jain, A; Butler, R S; Barnard, J; Schold, J D; Fung, J; Askar, M
Cytomegalovirus (CMV) infection remains a major source of morbidity and mortality in solid organ transplant recipients. Killer immunoglobulin-like receptors(KIR) are genetically polymorphic natural killer(NK) cell receptors important in antiviral responses. A retrospective, single-center cohort study was performed to study the interaction of KIR genotype and primary control of CMV infection after transplantation.Time to first CMV viremia was determined for a cohort of 531 CMV serology donor positive/recipient negative solid organ transplant recipients. Of the KIR genes,KIR2DL3 and KIR2DS2 were most strongly associated with time to CMV viremia in random survival forest analysis. As KIR2DL3 and KIR2DS2 both interact with HLA-C1, these interactions were evaluated. Seventy six recipients were found to be positive for both KIR2DL3 and KIR2DS2 and expressed only HLA-C1 antigens in both recipient and donor. These patients had a substantially reduced hazard of CMV viremia in the first year after solid organ transplantation (hazard ratio 0.44, 95% CI 0.27–0.72, p=0.0012). In KIR2DL3+/KIR2DS2+/HLA-C1/1 recipients who received an organ from a non-C1/1 donor, this protective effect was not observed. These results improve our understanding of human NK cell function in primary CMV infection after transplant.
Pirko, Istvan; Cardin, Rhonda; Chen, Yi; Lohrey, Anne K.; Lindquist, Diana M.; Dunn, R. Scott; Zivadinov, Robert; Johnson, Aaron J.
Recent evidence in multiple sclerosis (MS) suggests that active CMV infection may result in more benign clinical disease. The goal of this pilot study was to determine whether underlying murine CMV (MCMV) infection affects the course of the Theiler's murine encephalitis virus (TMEV) induced murine model of MS. A group of eight TMEV-infected mice were co-infected with MCMV at 2 weeks prior to TMEV infection while a second group of TMEV-infected mice received MCMV two weeks post TMEV. We also used 2 control groups, where at the above time points MCMV was replaced with PBS. Outcome measures included (1) monthly monitoring of disability via rotarod for 8 months; (2) in vivo MRI for brain atrophy studies and (3) FACS analysis of brain infiltrating lymphocytes at 8 months post TMEV infection. Co-infection with MCMV influenced the disease course in mice infected prior to TMEV infection. In this group, rotarod detectable motor performance was significantly improved starting 3 months post-infection and beyond (p≤0.024). In addition, their brain atrophy was close to 30% reduced at 8 months, but this was only present as a trend due to low power (p = 0.19). A significant reduction in the proportion of brain infiltrating CD3+ cells was detected in this group (p = 0.026), while the proportion of CD45+ Mac1+ cells significantly increased (p = 0.003). There was also a strong trend for a reduced proportion of CD4+ cells (p = 0.17) while CD8 and B220+ cell proportion did not change. These findings support an immunomodulatory effect of MCMV infection in this MS model. Future studies in this co-infection model will provide insight into mechanisms which modulate the development of demyelination and may be utilized for the development of novel therapeutic strategies. PMID:22393447
Harrison, Gail J
Congenital cytomegalovirus (CMV) infection has been called "the elephant in our living room" because it is a major public health problem that for decades has been unrecognized and unaddressed. Congenital CMV infection is a common cause of sensorineural hearing loss, vision loss, neurodevelopment disabilities, liver disease, and growth failure. Diagnostic tests are now widely available to identify newborns with congenital CMV infection, congenitally infected newborns now can be easily assessed for evidence of organ involvement, and there are now antiviral treatments and other interventions available to improve the outcome in children with congenital CMV disease. A licensed vaccine to prevent CMV infection is not yet available; however, a "CMV knowledge vaccine," composed of "an ounce of CMV awareness and three simple precautions" and that is endorsed by the Centers for Disease Control and Prevention is available for pregnant women who wish to reduce their contact with potentially CMV-infected secretions and therefore reduce their risk of acquiring CMV during pregnancy. Medical experts in the field of congenital CMV have been called upon for a consensus statement for diagnosis and treatment, and nonprofit organizations of families affected by congenital CMV from around the world have formed a collaborative coalition to facilitate the spread of CMV knowledge and awareness.
Brahmi, Djamel; Cassoux, Nathalie; Serruys, Camille; Giron, Alain; Lehoang, Phuc; Fertil, Bernard
To support ophthalmologists in their daily routine and enable the quantitative assessment of progression of Cytomegalovirus infection as observed on series of retinal angiograms, a methodology allowing an accurate comparison of retinal borders has been developed. In order to evaluate accuracy of borders, ophthalmologists have been asked to repeatedly outline boundaries between infected and noninfected areas. As a matter of fact, accuracy of drawing relies on local features such as contrast, quality of image, background..., all factors which make the boundaries more or less perceptible from one part of an image to another. In order to directly estimate accuracy of retinal border from image analysis, an artificial neural network (a succession of unsupervised and supervised neural networks) has been designed to correlate accuracy of drawing (as calculated form ophthalmologists' hand-outlines) with local features of the underlying image. Our method has been applied to the quantification of CMV retinitis. It is shown that accuracy of border is properly predicted and characterized by a confident envelope that allows, after a registration phase based on fixed landmarks such as vessel forks, to accurately assess the evolution of CMV infection.
Gabrielli, Liliana; Bonasoni, Maria Paola; Chiereghin, Angela; Piccirilli, Giulia; Santini, Donatella; Pavia, Claudia; Turello, Gabriele; Squarzoni, Diego; Lazzarotto, Tiziana
Salivary glands are a site of human cytomegalovirus (CMV) replication, latency, and persistence. Prolonged secretion of virus in saliva for months following a primary infection contribute to horizontal transmission. In order to better understand the early effects of CMV on salivary glands and the mechanisms of viral persistent replication, submandibular glands of six CMV congenitally infected fetuses at 21 weeks gestation were studied. Three fetuses at the same gestational age from CMV-seronegative women were compared as negative controls. Tissue viral load and the type of inflammatory infiltrate were evaluated. Moreover, development and branching of salivary glands, the number of myoepithelial cells, cellular proliferation, and expression of secretory proteins of the saliva (Gross Cystic Disease Fluid Protein-15 and lysozyme) were studied. A low viral load and rare CMV-positive cells associated with T CD8 cytotoxic lymphocytes were observed. Branching was impaired with a decrease in terminal acinar structures, the number of myoepithelial cells, and cellular proliferation were reduced. In addition, a compromised secretion of defense proteins involved in the oral humoral immunity was observed. These findings suggest that CMV may affect salivary glands, impairing structure development and secretion of defense proteins, probably responsible for the prolonged viral shedding in saliva. J. Med. Virol. 89:318-323, 2017. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.
Choi, K. Yeon; Root, Matthew
ABSTRACT Congenital cytomegalovirus (CMV) infection is a leading cause of mental retardation and deafness in newborns. The guinea pig is the only small animal model for congenital CMV infection. A novel CMV vaccine was investigated as an intervention strategy against congenital guinea pig cytomegalovirus (GPCMV) infection. In this disabled infectious single-cycle (DISC) vaccine strategy, a GPCMV mutant virus was used that lacked the ability to express an essential capsid gene (the UL85 homolog GP85) except when grown on a complementing cell line. In vaccinated animals, the GP85 mutant virus (GP85 DISC) induced an antibody response to important glycoprotein complexes considered neutralizing target antigens (gB, gH/gL/gO, and gM/gN). The vaccine also generated a T cell response to the pp65 homolog (GP83), determined via a newly established guinea pig gamma interferon enzyme-linked immunosorbent spot assay. In a congenital infection protection study, GP85 DISC-vaccinated animals and a nonvaccinated control group were challenged during pregnancy with wild-type GPCMV (105 PFU). The pregnant animals carried the pups to term, and viral loads in target organs of pups were analyzed. Based on live pup births in the vaccinated and control groups (94.1% versus 63.6%), the vaccine was successful in reducing mortality (P = 0.0002). Additionally, pups from the vaccinated group had reduced CMV transmission, with 23.5% infected target organs versus 75.9% in the control group. Overall, these preliminary studies indicate that a DISC CMV vaccine strategy has the ability to induce an immune response similar to that of natural virus infection but has the increased safety of a non-replication-competent virus, which makes this approach attractive as a CMV vaccine strategy. IMPORTANCE Congenital CMV infection is a leading cause of mental retardation and deafness in newborns. An effective vaccine against CMV remains an elusive goal despite over 50 years of CMV research. The guinea pig, with
Choi, K Yeon; Root, Matthew; McGregor, Alistair
Congenital cytomegalovirus (CMV) infection is a leading cause of mental retardation and deafness in newborns. The guinea pig is the only small animal model for congenital CMV infection. A novel CMV vaccine was investigated as an intervention strategy against congenital guinea pig cytomegalovirus (GPCMV) infection. In this disabled infectious single-cycle (DISC) vaccine strategy, a GPCMV mutant virus was used that lacked the ability to express an essential capsid gene (the UL85 homolog GP85) except when grown on a complementing cell line. In vaccinated animals, the GP85 mutant virus (GP85 DISC) induced an antibody response to important glycoprotein complexes considered neutralizing target antigens (gB, gH/gL/gO, and gM/gN). The vaccine also generated a T cell response to the pp65 homolog (GP83), determined via a newly established guinea pig gamma interferon enzyme-linked immunosorbent spot assay. In a congenital infection protection study, GP85 DISC-vaccinated animals and a nonvaccinated control group were challenged during pregnancy with wild-type GPCMV (10(5) PFU). The pregnant animals carried the pups to term, and viral loads in target organs of pups were analyzed. Based on live pup births in the vaccinated and control groups (94.1% versus 63.6%), the vaccine was successful in reducing mortality (P = 0.0002). Additionally, pups from the vaccinated group had reduced CMV transmission, with 23.5% infected target organs versus 75.9% in the control group. Overall, these preliminary studies indicate that a DISC CMV vaccine strategy has the ability to induce an immune response similar to that of natural virus infection but has the increased safety of a non-replication-competent virus, which makes this approach attractive as a CMV vaccine strategy. Congenital CMV infection is a leading cause of mental retardation and deafness in newborns. An effective vaccine against CMV remains an elusive goal despite over 50 years of CMV research. The guinea pig, with a placenta
Moteki, Hideaki; Suzuki, Mika; Naito, Yasushi; Fujiwara, Keizo; Oguchi, Kazuhiro; Nishio, Shin-ya; Iwasaki, Satoshi; Usami, Shin-ichi
To predict cochlear implant efficacy and investigate the cortical processing of the visual component of language in profoundly deafened patients with asymptomatic congenital cytomegalovirus (CMV) infection. The cortical activity of two children with CMV-related hearing loss was evaluated with fluorodeoxyglucose-positron emission tomography (FDG-PET) with a visual language task before cochlear implantation. Total development and auditory perception ability were assessed one year after implantation. The two children with CMV-related hearing loss showed activation in the auditory association area where no activation was found in the controls, and exhibited nearly identical cortical activation patterns to those seen in patients with profound congenital hearing loss. In contrast, differences in total development in verbal ability and discrimination of sentences between the two cases were revealed one year after implantation. These results might indicate that the differences of cortical activities according to hearing abilities could have been influenced by CMV infection that involves higher function of the brain directly and/or affects the cochlea peripherally. Additionally, if CMV infection might have affected only the cochlea, these cortical activation patterns were influenced secondary by the time course of hearing loss characterized by CMV infection, which had varied manifestations. Accurate diagnosis and cochlear implantation at the appropriate time are important for successful speech development, and each patient needs a personalized habilitation program based on their etiology and brain function. Copyright © 2013 The Authors. Published by Elsevier Ireland Ltd.. All rights reserved.
Accelerated Phase Chronic Myelogenous Leukemia, BCR-ABL1 Positive; Acute Lymphoblastic Leukemia in Remission; Acute Myeloid Leukemia in Remission; Chronic Lymphocytic Leukemia; Chronic Phase Chronic Myelogenous Leukemia, BCR-ABL1 Positive; Cytomegaloviral Infection; Hodgkin Lymphoma; Lymphadenopathy; Lymphoblastic Lymphoma; Myelodysplastic Syndrome; Myelofibrosis; Myeloproliferative Neoplasm; Non-Hodgkin Lymphoma
Zeng, Zhao-cheng; Chang, Qing; Sun, Zhi-wei; Song, Ming-mei; Jin, Xin-ling; Jiang, Shu-ya; Yang, Xia
Background The aim of this study was to investigate the involvement of CMV infection in wheezing infants and the association between CMV-DNA and immunoglobulins (Igs). Material/Methods A total of 243 wheezing infants and 3,000 parturients were enrolled in this study. The infants were randomly grouped to receive blood HCMV-DNA tests (n=46) or urine HCMV-DNA tests (n=197). Furthermore, all participants had serum CMV-specific IgM and IgG testing. Afterwards, 10 HCMV-IgG positive infants were randomly selected for simultaneous blood and urine HCMV-DNA tests, and 25 HCMV-IgG positive puerperants were randomly selected for urine HCMV-DNA tests. Results The detection rate of urine HCMV-DNA was significantly higher than that of blood HCMV-DNA (67.5% vs. 13.0%, p<0.001). Fifteen (6.2%) and 190 (80.0%) infants showed positive CMV-specific IgM and IgG results (p<0.001), respectively. Among the 10 HCMV-IgG positive infants tested further, only two infants had positive HCMV-DNA blood tests, while all of the 10 infants had positive HCMV-DNA urine tests. However, HCMV-DNA was not detected in the urine of the 25 randomly selected parturients positive for HCMV-IgG. Conclusions CMV infection may be one of the causes of wheezing in infants; CMV infection can be detected by urine-HCMV-DNA and serum HCMV-IgG testing. Infants were more susceptible to CMV infection than parturients. PMID:28283676
Jeon, Jiyeon; Victor, Marcia; Adler, Stuart P.; ...
Bmore » ackground . Congenital cytomegalovirus (CMV) infection is a leading cause of disabilities in children, yet the general public appears to have little awareness of CMV. Methods . Women were surveyed about newborn infections at 7 different geographic locations. Results . Of the 643 women surveyed, 142 ( 22 % ) had heard of congenital CMV. Awareness increased with increasing levels of education ( P < .0001 ). Women who had worked as a healthcare professional had a higher prevalence of awareness of CMV than had other women ( 56 % versus 16 % , P < .0001 ). Women who were aware of CMV were most likely to have heard about it from a healthcare provider ( 54 % ), but most could not correctly identify modes of CMV transmission or prevention. Among common causes of birth defects and childhood illnesses, women's awareness of CMV ranked last. Conclusion . Despite its large public health burden, few women had heard of congenital CMV, and even fewer were aware of prevention strategies.« less
Serriari, Nacer-Eddine; Gondois-Rey, Françoise; Guillaume, Yves; Remmerswaal, Ester B M; Pastor, Sonia; Messal, Nassima; Truneh, Alemseged; Hirsch, Ivan; van Lier, René A W; Olive, Daniel
B and T lymphocyte attenuator (BTLA), like its relative programmed cell death-1 (PD-1), is a receptor that negatively regulates murine T cell activation. However, its expression and function on human T cells is currently unknown. We report in this study on the expression of BTLA in human T cell subsets as well as its regulation on virus-specific T cells during primary human CMV infection. BTLA is expressed on human CD4(+) T cells during different stages of differentiation, whereas on CD8(+) T cells, it is found on naive T cells and is progressively downregulated in memory and differentiated effector-type cells. During primary CMV infection, BTLA was highly induced on CMV-specific CD8(+) T cells immediately following their differentiation from naive cells. After control of CMV infection, BTLA expression went down on memory CD8(+) cells. Engagement of BTLA by mAbs blocked CD3/CD28-mediated T cell proliferation and Th1 and Th2 cytokine secretion. Finally, in vitro blockade of the BTLA pathway augmented, as efficient as anti-PD-1 mAbs, allogeneic as well as CMV-specific CD8(+) T cell proliferation. Thus, our results suggest that, like PD-1, BTLA provides a potential target for enhancing the functional capacity of CTLs in viral infections.
Persistent CMV infection after allogeneic hematopoietic stem cell transplantation in a CMV-seronegative donor-to-positive recipient constellation: Development of multidrug resistance in the absence of anti-viral cellular immunity.
Herling, Marco; Schröder, L; Awerkiew, Sabine; Chakupurakal, Geothy; Holtick, Udo; Kaiser, Rolf; Pfister, Herbert; Scheid, Christof; Di Cristanziano, Veronica
We describe a case of persistent cytomegalovirus (CMV) infection after allogeneic hematopoietic stem cell transplantation (allo-HSCT) with discordant and high-risk (D-/R+) constellation of CMV serostatus. Despite the use of different and innovative antiviral strategies, viral replication could not be suppressed successfully promoting a protracted CMV colitis associated with severe gastrointestinal graft-versus-host disease (GI GVHD). We illustrate that the development of multidrug viral resistance, the failure to mount a CMV-specific cellular immune response, as confirmed by QuantiFERON(®)-CMV (Qiagen) assay, and the refractory GVHD requiring prolonged immunosuppression were the main factors contributing to persistent viral replication and the fulminant unfavorable course.
Ross, Shannon A; Novak, Zdenek; Kumbla, Rekha A; Zhang, Kui; Fowler, Karen B; Boppana, Suresh
Congenital cytomegalovirus (CMV) infection is a leading cause of sensorineural hearing loss (SNHL) in children. Whether connexin mutations are factors in the development of CMV-related hearing loss has not been explored. We examined gap junction protein beta-2 (GJB2) and gap junction protein beta-6 (GJB6) mutations in 149 children with congenital CMV infection and 380 uninfected neonates. Mutations in GJB2 and GJB6 were assessed by nucleotide sequencing and polymerase chain reaction (PCR) methods, respectively. The study population was predominantly African American, and 4.3% of the subjects were carriers of a connexin 26 mutation. The overall frequency of GJB2 mutations was significantly higher in the group of children with CMV infection and hearing loss (21%) compared with those with CMV infection and normal hearing (3%, p = 0.017) and the group of uninfected newborns (3.9%, p = 0.016). Eight previously reported mutations (M34T, V27I, R127H, F83L, R143W, V37I, V84L, G160S), and four novel mutations (V167M, G4D, A40T, and R160Q) were detected. None of the study children had the 342-kb deletion (delGJB6-D13S1830) in GJB6, which suggests that this mutation does not play a role in hereditary deafness in the African American population. Although GJB2 mutations were detected in children with and without CMV-related hearing loss, those with hearing loss had a higher frequency of GJB2 mutations.
Boivin, G; Handfield, J; Murray, G; Toma, E; Lalonde, R; Lazar, J G; Bergeron, M G
We report the development of a simple and rapid PCR assay for quantitation of the cytomegalovirus (CMV) DNA load in polymorphonuclear leukocytes. Using this system, a very good correlation was found between a high number of CMV copies in the blood and the presence of CMV disease in subjects with AIDS.
Boivin, G; Handfield, J; Murray, G; Toma, E; Lalonde, R; Lazar, J G; Bergeron, M G
We report the development of a simple and rapid PCR assay for quantitation of the cytomegalovirus (CMV) DNA load in polymorphonuclear leukocytes. Using this system, a very good correlation was found between a high number of CMV copies in the blood and the presence of CMV disease in subjects with AIDS. PMID:9003635
Goycochea-Valdivia, Walter-Alfredo; Baquero-Artigao, Fernando; Del Rosal, Teresa; Frick, Marie-Antoinette; Rojo, Pablo; Echeverría, María-Juncal; Noguera-Julian, Antoni; Bringué, Xavier; Saavedra-Lozano, Jesús; Vives-Oñós, Isabel; Moliner, Elisenda; Cilleruelo, María-José; Cuadrado, Irene; Colino, Elena; Castells, Laura; Tagarro, Alfredo; Vilas, Javier; Soler-Palacin, Pere; Blázquez-Gamero, Daniel
DNA detection of human cytomegalovirus (hCMV) in cerebrospinal fluid (CSF) by polymerase chain reaction (PCR) is a marker of central nervous system (CNS) involvement in congenital hCMV infection (cCMV), but its prognostic value is unknown. A multicenter, retrospective study was performed using the Spanish Congenital Cytomegalovirus Infection Database (REDICCMV; http://www.cmvcongenito.es). Newborns with cCMV and a lumbar puncture performed were included and classified according to their hCMV-PCR in CSF result (positive/negative). Clinical characteristics, neuroimaging abnormalities, plasma viral load, and audiological and neurological outcomes of both groups were compared. A total of 136 neonates were included in the study: 21 (15.4%) with positive CSF hCMV-PCR and 115 (84.6%) with negative results. Seventeen patients (81%) in the positive group were symptomatic at birth compared with 52.2% of infants in the negative group (odds ratio [OR], 3.86; 95% confidence interval [CI], 1.28-14.1; P = .01). Only 4 asymptomatic newborns (6.8%) had a positive CSF hCMV-PCR. There were no differences between groups regarding the rate of microcephaly, neuroimaging abnormalities, neurological sequelae at 6 months of age, or plasma viral load. Sensorineural hearing loss (SNHL) at birth was associated with a positive CSF hCMV-PCR result (OR, 3.49; 95% CI, 1.08-11.27; P = .04), although no association was found at 6 months of age. A positive hCMV-PCR result in CSF is associated with symptomatic cCMV and SNHL at birth. However, no differences in neuroimaging studies, plasma viral load, or outcomes at 6 months were found. These results suggest that hCMV-PCR in CSF may not be a useful prognostic marker in cCMV.
Ross, S.A.; Novak, Z.; Pati, S.; Boppana, S.B.
Cytomegalovirus (CMV) is recognized as the most common congenital viral infection in humans and an important cause of morbidity and mortality in immunocompromised hosts. This recognition of the clinical importance of invasive CMV disease in the setting of immunodeficiency and in children with congenital CMV infection has led to the development of new diagnostic procedures for the rapid identification of immunocompromised individuals with CMV disease, as well as fetuses and infants with congenital infection. Diagnosis of acute maternal CMV infection by the presence of IgM and low IgG avidity requires confirmation of fetal infection which is typically performed by CMV PCR of the amniotic fluid. Viral culture of the urine and saliva obtained within the first two weeks of life continue to be the gold standard for diagnosis of congenitally infected infants. PCR assays of dried blood spots from infants have not been shown to have sufficient sensitivity for the identification of most infants with congenital CMV infection. However, saliva PCR assays are currently being assessed as a useful screening method for congenital CMV infection. In the immunocompromised host, newer rapid diagnostic assays such as pp65 antigenemia and real-time CMV PCR of blood or plasma have allowed for preemptive treatment reducing morbidity and mortality. However, lack of standardized real-time PCR protocols hinders the comparison of the data across different centers and the development of uniform guidelines for the management of invasive CMV infections in immunocompromised individuals. PMID:21827433
Effect of a 14-day course of foscarnet on cytomegalovirus (CMV) blood markers in a randomized study of human immunodeficiency virus-infected patients with persistent CMV viremia. Agence National de Recherche du SIDA 023 Study Group.
Salmon-Céron, D; Fillet, A M; Aboulker, J P; Gérard, L; Houhou, N; Carrière, I; Ostinelli, J; Vildé, J L; Brun-Vézinet, F; Leport, C
A randomized open-label phase 2 trial compared the virological and clinical effects on cytomegalovirus (CMV) infection of a 14-day course of intravenous foscarnet (100 mg/[kg x 12 h]) or no treatment in 42 HIV-infected patients with < 100 CD4 cells/mm3 and persistent asymptomatic CMV viremia. All CMV markers (blood culture, pp65 antigenemia, plasma and leukocyte DNA) either became negative or decreased significantly at day 14 in the foscarnet group. CMV blood culture results at day 14 were positive in 14% of those receiving foscarnet versus 60% of control patients (P = .004). However, after the end of treatment, all markers reappeared or the virus load rapidly increased. The probability of CMV disease at 6 months was 43% in both groups. Patients who had or who achieved a negative blood culture at any time had a reduced risk of CMV disease (RR = 2.64; 95% CI = 1.24-5.62; P = .02). This study suggests that sequential courses of intravenous foscarnet might not be a good strategy for preemptive therapy in this population and that in patients with a positive blood marker, treatment able to induce and maintain negative CMV blood cultures could constitute an effective intervention.
Chiereghin, Angela; Pavia, Claudia; Gabrielli, Liliana; Piccirilli, Giulia; Squarzoni, Diego; Turello, Gabriele; Gibertoni, Dino; Simonazzi, Giuliana; Capretti, Maria Grazia; Lanari, Marcello; Lazzarotto, Tiziana
Clinical evaluation of the Elecsys(®) CMV IgM, IgG, IgG Avidity and COBAS AmpliPrep/COBAS TaqMan CMV (COBAS CMV) assays (Roche Diagnostics AG) in the diagnosis and prognosis of congenital CMV infection was performed. In this study, 150 preselected clinical samples (50 primary infection sera, 50 amniotic fluid [AF] and 50 newborn urine) were processed using Roche serological/molecular CMV-specific tests. Results were compared with those obtained by routine assays (comparator assays). The Elecsys(®) CMV IgM and IgG assays showed a perfect agreement (100%) with the comparator assays. Using the combination of the Elecsys(®) CMV IgM and IgG Avidity assays results, a primary infection was identified in 100% of cases. Inappropriate avidity CMV IgG values in two samples with very low IgG values (<6 AU/mL) were observed. COBAS CMV assay showed an agreement equal to 98% and 100% with comparator assays by processing AF and urine samples, respectively. Among AF with quantitative results, Lin's concordance correlation was 0.933 and comparator-COBAS CMV assays gave CMV-DNA loads differing by <0.5 log10 DNA. Finally, higher CMV-DNA levels in AF samples were associated with a symptomatic outcome (p=0.003). The Roche CMV-specific assays compared well with the comparator assays, thus providing to be suitable for clinical use. Copyright © 2017 Elsevier B.V. All rights reserved.
Jin, Haoxing Douglas; Demmler-Harrison, Gail J; Coats, David K; Paysse, Evelyn A; Bhatt, Amit; Edmond, Jane C; Yen, Kimberly G; Steinkuller, Paul; Miller, Jerry
Cytomegalovirus (CMV) is the most common congenital viral infection in the United States. Visual and ocular sequelae in adolescents and adults who are congenitally infected with CMV have not been well studied. Better understanding of the long-term visual and ocular sequelae can help with early detection, intervention and appropriate educational accommodations. This study evaluated 237 patients (77 symptomatic, 109 asymptomatic and 51 control) who underwent a series of age-appropriate ophthalmologic, audiologic and neurodevelopmental examinations from 1982 to 2013. The frequency and etiology of visual impairment and other nonophthalmologic findings were recorded for each patient. Ophthalmologic findings were tabulated, and risk factors for abnormalities were analyzed. Fourteen of the 77 (18.2%) symptomatic and none of the asymptomatic and control subjects had severe visual impairments (P ≤ 0.006). Moderate visual impairment did not differ between symptomatic and asymptomatic subjects. Three asymptomatic subjects had retinal scars. The most common visual or ocular sequelae in the symptomatic group were strabismus (23.4%), chorioretinal scars (19.5%), cortical visual impairment (14.3%), nystagmus (14.3%) and optic nerve atrophy (11.7%). Three symptomatic patients had delayed visual deterioration because of later occurring retinal disorders: peripheral retinal scar, rhegmatogenous retinal detachment and Coats' disease. Symptomatic CMV patients experienced more ophthalmologic sequelae and significantly worse visual outcomes than asymptomatic CMV and control patients. Later occurring retinal disorders were found in symptomatic patients, and there is no clear evidence that CMV can reactivate in the retinas of children who were congenitally infected. Major risk factors for severe visual impairment included symptomatic status, optic nerve atrophy, chorioretinitis, cortical visual impairment and sensorineural hearing loss.
Gordon, Claire L.; Thome, Joseph J.C.; Igarashi, Suzu
T cell responses to viruses are initiated and maintained in tissue sites; however, knowledge of human antiviral T cells is largely derived from blood. Cytomegalovirus (CMV) persists in most humans, requires T cell immunity to control, yet tissue immune responses remain undefined. Here, we investigated human CMV-specific T cells, virus persistence and CMV-associated T cell homeostasis in blood, lymphoid, mucosal and secretory tissues of 44 CMV seropositive and 28 seronegative donors. CMV-specific T cells were maintained in distinct distribution patterns, highest in blood, bone marrow (BM), or lymph nodes (LN), with the frequency and function in blood distinct from tissues. CMV genomes were detected predominantly in lung and also in spleen, BM, blood and LN. High frequencies of activated CMV-specific T cells were found in blood and BM samples with low virus detection, whereas in lung, CMV-specific T cells were present along with detectable virus. In LNs, CMV-specific T cells exhibited quiescent phenotypes independent of virus. Overall, T cell differentiation was enhanced in sites of viral persistence with age. Together, our results suggest tissue T cell reservoirs for CMV control shaped by both viral and tissue-intrinsic factors, with global effects on homeostasis of tissue T cells over the lifespan. PMID:28130404
Sweeten, Thayne L.; Posey, David J.; McDougle, Christopher J.
Previous research has identified a relationship between autistic disorder (autism) and specific congenital infections. Three cases of congenital or perinatal cytomegalovirus (CMV) infection occurring in association with autism are described. Hypothetical mechanisms relating congenital infection, such as CMV, to the development of autism are…
Sweeten, Thayne L.; Posey, David J.; McDougle, Christopher J.
Previous research has identified a relationship between autistic disorder (autism) and specific congenital infections. Three cases of congenital or perinatal cytomegalovirus (CMV) infection occurring in association with autism are described. Hypothetical mechanisms relating congenital infection, such as CMV, to the development of autism are…
López-Oliva, Maria Ovidia; Martinez, Virginia; Buitrago, Agueda; Jiménez, Carlos; Rivas, Begoña; Escuin, Fernando; Santana, María José; Selgas, Rafael; Bellón, Teresa
Cytomegalovirus (CMV) infection is an ongoing clinical problem in solid-organ transplantation (SOT). Pretransplant CMV serology is currently the only tool for assessing the risk of CMV infection, although cellular immune responses driven by CMV-specific CD4 and CD8 T lymphocytes are important for controlling viral replication. Therefore, the analysis of CMV-specific T cells may be useful for estimating the risk of infection. This is a prospective study of patients with kidney transplants and no prophylactic treatment for CMV replication. CD4 and CD8 T-cell responses to the major CMV pp65 and IE-1 antigens in 15 seropositive patients at intermediate risk of CMV infection were investigated, according to current algorithms. Intracellular flow cytometry was employed to determine IFN-γ production as a functional readout. The response was analyzed in pretransplant samples and prospectively at 1 and 6 months and at 1 year posttransplant. It was observed that the CD8 responses to IE-1 antigen were practically absent pretransplant in patients who developed CMV infection posttransplant. Within the group of patients free of infection, CD8 responses to IE-1 were detected more frequently and were significantly higher (P=0.0083). In a receiver operating characteristics curve analysis (AUC=0.929; P=0.010; 95% CI: 0.078-1.0), low CD8 responses to IE-1 (≤0.05%) pretransplant predicted the development of CMV infection under the immunosuppressive regime after transplant with 100% specificity and 85.7% sensitivity. Assessment of IE-1-specific CD8 T-cell frequencies pretransplant may be a useful tool for identifying seropositive SOT patients at risk of developing CMV infection posttransplant.
Kaneko, Masatoki; Ohhashi, Masanao; Minematsu, Toshio; Muraoka, Junsuke; Kusumoto, Kazumi; Sameshima, Hiroshi
The immunoglobulin (Ig) G avidity index (AI) is useful to detect primary cytomegalovirus (CMV) infection. However, because IgG matures with time, this index is not useful to detect a primary infection, unless measured at an appropriate time. We aimed to clarify the difference between using IgG AI and IgM positivity according to the stage of pregnancy to identify congenital CMV infection risk. We collected the serum samples from 1115 pregnant women who underwent maternal screening for primary infection (n = 956) and were referred to our hospital because of CMV IgM positivity (n = 155) or had abnormal fetal ultrasonography findings (n = 4). The same sera samples were used to measure CMV IgM, IgG, and IgG AI. An IgG AI of <35% was defined as low. Neonatal urine collected within 5 days after birth was examined by polymerase chain reaction to confirm congenital infection. Fourteen mothers gave birth to infected neonates. The sensitivity, specificity, and negative predictive values of the low IgG AI group with IgM-positive samples to discriminate between women with congenital infection at ≤14 weeks of gestation were 83.3, 83.8, and 99.1, respectively, which were higher than those of other subjects. Uni- and multivariate analyses revealed that IgM positivity and low IgG AI were independent variables associated with congenital infection at any stage of pregnancy, except low IgG AI at ≥15 weeks of gestation. Low IgG AI with IgM positivity at ≤14 weeks of gestation was a good indicator of congenital infection, which should prove useful in obstetric practice. Copyright © 2016 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.
Gil, Lidor; Ben-Ari, Julius; Turgeon, Robert; Wolf, Shmuel
Ultrastructural and molecular studies have provided experimental evidence for the classification of cucurbits as symplastic loaders, mainly translocating the raffinose family oligosaccharides (RFOs) raffinose and stachyose. Earlier studies established that cucumber mosaic virus (CMV) infection causes a significant increase in the sucrose-to-RFO ratio in the phloem sap of melon plants. The alteration in phloem sap sugar composition was associated with upregulation of CmSUT1 transcript within the vascular bundles. The current research aimed to explore the effect of CMV infection on the enzymes involved in symplastic phloem loading and RFO biosynthesis. Viral infection did not affect the activity of either raffinose or stachyose synthases in source leaves, but caused upregulation of the respective transcripts. Interestingly, activity of galactinol synthase was higher in CMV-infected leaves, associated with upregulation of CmGAS2. A significant increase in CmGAS2 expression in source leaves of melon plants exposed to high temperatures indicated that this response is common for both biotic and abiotic stresses. However, the effect of CMV or heat stress on phloem sap sugar composition is not due to alteration in RFO biosynthesis.
Nigro, Giovanni; Capretti, Ilaria; Manganello, Anne-Marie; Best, Al M; Adler, Stuart P
Cytomegalovirus (CMV) hyperimmune globulin (HIG) may be helpful after a primary maternal CMV infection during pregnancy as a therapy for infected fetuses or to prevent maternal-to-fetus transmission of CMV. Although immunoglobulins administered during pregnancy appear safe, previous studies have not monitored HIG for a possible effect on duration of gestation and birth weight. We used clinical data on 358 women with a primary CMV infection during pregnancy, 164 of whom received one or more infusions of HIG. The average birth weight of the 358 infants was 3076 g and the average gestational age at delivery for 351 women was 38.2 weeks. After adjusting for potential confounding variables, the only factor associated with low birth weight and the duration of gestation was the presence of symptoms at birth. The receipt of HIG was not associated with either a diminished birth weight or a reduced duration of pregnancy. The receipt of multiple doses of HIG (range 1-8) was significantly correlated with an increase in birth weight (p=0.006) and gestational age at delivery (p=0.014). This correlation was also significant for all asymptomatic infants and for infants whose mothers received multiple doses of HIG to prevent fetal infection. HIG administration during pregnancy is not associated with either diminished gestation or decreased birth weight and may enhance these parameters among women who receive multiple doses starting in early gestation.
Streitenberger, Edgardo Raúl; Suárez, Ariel Ignacio; Masciovecchio, María Verónica; Laurnagaray, Diana; Alda, Ernesto
Hearing loss may be attributed to genetic and environmental factors. Mutations in the gene of the CX26 protein (connexin 26), are responsible for 30-80% of all cases of non-syndromic profound hearing loss. The 35delG is the most frequent variant in the caucasian population. As to environmental factors, the cytomegalovirus (CMV) is the main cause of congenital infection. To determine the prevalence of congenital CMV infection and the frequency of the 35delG mutation in newborns. To identify those at risk of suffering hearing loss in order to do an audiologic follow-up of detected cases. One thousand and twenty samples of dry blood spots corresponding to newborns were tested using conventional and real time PCR. Audiologic screening was performed to all newborns before hospital discharge. Fifteen out of 1020 subjects were heterozygous for the mutation. No homozygous patients were found. Six out of the samples tested positive for CMV (confirmed by a urine sample), out of which only one newborn was symptomatic. The auditory brainstem response was recorded in all these children. Hearing loss was found in three children with congenital CMV infection and two with 35delG mutation. The frecuency of 35delG mutation carriers in our population was 1.3% and the CMV congenital infection prevalence was 0.6%. Audiologic monitoring of these two populations allowed detection of hearing loss of late onset.
Nijman, Joppe; Mandemaker, Femke S; Verboon-Maciolek, Malgorzata A; Aitken, Susan C; van Loon, Anton M; de Vries, Linda S; Schuurman, Rob
Congenital cytomegalovirus infection is a leading cause of long-term sequelae. Cytomegalovirus is also frequently transmitted to preterm infants postnatally, but these infections are mostly asymptomatic. A correlation between cytomegalovirus genotypes and clinical manifestations has been reported previously in infants with congenital infection, but not in preterm infants with postnatal infection. The main objective of this study was to investigate cytomegalovirus genotype distribution in postnatal and congenital cytomegalovirus infection and its association with disease severity. Infants admitted to the neonatal intensive care unit of the University Medical Center Utrecht, The Netherlands between 2003-2010 and diagnosed with postnatal or congenital cytomegalovirus infection were included. Classification of cytomegalovirus isolates in genotypes was performed upon amplification and sequencing of the cytomegalovirus UL55 (gB) and UL144 genes. Clinical data, cerebral abnormalities, neurodevelopmental outcome and viral load were studied in relation to genotype distribution. Genotyping results were obtained from 58 preterm infants with postnatal cytomegalovirus infection and 13 infants with congenital cytomegalovirus infection. Postnatal disease was mild in all preterm infants and all had favourable outcome. Infants with congenital infection were significantly more severely affected than infants with postnatal infection. Seventy-seven percent of these infants were symptomatic at birth, 2/13 died and 3/13 developed long-term sequelae (median follow-up 6 (range 2-8) years). The distribution of cytomegalovirus genotypes was comparable for postnatal and congenital infection. UL55 genotype 1 and UL144 genotype 3 were predominant genotypes in both groups. Distribution of UL55 and UL144 genotypes was similar in asymptomatic postnatal and severe congenital CMV infection suggesting that other factors rather than cytomegalovirus UL55 and UL144 genotype are responsible for the
DePasquale, John M; Freeman, Karen; Amin, Minal M; Park, Sohyun; Rivers, Samantha; Hopkins, Richard; Cannon, Michael J; Dy, Bonifacio; Dollard, Sheila C
The objectives of this study are (1) to design an accurate method for linking newborn screening (NBS) and state birth certificate databases to create a de-identified study database; (2) To assess maternal cytomegalovirus (CMV) seroprevalence by measuring CMV IgG in newborn dried blood spots; (3) To assess congenital CMV infection among newborns and possible association with preterm birth. NBS and birth databases were linked and patient records were de-identified. A stratified random sample of records based on gestational age was selected and used to retrieve blood spots from the state NBS laboratory. Serum containing maternal antibodies was eluted from blood spots and tested for the presence of CMV IgG. DNA was extracted from blood spots and tested for the presence of CMV DNA. Analyses were performed with bivariable and multivariable logistic regression models. Linkage rates and specimen collection exceeded 98% of the total possible yielding a final database with 3,101 newborn blood spots. CMV seroprevalence was 91% among Black mothers, 83% among Hispanic mothers, 59% among White mothers, and decreased with increasing amounts of education. The prevalence of CMV infection in newborns was 0.45% and did not vary significantly by gestational age. Successful methods for database linkage, newborn blood spots collection, and de-identification of records can serve as a model for future congenital exposure surveillance projects. Maternal CMV seroprevalence was strongly associated with race/ethnicity and educational level. Congenital CMV infection rates were lower than those reported by other studies and lacked statistical power to examine associations with preterm birth.
Ross, Shannon A; Ahmed, Amina; Palmer, April L; Michaels, Marian G; Sánchez, Pablo J; Bernstein, David I; Tolan, Robert W; Novak, Zdenek; Chowdhury, Nazma; Fowler, Karen B; Boppana, Suresh B
Viral culture of urine or saliva has been the gold standard technique for the diagnosis of congenital cytomegalovirus (CMV) infection. Results of rapid culture and polymerase chain reaction (PCR) analysis of urine and saliva specimens from 80 children were compared to determine the clinical utility of a real-time PCR assay for diagnosis of congenital CMV infection. Results of urine PCR were positive in 98.8% of specimens. Three PCR-positive urine samples were culture negative. Results of saliva PCR and culture were concordant in 78 specimens (97.5%). Two PCR-positive saliva samples were culture negative. These findings demonstrate that PCR performs as well as rapid culture of urine or saliva specimens for diagnosing congenital CMV infection and saliva specimens are easier to collect. Because PCR also offers more rapid turnaround, is unlikely to be affected by storage and transport conditions, has lower cost, and may be adapted to high-throughput situations, it is well suited for targeted testing and large-scale screening for CMV.
Vives-Oñós, Isabel; Soler-Palacín, Pere; Codina-Grau, María Gemma; Martín-Nalda, Andrea; López-Galera, Rosa María; Marín-Soria, José Luís; Figueras-Nadal, Concepció
The detection of cytomegalovirus (CMV) DNA by real time polymerase chain reaction (rt-PCR) in dried blood spots collected routinely for metabolic screening has been assessed for the retrospective diagnosis of congenital CMV (cCMV) infection in many studies, but not in Spain. The aim of this study is to analyze the diagnostic accuracy of this technique in our hospital. A cross-sectional retrospective observational study was conducted including all patients born between January, 2007 and September, 2012 with confirmed cCMV infection. The assessment of CMV DNA was made by using rt-PCR in dried blood spots of these patients. Fourteen patients were included: 4/14 were symptomatic and 4/14 had sequelae. The detection of CMV DNA by rt-PCR was positive in only 7 patients. A statistically significant relationship between low viral load at birth and negative rt-PCR in dried blood spots was demonstrated. Despite the low number of patients included, our data highlight an important amount of false negative results in the DNA CMV detection by rt-PCR in these samples for the retrospective diagnosis of cCMV infection, especially in cases with low viral load at birth. Copyright © 2013 Elsevier España, S.L.U. y Sociedad Española de Enfermedades Infecciosas y Microbiología Clínica. All rights reserved.
Poizot-Martin, Isabelle; Allavena, Clotilde; Duvivier, Claudine; Cano, Carla Eliana; Guillouet de Salvador, Francine; Rey, David; Dellamonica, Pierre; Cuzin, Lise; Cheret, Antoine; Hoen, Bruno
Cytomegalovirus (CMV) infection is common among HIV-infected patients but its repercussion on the course of CD4+ and CD8+ T cells after cART initiation remains elusive. The French Dat'AIDS cohort enrolled 5,688 patients on first-line cART, from which we selected patients who achieved HIV suppression for at least 12 months without modification of cART, and for whom CMV serostatus was available. Five hundred and three patients fulfilled the selection criteria (74% male, median age 43 yrs, 15.5% CDC stage C), of whom 444 (88.3%) were seropositive for CMV (CMV+). Multivariate analyses using mixed-linear models adjusted for the time from HIV suppression, sex, age, transmission risk group, duration of HIV follow-up, the interaction between time from HIV suppression and CMV+ serology, and the nadir CD4 count revealed a negative correlation between CMV+ and CD4:CD8 ratio (coeff. = -0.16; p = 0.001). This correlation was also observed among patients displaying optimal CD4 recovery (≥500 cells/mm3 at M12; coeff. = -0.24; p = 0.002). Hence, CMV+ serostatus antagonizes normalization of the CD4:CD8 ratio, although further analyses of the impact of co-morbidities that associate with CMV serostatus, like HCV infection, are needed to elucidate this antagonism formally. However, this might reflect a premature T cell senescence, thus advocating for a close monitoring of T cells in CMV co-infected patients. In addition, our results raise the question of the benefit of treatment for asymptomatic CMV co-infection in HIV-infected patients. PMID:27824907
Kadambari, Seilesh; Atkinson, Claire; Luck, Suzanne; Macartney, Malcolm; Conibear, Tim; Harrison, Ian; Booth, Clare; Sharland, Mike; Griffiths, Paul D
Cytomegalovirus (CMV) is the most common congenital infection in humans and a leading cause of sensorineural hearing loss. Ganciclovir (6 mg/kg twice daily for 42 days) has been shown to reduce hearing deterioration and is used in clinical practice. Vaccines and passive administration of antibody are being evaluated in randomized controlled trials in allograft candidates, women of childbearing age, and pregnant women with primary CMV infection. To help define genetic variation in each of the targets of these therapeutic interventions, we amplified and sequenced genes UL97 (site utilised for ganciclovir phosphorylation), UL55 (glycoprotein B (gB) vaccine target) and UL128, UL130, and UL131a (specific monoclonal antibody targets). Serial blood, saliva, and urine samples (total 120) obtained from nine infants with symptomatic congenital CMV treated with 42 days' ganciclovir were analyzed. All samples tested were UL97 wild type at baseline and none developed mutations during treatment, showing no selection of resistance. The prevalences of UL55 genotypes were 28% gB1, 22% gB2, 1% gB3, and mixed in 20% samples. No mutations were noted in UL128-131a. Phylogenetic tree analysis showed that sequences with variations were found in multiple body sites of individual patients, so there was no evidence of body site compartmentalization of particular strains of CMV. The significance of these results for changes in diagnostic practices and therapeutic interventions against CMV are discussed. J. Med. Virol. 89:502-507, 2017. © 2016 Wiley Periodicals, Inc.
Maes, Leen; De Kegel, Alexandra; Van Waelvelde, Hilde; De Leenheer, Els; Van Hoecke, Helen; Goderis, Julie; Dhooge, Ingeborg
Hearing-impaired children are at risk for vestibular damage and delayed motor development. Two major causes of congenital hearing loss are cytomegalovirus (CMV) infection and connexin (Cx) 26 mutations. Comparison of the motor performance and vestibular function between these specific groups is still underexplored. The objective of this study was to investigate the impact of congenital (c)CMV and Cx26 on the motor performance and vestibular function in 6 months old infants. Forty children (mean age 6.7 months; range 4.8 to 8.9 months) participated in this cross-sectional design and were recruited from the Flemish CMV registry. They were divided into five age-matched groups: normal-hearing control, asymptomatic cCMV, normal-hearing symptomatic cCMV, hearing-impaired symptomatic cCMV, and hearing-impaired Cx26. Children were examined with the Peabody Developmental Motor Scales-2 and cervical vestibular-evoked myogenic potential (cVEMP) test. Symptomatic hearing-impaired cCMV children demonstrated a significantly lower gross motor performance compared with the control group (p = 0.005), the asymptomatic cCMV group (p = 0.034), and the Cx26 group (0.016). In this symptomatic hearing-impaired cCMV group, 4 out of 8 children had absent cVEMP responses that were related to the weakest gross motor performance. The Cx26 children showed no significant delay in motor development compared with the control children and none of these children had absent cVEMP responses. The weakest gross motor performance was found in symptomatic hearing-impaired cCMV-infected children with absent cVEMP responses. These results suggest that abnormal saccular responses are a major factor for this delayed motor development, although more work is needed including comprehensive vestibular function testing to verify this.
Wang, Y; Lee, K C; Gaba, V; Wong, S M; Palukaitis, P; Gal-On, A
Resistance to the cucumovirus Cucumber mosaic virus (CMV) in cucumber cv. Delila was manifested as a very low level of accumulation of viral RNA and capsid protein, and an absence of CMV-induced symptoms. In addition, resistance was observed at the single cell level, with a reduction in accumulation of CMV RNAs, compared to accumulation in cells of the susceptible cucumber cv. Bet Alpha. Resistance to CMV in cv. Delila was broken by co-infection with the potyvirus Zucchini yellow mosaic virus (ZYMV). Resistance breakage in cv. Delila plants was manifested by an increase in the accumulation of (+) and (-) CMV RNA as well as CMV capsid protein, with no increase in the level of accumulation of ZYMV. Resistance breakage in the resistant cultivar by ZYMV also occurred at the single cell level. Thus, synergistic interactions known to occur between a potyvirus and a cucumovirus led to resistance breakage during a double infection. However, resistance breakage was not accompanied by an increase in disease symptoms beyond those induced by ZYMV itself. On co-inoculation with an asymptomatic variant of ZYMV-AG an enhancement of CMV infection occurred without disease manifestation. Consequently, intensification of viral RNA and capsid protein accumulation can occur without a corresponding increase in disease development, suggesting that different host genes regulate viral accumulation and disease development in the CMV-resistant cucumber plants.
Willeford, Wesley G; Lichstein, Peter; Ohar, Jill
Hemophagocytic lymphohistiocytosis (HLH) is a rare and often deadly syndrome characterized by severe inflammation and cytokine dysregulation. The disease is defined by the HLH-2004 criteria, requiring five of eight findings, and is further differentiated into either primary or secondary causes. Primary HLH tends to be of genetic etiology, while secondary HLH results from other insults such as infection. Secondary HLH is most commonly associated with viral infections in immunocompromised patients. Acute cytomegalovirus (CMV) associated HLH in the immunocompetent host is exceedingly rare and only documented in four case reports to date. We describe the fifth documented case of CMV-associated HLH in an immunocompetent patient, and furthermore, we demonstrate that this patient is the first published case of its type to satisfy all eight of HLH-2004 criteria. PMID:28409071
Hogea, Cosmina; Dieussaert, Ilse; Van Effelterre, Thierry; Guignard, Adrienne; Mols, Johann
We present an age-structured dynamic transmission model for cytomegalovirus (CMV) in the United States, based on natural history and available data, primarily aiming to combine the available qualitative and quantitative knowledge toward more complex modeling frameworks to better reflect the underlying biology and epidemiology of the CMV infection. The model structure explicitly accounts for primary infections, reactivations and re-infections. Duration of infectiousness and likelihood of reactivation were both assumed to be age-dependent, and natural reduction in the re-infection risk following primary infection was included. We used an empirical social contact matrix (POLYMOD-based) as support for CMV transmission between different age groups. The baseline model reproduced well the age-stratified seroprevalence data (National Health and Nutrition Examination Survey III) used for calibration. The model was further used to explore the potential impact of hypothetical vaccination on reducing congenital CMV infection under various vaccine profiles and vaccination scenarios. Our preliminary model-based simulations suggested that while infant vaccination may represent an attractive way to reduce congenital CMV infection over time, adolescent female vaccination with an adequate routine booster platform may, under certain conditions, provide an alternative. However, for such tools to be considered toward actual decision-making, enhanced validations based on additional studies and data would be further necessary. The modeling framework presented in this paper was designed to be sufficiently general and flexible, such that it can allow for further adaptations to reflect new knowledge or data that may become available in the future.
Dahle, Arthur J.; And Others
When the hearing sensitivity of children with subclinical congenital cytomegalovirus infection was evaluated and compared with that of a group of matched control subjects, nine of the 18 infected subjects were found to have some hearing loss, ranging from slight high-frequency impairments to a severe-to-profound unilateral loss. (MYS)
Friedman, Smadar; Ford-Jones, E Lee
Cytomegalovirus is estimated to be the leading infectious cause of nonheriditary sensorneural loss and a significant cause of mental retardation. Approximately 1% of newborn infants are congenitally infected with the virus. This review summarizes recent developments concerning this infection, including clinical outcome, risk factors for aquisition diagnosis and therapy. PMID:20212987
Broadley, Iain; Pera, Alejandra; Morrow, George; Davies, Kevin A.; Kern, Florian
A large proportion of cardiovascular (CV) pathology results from immune-mediated damage, including systemic inflammation and cellular proliferation, which cause a narrowing of the blood vessels. Expansions of cytotoxic CD4+ T cells characterized by loss of CD28 (“CD4+CD28− T cells” or “CD4+CD28null cells”) are closely associated with cardiovascular disease (CVD), in particular coronary artery damage. Direct involvement of these cells in damaging the vasculature has been demonstrated repeatedly. Moreover, CD4+CD28− T cells are significantly increased in rheumatoid arthritis (RA) and other autoimmune conditions. It is striking that expansions of this subset beyond 1–2% occur exclusively in CMV-infected people. CMV infection itself is known to increase the severity of autoimmune diseases, in particular RA and has also been linked to increased vascular pathology. A review of the recent literature on immunological changes in CVD, RA, and CMV infection provides strong evidence that expansions of cytotoxic CD4+CD28− T cells in RA and other chronic inflammatory conditions are limited to CMV-infected patients and driven by CMV infection. They are likely to be responsible for the excess CV mortality observed in these situations. The CD4+CD28− phenotype convincingly links CMV infection to CV mortality based on a direct cellular-pathological mechanism rather than epidemiological association. PMID:28303136
Fernández-Ruiz, M; Corrales, I; Arias, M; Campistol, J M; Giménez, E; Crespo, J; López-Oliva, M O; Beneyto, I; Martín-Moreno, P L; Llamas-Fuente, F; Gutiérrez, A; García-Álvarez, T; Guerra-Rodríguez, R; Calvo, N; Fernández-Rodríguez, A; Tabernero-Romo, J M; Navarro, M D; Ramos-Verde, A; Aguado, J M; Navarro, D
In this study, we assessed the association between single-nucleotide polymorphisms (SNPs) in seven candidate genes involved in orchestrating the immune response against cytomegalovirus (CMV) and the 12-month incidence of CMV infection in 315 CMV-seropositive kidney transplant (KT) recipients. Patients were managed either by antiviral prophylaxis or preemptive therapy. CMV infection occurred in 140 patients (44.4%), including 13 episodes of disease. After adjusting for various clinical covariates, patients harboring T-allele genotypes of interleukin-28B (IL28B) (rs12979860) SNP had lower incidence of CMV infection (adjusted hazard ratio [aHR]: 0.66; 95% confidence interval [CI]: 0.46-0.96; p-value = 0.029). In the analysis restricted to patients not receiving prophylaxis, carriers of the TT genotype of toll-like receptor 9 (TLR9) (rs5743836) SNP had lower incidence of infection (aHR: 0.61; 95% CI: 0.38-0.96; p-value = 0.035), whereas the GG genotype of dendritic cell-specific ICAM 3-grabbing nonintegrin (DC-SIGN) (rs735240) SNP exerted the opposite effect (aHR: 1.86; 95% CI: 1.18-2.94; p-value = 0.008). An independent association was found between the number of unfavorable SNP genotypes carried by the patient and the incidence of CMV infection. In conclusion, specific SNPs in IL28B, TLR9 and DC-SIGN genes may play a role in modulating the susceptibility to CMV infection in CMV-seropositive KT recipients.
Yoon, Hoi Soo; Choi, Yong-Sung; Im, Ho Joon
Hepatic angiosarcomas are uncommon, highly aggressive tumors, rarely seen in children. A 3-month-old female infant was admitted to hospital for evaluation of multiple petechiae on her body. She had hepatosplenomegaly and scattered petechiae over her entire body. Laboratory tests indicated thrombocytopenia and positive cytomegalovirus (CMV) polymerase chain reaction. Ganciclovir was started, and the platelet count increased. After 4 months the patient was readmitted to hospital for drowsy mental status and eventually died from severe bleeding. Needle biopsy of the liver was performed after receiving written consent from the parents. Pathological findings of the liver lesion included features consistent with hepatic angiosarcoma. There have been no previous reports of hepatic angiosarcoma in Korean infants. Here, we report an infant with hepatosplenomegaly and thrombocytopenia who was diagnosed with hepatic angiosarcoma mimicking congenital CMV infection.
Boppana, Suresh B.; Ross, Shannon A.; Novak, Zdenek; Shimamura, Masako; Tolan, Robert W.; Palmer, April L.; Ahmed, Amina; Michaels, Marian G.; Sánchez, Pablo J.; Bernstein, David I.; Britt, William J.; Fowler, Karen B.
Context Reliable methods to screen newborns for congenital cytomegalovirus (CMV) infection are needed for identification of infants at increased risk for hearing loss. Since dried blood spots (DBS) are routinely collected for metabolic screening from all newborns in the United States, there has been interest in using DBS polymerase chain reaction (PCR)-based methods for newborn CMV screening. Objective To determine the diagnostic accuracy of DBS real-time PCR assays for newborn CMV screening Design, Setting, and Participants Between March 2007 and May 2008, infants born at seven medical centers in the U.S. were enrolled in the CMV and Hearing Multicenter Screening (CHIMES) study. Newborn saliva specimens were tested for the detection of early antigen fluorescent foci (DEAFF). Results of saliva DEAFF were compared with a single-primer (from 03/07 to 12/07) and a two-primer (from 01/08 to 05/08) DBS real-time PCR. Infants positive by screening DEAFF or PCR were enrolled in follow-up to confirm congenital infection by the reference standard method, DEAFF on saliva or urine. Main Outcome Measures Sensitivity, specificity and positive and negative likelihood ratios (LRs) of single-primer and two-primer DBS real-time PCR assays for identifying infants with confirmed congenital CMV infection. Results Congenital CMV infection was confirmed in 92 of 20,448 (0.45%; 95% CI, 0.36–0.55) infants. Ninety-one of 92 infants were saliva DEAFF positive on screening. Of the 11,422 infants screened using the single-primer DBS PCR, 17 of 60 (28%) infants were positive with this assay, whereas, among the 9,026 infants screened using the two-primer DBS PCR, 11 of 32 (34%) infants were positive. The single-primer DBS PCR identified congenital CMV infection with a sensitivity of 28.3% (95% CI, 17.4–41.4%), specificity, 99.9% (95% CI, 99.9–100%), positive LR, 803.7 (95% CI, 278.7–2317.9), and negative LR, 0.7 (95% CI, 0.6–0.8). The positive and negative predictive values of the
Pipeling, Matthew R.; West, Erin E.; Osborne, Christine M.; Whitlock, Amanda B.; Dropulic, Lesia K.; Willett, Matthew H.; Forman, Michael; Valsamakis, Alexandra; Orens, Jonathan B.; Moller, David R.; Lechtzin, Noah; Migueles, Stephen A.; Connors, Mark; McDyer, John F.
Acquisition of T cell responses during primary CMV infection in lung transplant recipients (LTRs) appear critical for host defense and allograft durability, with increased mortality in donor+/recipient− (D+R−) individuals. In 15 D+R− LTRs studied, acute primary CMV infection was characterized by viremia in the presence or absence of pneumonitis, with viral loads higher in the lung airways/allograft compared with the blood. A striking influx of CD8+ T cells into the lung airways/allograft was observed, with inversion of the CD4+:CD8+ T cell ratio. De novo CMV-specific CD8+ effector frequencies in response to pooled peptides of pp65 were strikingly higher in lung mononuclear cells compared with the PBMC and predominated over IE1-specific responses and CD4+ effector responses in both compartments. The frequencies of pp65-specific cytokine responses were significantly higher in lung mononuclear cells compared with PBMC and demonstrated marked contraction with long-term persistence of effector memory CD8+ T cells in the lung airways following primary infection. CMV-tetramer+CD8+ T cells from PBMC were CD45RA− during viremia and transitioned to CD45RA+ following resolution. In contrast, CMV-specific CD8+ effectors in the lung airways/allograft maintained a CD45RA− phenotype during transition from acute into chronic infection. Together, these data reveal differential CMV-specific CD8+ effector frequencies, immunodominance, and polyfunctional cytokine responses predominating in the lung airways/allograft compared with the blood during acute primary infection. Moreover, we show intercompartmental phenotypic differences in CMV-specific memory responses during the transition to chronic infection. PMID:18566421
Berth, M; Benoy, I; Christensen, N
Cytomegalovirus (CMV) DNA detection in blood could, as a supplementary test to serology, improve the accuracy and speed of diagnosis of an acute CMV infection. In this study we evaluated the performance of a commercially available and standardised CMV PCR assay in whole blood for the diagnosis of a primary infection in immunocompetent adults. Moreover, the kinetics of viral DNA was evaluated in order to provide a time frame in which viral DNA could be detected during an acute primary infection. Whole blood samples were collected from 66 patients with an acute CMV infection, 65 patients with an acute Epstein-Barr virus infection, 27 patients with various other acute infections (parvovirus B19, HIV, Toxoplasma gondii), 20 patients with past CMV infections (>1 year) and 20 apparently healthy persons. For CMV DNA detection and quantification a commercially available real-time PCR was applied (RealStar®, altona Diagnostics). The clinical sensitivity of CMV PCR in whole blood for the diagnosis of a recent primary CMV infection was 93.9 % and the diagnostic specificity 99.2 %. In the majority of the patients CMV DNA was not detectable anymore approximately within 4 weeks after the first blood sample was taken. From these data we concluded that, together with a suggestive serological profile, a positive CMV PCR result in whole blood can be regarded as a diagnostic confirmation of a recent CMV infection on a single blood sample in an immunocompetent patient. However, a negative CMV PCR result does not exclude a recent CMV infection.
Gunkel, J; Nijman, J; Verboon-Maciolek, M A; Wolfs, Tfw; de Vries, L S
This study evaluated the recognition and management practices with regard to congenital cytomegalovirus (cCMV) infections by a select group of experts and through a national surveillance study. A questionnaire was sent to international experts involved in mother and infant care in 2014-2015. Monthly surveillance was conducted among Dutch paediatricians for cases of cCMV infections from 2013 until 2015. The questionnaire was completed by 63/103 (62%) respondents, who indicated that recognition and management practices varied. Maternal screening was performed by 17/63 (27%) and infant screening by 3/61 (5%) of the respondents. Infant CMV diagnostics were most frequently initiated due to hepatosplenomegaly and/or an increase in liver transaminases. Management practices included cranial ultrasound (57/63, 91%) and audiological follow-up in symptomatic (61/63, 97%) and asymptomatic (52/63, 83%) infants. In terms of antiviral treatment, 46/63 (73%) treated symptomatic infants only and 6/63 (9%) treated all infected infants. In total, 48 cases were registered through the Dutch surveillance study and 43/48 (90%) infants were symptomatic. This study indicates that infants with cCMV infection were insufficiently recognised and highlights the need for consensus on management practices. Screening of infants and the development of an international management guideline are recommended. ©2017 Foundation Acta Paediatrica. Published by John Wiley & Sons Ltd.
Gómez-Mora, Elisabet; García, Elisabet; Urrea, Victor; Massanella, Marta; Puig, Jordi; Negredo, Eugenia; Clotet, Bonaventura; Blanco, Julià; Cabrera, Cecilia
Poor CD4(+) T-cell recovery after cART has been associated with skewed T-cell maturation, inflammation and immunosenescence; however, T-cell functionality in those individuals has not been fully characterized. In the present study, we assessed T-cell function by assessing cytokine production after polyclonal, CMV and HIV stimulations of T-cells from ART-suppressed HIV-infected individuals with CD4(+) T-cell counts >350 cells/μL (immunoconcordants) or <350 cells/μL (immunodiscordants). A group of HIV-uninfected individuals were also included as controls. Since CMV co-infection significantly affected T-cell maturation and polyfunctionality, only CMV(+) individuals were analyzed. Despite their reduced and skewed CD4(+) T-cell compartment, immunodiscordant individuals showed preserved polyclonal and HIV-specific responses. However, CMV response in immunodiscordant participants was significantly different from immunoconcordant or HIV-seronegative individuals. In immunodiscordant subjects, the magnitude of IFN-γ(+) CD8(+) and IL-2(+) CD4(+) T-cells in response to CMV was higher and differently associated with the CD4(+) T-cell maturation profile., showing an increased frequency of naïve, central memory and EMRA CMV-specific CD4(+) T-cells. In conclusion, CD4(+) and CD8(+) T-cell polyfunctionality was not reduced in immunodiscordant individuals, although heightened CMV-specific immune responses, likely related to subclinical CMV reactivations, may be contributing to the skewed T-cell maturation and the higher risk of clinical progression observed in those individuals.
Hua, Na; Wei, Lai; Jiang, Tao; Guo, Ying; Wang, Meiyi; Wang, Zhiqiang
To investigate the pathology characteristics of congenital preauricular fistula with infection, in order to reduce the recurrence rate after surgery and improve operative technique. Twenty-five patients diagnosed as congenital preauricular fistula with infection were analyzed. There were 14 patients in infection history group, 9 in infective stage group, and 2 in recurrence group respectively. The whole piece of fistula and scar tissue was completely excised during operation. The specimens were observed by naked eye and serial tissue sections were analyzed. (1) Macroscopically, in infection history group, initial morphology can be maintained near the fistula orifice, but the distal tissue was dark red scar tissue. In infective stage group, the distal tissue of the specimens was granulation tissue and cicatricial tissue. The granulation tissue was crisp and bright red. In recurrence group, multicystic lesions with severe edema was observed, with a classical dumb-bell appearence. (2) Microscopically, in infection history group and recurrence group, we can see that the distal fistula tissue was discontinuous and was separated by scar tissue. In infective stage group, we can find neo-angiogenesis and infiltration of plasma cells, lymphocytes, neutrophil between interrupted fistula tissues. (3) All patients were followed up for 6-12 month, without recurrence. The fistula tissue of congenital preauricular fistula with infection was divided by the scar tissue, and they did not communicate with each other. Complete delineation of fistula is hardly achieved by methylene blue staining. Radical excision of the fistula and scar tissue may help to avoid leaving viable squamous epithelial remnants and reduce the recurrence rate.
Stranzinger, Johanna; Kozak, Agnessa; Schilgen, Benjamin; Paris, Diana; Nießen, Thomas; Schmidt, Lutz; Wille, Andreas; Wagner, Norbert L.; Nienhaus, Albert
Background: Close contact with asymptomatic children younger than three years is a risk factor for a primary cytomegalovirus (CMV) infection. In pregnant women, such primary infection increases the risk of CMV-induced feto- or embryopathy. Daycare providers have therefore implemented working restrictions for pregnant daycare workers (DCWs) in accordance with legislation and guidelines for maternity protection. However, little is known about the infection risk for DCWs. We therefore compared the prevalence of CMV antibodies of pregnant DCWs to that of female blood donors (BDs). Method: In a secondary data analysis, the prevalence of anti-CMV IgG among pregnant DCWs (N=509) in daycare centers (DCCs) was compared to the prevalence of female first-time BDs (N=14,358) from the greater region of Hamburg, Germany. Data collection took place between 2010 and 2013. The influence of other risk factors such as age, pregnancies and place of residence was evaluated using logistic regression models. Results: The prevalence of CMV antibodies in pregnant DCWs was higher than in female BDs (54.6 vs 41.5%; OR 1.6; 95%CI 1.3–1.9). The subgroup of BDs who had given birth to at least one child and who lived in the city of Hamburg (N=2,591) had a prevalence of CMV antibodies similar to the prevalence in pregnant DCWs (53.9 vs 54.6%; OR 0.9; 95%CI 0.8–1.2). Age, pregnancy history and living in the center of Hamburg were risk factors for CMV infections. Conclusion: The comparison of pregnant DCWs to the best-matching subgroup of female first-time BDs with past pregnancies and living in the city of Hamburg does not indicate an elevated risk of CMV infection among DCWs. However, as two secondary data sets from convenience samples were used, a more detailed investigation of the risk factors other than place of residence, age and maternity was not possible. Therefore, the CMV infection risk in DCWs should be further studied by taking into consideration the potential preventive effect of
Melo, Adriana Suely de Oliveira; Aguiar, Renato Santana; Amorim, Melania Maria Ramos; Arruda, Monica B; Melo, Fabiana de Oliveira; Ribeiro, Suelem Taís Clementino; Batista, Alba Gean Medeiros; Ferreira, Thales; Dos Santos, Mayra Pereira; Sampaio, Virgínia Vilar; Moura, Sarah Rogéria Martins; Rabello, Luciana Portela; Gonzaga, Clarissa Emanuelle; Malinger, Gustavo; Ximenes, Renato; de Oliveira-Szejnfeld, Patricia Soares; Tovar-Moll, Fernanda; Chimelli, Leila; Silveira, Paola Paz; Delvechio, Rodrigo; Higa, Luiza; Campanati, Loraine; Nogueira, Rita M R; Filippis, Ana Maria Bispo; Szejnfeld, Jacob; Voloch, Carolina Moreira; Ferreira, Orlando C; Brindeiro, Rodrigo M; Tanuri, Amilcar
Recent studies have reported an increase in the number of fetuses and neonates with microcephaly whose mothers were infected with the Zika virus (ZIKV) during pregnancy. To our knowledge, most reports to date have focused on select aspects of the maternal or fetal infection and fetal effects. To describe the prenatal evolution and perinatal outcomes of 11 neonates who had developmental abnormalities and neurological damage associated with ZIKV infection in Brazil. We observed 11 infants with congenital ZIKV infection from gestation to 6 months in the state of Paraíba, Brazil. Ten of 11 women included in this study presented with symptoms of ZIKV infection during the first half of pregnancy, and all 11 had laboratory evidence of the infection in several tissues by serology or polymerase chain reaction. Brain damage was confirmed through intrauterine ultrasonography and was complemented by magnetic resonance imaging. Histopathological analysis was performed on the placenta and brain tissue from infants who died. The ZIKV genome was investigated in several tissues and sequenced for further phylogenetic analysis. Description of the major lesions caused by ZIKV congenital infection. Of the 11 infants, 7 (63.6%) were female, and the median (SD) maternal age at delivery was 25 (6) years. Three of 11 neonates died, giving a perinatal mortality rate of 27.3%. The median (SD) cephalic perimeter at birth was 31 (3) cm, a value lower than the limit to consider a microcephaly case. In all patients, neurological impairments were identified, including microcephaly, a reduction in cerebral volume, ventriculomegaly, cerebellar hypoplasia, lissencephaly with hydrocephalus, and fetal akinesia deformation sequence (ie, arthrogryposis). Results of limited testing for other causes of microcephaly, such as genetic disorders and viral and bacterial infections, were negative, and the ZIKV genome was found in both maternal and neonatal tissues (eg, amniotic fluid, cord blood, placenta, and
is to develop DNA vaccine strategies to treat and/or prevent primate lentivirus infection in infant rhesus macaques . As outlined in the year 02...natural vaginal birth, and the dams were returned to their breeding colonies. The neonatal macaques were given the DNA vaccines as outlined (Table 2...involving neonatal rhesus macaques has been initiated at the Yerkes Regional Primate Research Center. The course of DNA inoculations has been completed
De Monte, Anne; Cannavo, Isabelle; Caramella, Anne; Ollier, Laurence; Giordanengo, Valérie
Congenital cytomegalovirus (CMV) infection is the leading cause of sensoneurinal disability due to infectious congenital disease. The diagnosis of congenital CMV infection is based on the search of CMV in the urine within the first two weeks of life. Viral culture of urine is the gold standard. However, the PCR is highly sensitive and faster. It is becoming an alternative choice. The objective of this study is the validation of real-time PCR by Abbott RealTime CMV with m2000 for the detection of cytomegalovirus in urine. Repeatability, reproducibility, detection limit and inter-sample contamination were evaluated. Urine samples from patients (n=141) were collected and analyzed simultaneously in culture and PCR in order to assess the correlation of these two methods. The sensitivity and specificity of PCR were also calculated. The Abbott RealTime CMV PCR in urine is an automated and sensitive method (detection limit 200 UI/mL). Fidelity is very good (standard deviation of repeatability: 0.08 to 0.15 LogUI/mL and reproducibility 0.18 LogUI/mL). We can note a good correlation between culture and Abbott RealTime CMV PCR (kappa 96%). When considering rapid culture as reference, real-time PCR was highly sensitive (100%) and specific (98.2%). The real-time PCR by Abbott RealTime CMV with m2000 is optimal for CMV detection in urine.
Guo, Gangqiang; Zhang, Liang; Ye, Sisi; Hu, Yingying; Li, Baoqing; Sun, Xiangwei; Mao, Chenchen; Xu, Jianfeng; Chen, Yiping; Zhang, Lifang; Xue, Xiangyang
Human cytomegalovirus is a significant agent of hepatic involvement in neonates. In this study, we investigated the polymorphisms and features of the viral genes UL144 and UL146 as well as their significance to congenital hepatic involvement. In 79 neonates with congenital cytomegalovirus infection and hepatic involvement, full length UL144 and UL146 were successfully amplified in 73.42% and 60.76% of cases, respectively. Sequencing indicated that both genes were hypervariable. Notably, UL144 genotype B was highly associated with aspartate aminotransferase (P = 0.028) and lactate dehydrogenase (P = 0.046). Similarly, UL146 genotype G1 and G13 were significantly associated with CMV IgM (P = 0.026), CMV IgG (P = 0.034), alanine aminotransferase (P = 0.019), and aspartate aminotransferase (P = 0.032). In conclusion, dominant UL144 (genotype B) and UL146 (genotype G1 and G13) genotypes are associated with elevated levels of enzymes and CMV IgM and IgG of cytomegalovirus infection.
Ye, Sisi; Hu, Yingying; Li, Baoqing; Sun, Xiangwei; Mao, Chenchen; Xu, Jianfeng; Chen, Yiping; Zhang, Lifang; Xue, Xiangyang
Human cytomegalovirus is a significant agent of hepatic involvement in neonates. In this study, we investigated the polymorphisms and features of the viral genes UL144 and UL146 as well as their significance to congenital hepatic involvement. In 79 neonates with congenital cytomegalovirus infection and hepatic involvement, full length UL144 and UL146 were successfully amplified in 73.42% and 60.76% of cases, respectively. Sequencing indicated that both genes were hypervariable. Notably, UL144 genotype B was highly associated with aspartate aminotransferase (P = 0.028) and lactate dehydrogenase (P = 0.046). Similarly, UL146 genotype G1 and G13 were significantly associated with CMV IgM (P = 0.026), CMV IgG (P = 0.034), alanine aminotransferase (P = 0.019), and aspartate aminotransferase (P = 0.032). In conclusion, dominant UL144 (genotype B) and UL146 (genotype G1 and G13) genotypes are associated with elevated levels of enzymes and CMV IgM and IgG of cytomegalovirus infection. PMID:28222150
Moylan, David C; Pati, Sunil K; Ross, Shannon A; Fowler, Karen B; Boppana, Suresh B; Sabbaj, Steffanie
The role of HCMV-specific T-cell responses in breast milk of HCMV-seropositive mothers is not well defined. In these studies, we demonstrate that the frequency of CMV-pp65-specific T-cell responses in PBMC and breast milk cells (BMC) is increased for CD8+ T-cells in both sample sources when compared to CD4+ T-cells. The frequency of pp55-specific CD8 T-cells producing IFN- alone or dual IFN-/GrB producers is increased in breast milk compared to PBMC. Lastly, we observed a positive correlation between breast milk viral load and the CD8 pp65-specific response suggesting that local virus replication drives antigen-specific CD8 T-cells into the breast. © The Author 2017. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: firstname.lastname@example.org.
Yamada, Kazuhiko; Tasaki, Masayuki; Sekijima, Mitsuhiro; Wilkinson, Robert A.; Villani, Vincenzo; Moran, Shannon G.; Cormack, Taylor A.; Hanekamp, Isabel M.; Arn, J. Scott; Fishman, Jay A.; Shimizu, Akira; Sachs, David H.
Background Recent survivals of our pig-to-baboon kidney xenotransplants have been markedly shorter than the graft survivals we previously reported. The discovery of high levels of porcine CMV (pCMV) in one of the rejected xenografts led us to evaluate whether this reduction in graft survival might be due to the inadvertent introduction of pCMV into our GalT-KO swine herd. Methods Archived frozen sections of xeno-kidney grafts over the past 10 years were analyzed for the presence of pCMV, using real-time PCR. Three prospective pig-to-baboon renal transplants using kidneys from swine delivered by caesarian section (C-section) and raised in isolation were likewise analyzed. Results Kidney grafts from which 8 of the 18 archived samples were derived were found to be pCMV-negative, had a mean graft survival of 48.3 days and were from transplants performed before 2008. None had shown signs of DIC and were lost due to either proteinuria or infectious complications. In contrast, 10 of the archived samples were pCMV positive, were from kidney transplants with a mean graft survival of 14.1 days, had been performed after 2008 and had demonstrated early vascular changes and decreased platelet counts. Three prospective xenografts from swine delivered by C-section were pCMV negative and survived an average of 53.0 days. Conclusions Decreased survivals of GalT-KO renal xenografts in this laboratory correlate temporally with latent pCMV in the donor animals and pCMV in the rejected xeno-kidneys. Transmission of pCMV to swine offspring may be avoided by C-section delivery and scrupulous isolation of donor animals. PMID:25243511
Markowitz, Phillip I.
A case study is described in which early infantile autism was diagnosed in a child with congenital cytomegalovirus (CMU) infection. It is suggested that congenital infection should be considered as an etiological agent in autism. The case's synergistic effect of CMU-induced brain damage, deafness, and maternal deprivation in noted. (CL)
Markowitz, Phillip I.
A case study is described in which early infantile autism was diagnosed in a child with congenital cytomegalovirus (CMU) infection. It is suggested that congenital infection should be considered as an etiological agent in autism. The case's synergistic effect of CMU-induced brain damage, deafness, and maternal deprivation in noted. (CL)
Clerico, Marinella; De Mercanti, Stefania; Artusi, Carlo Alberto; Durelli, Luca; Naismith, Robert T
Alemtuzumab is a humanized monoclonal antibody targeting the surface molecule CD52, resulting in a rapid depletion of innate and adaptive immune cells. Infection rates in multiple sclerosis (MS) treatment trials were higher in alemtuzumab than in interferon beta-treated patients. We report two MS patients who developed cytomegalovirus disease within 1 month after the first 5-day cycle of alemtuzumab. Upon identification and appropriate treatment of the infection, each recovered completely. Neurologists should be aware of this serious but treatable complication.
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Transfusion in CMV seronegative T-depleted allogeneic stem cell transplant recipients with CMV-unselected blood components results in zero CMV transmissions in the era of universal leukocyte reduction: a U.K. dual centre experience.
Hall, S; Danby, R; Osman, H; Peniket, A; Rocha, V; Craddock, C; Murphy, M; Chaganti, S
To establish rates of cytomegalovirus (CMV) transmission with use of CMV-unselected (CMV-U), leukocyte-reduced blood components transfused to CMV-seronegative patient/CMV-seronegative donor (CMV neg/neg) allogeneic stem cell transplantation (SCT) recipients including those receiving T-depleted grafts. CMV infection remains a major cause of morbidity following SCT. CMV-seronegative SCT recipients are particularly at risk of transfusion transmitted CMV (TT-CMV) and until recently they have received blood components from CMV-seronegative donors with significant resource implications. Although leukocyte reduction of blood components is reported to minimise risk of TT-CMV, its efficacy in high-risk situations, such as in T-depleted transplant recipients, is unknown. We retrospectively analysed the incidence of TT-CMV in CMV neg/neg allogeneic SCT recipients transfused with CMV-U, leukocyte-reduced blood components in two transplantation centres in the UK. Patients were monitored for CMV infection by weekly CMV polymerase chain reaction testing. Leukocyte reduction of blood components was in accordance with current UK standards. Among 76 patients, including 59 receiving in vivo T-depletion, no episodes of CMV infection were detected. Patients were transfused with 1442 CMV-unselected, leukocyte-reduced components, equating to 1862 donor exposures. Our findings confirm the safety of leukocyte reduction as a strategy in preventing TT-CMV in high-risk allogeneic SCT recipients. © 2015 British Blood Transfusion Society.
Mustafa Ali, Moaath; Ruano Mendez, Ana Lucia; Carraway, Hetty E.
Hemophagocytic lymphohistiocytosis (HLH) is a syndrome characterized by immune activation and subsequent widespread organ damage. Patients affected by HLH commonly develop fever, cytopenias, liver damage, neurologic manifestations, and hypercytokinemia. In this case, we describe a 60-year-old male who presented with HLH and concurrent Epstein-Barr virus, cytomegalovirus, and Candida infections and was subsequently diagnosed with a Hodgkin lymphoma. This case highlights the importance of considering a cancer diagnosis in the differential diagnosis of patients presenting with HLH. PMID:28210636
van Zuylen, Wendy J; Hamilton, Stuart T; Naing, Zin; Hall, Beverly; Shand, Antonia
Cytomegalovirus is the most common congenital infection causing serious disease in infants. It is the leading infectious cause of sensorineural hearing loss and neurodevelopmental disability in developed countries. Despite the clinical importance of congenital cytomegalovirus, surveys show there is limited awareness and knowledge in the medical and general community about congenital cytomegalovirus infection. This article reviews the clinical features, global epidemiology, transmission and risk factors for cytomegalovirus infections. It also highlights several major advances made in recent years in the diagnosis and prevention of cytomegalovirus infection during pregnancy. Although research is ongoing, no therapy is currently proven to prevent or treat maternal, fetal or neonatal cytomegalovirus infection. Education of women regarding hygiene measures can help prevent cytomegalovirus infection and are currently the best strategy to prevent congenital cytomegalovirus disease. PMID:27512442
Saldan, Alda; Forner, Gabriella; Mengoli, Carlo; Gussetti, Nadia; Palù, Giorgio; Abate, Davide
Human cytomegalovirus (CMV) represents one of the leading causes of congenital infections worldwide. Early diagnosis of fetal infection and consequent rapid therapeutic intervention with immunoglobulin treatment may prevent fetal transmission and virus-related sequelae. In this study, the cell-mediated immunity and immunoglobulin avidity were evaluated as potential predictors of congenital transmission of the infection. CMV immunoglobulin G (IgG) avidity and CMV enzyme-linked immunospot (ELISpot) assays were employed in 80 pregnant women including 57 primary and 23 nonprimary CMV infections. Congenital infection was assessed using CMV DNA quantitative polymerase chain reaction on amniotic fluid or offspring urine. Logistic regression and receiver operating characteristic statistical methods were employed to determine the association with congenital infection. Low CMV IgG avidity (25%) alone correlated with a probability of congenital transmission of 18.2% (95% confidence interval, 7.7%-28.8%). In contrast to the expectations, an increase in CMV ELISpot levels was statistically associated with congenital transmission (P = .006). The combined use of CMV ELISpot and low CMV IgG avidity resulted in a higher level of association than either method alone with the incidence of fetal transmission (area under the curve, 0.8685). CMV-specific cell-mediated immunity represents a relevant marker in assessing the likelihood of congenital CMV transmission, particularly in combination with CMV IgG avidity. © The Author 2015. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: email@example.com.
Ghrenassia, Etienne; Guihot, Amélie; Dong, Yuan; Robinet, Pauline; Fontaine, Thierry; Lacombe, Karine; Lescot, Thomas; Meyohas, Marie-Caroline; Elbim, Carole
We report the case of a patient with acute necrotizing colitis due to invasive amebiasis associated with CD4 lymphopenia and impaired neutrophil responses. The course of the disease was characterized by CMV reactivation and severe and recurrent bacterial and fungal infections, which might be related to the decreased CD4 T cell count and the impaired functional capacities of neutrophils, respectively. The clinical outcome was positive with normalization of both CD4 cell count and neutrophil functions. PMID:28243230
Emery, Vincent C.; Lazzarotto, Tiziana; Gupta, Ravindra K.
Human cytomegalovirus (CMV) is a leading cause of congenital infections worldwide. In the developed world, following the virtual elimination of circulating rubella, it is the commonest nongenetic cause of childhood hearing loss and an important cause of neurodevelopmental delay. The seroprevalence of CMV in adults and the incidence of congenital CMV infection are highest in developing countries (1 to 5% of births) and are most likely driven by nonprimary maternal infections. However, reliable estimates of prevalence and outcome from developing countries are not available. This is largely due to the dogma that maternal preexisting seroimmunity virtually eliminates the risk for sequelae. However, recent data demonstrating similar rates of sequelae, especially hearing loss, following primary and nonprimary maternal infection have underscored the importance of congenital CMV infection in resource-poor settings. Although a significant proportion of congenital CMV infections are attributable to maternal primary infection in well-resourced settings, the absence of specific interventions for seronegative mothers and uncertainty about fetal prognosis have discouraged routine maternal antibody screening. Despite these challenges, encouraging results from prototype vaccines have been reported, and the first randomized phase III trials of prenatal interventions and prolonged postnatal antiviral therapy are under way. Successful implementation of strategies to prevent or reduce the burden of congenital CMV infection will require heightened global awareness among clinicians and the general population. In this review, we highlight the global epidemiology of congenital CMV and the implications of growing knowledge in areas of prevention, diagnosis, prognosis, and management for both low (50 to 70%)- and high (>70%)-seroprevalence settings. PMID:23297260
Terrazzini, Nadia; Bajwa, Martha; Thomas, David; Smith, Helen; Kern, Florian
Body mass index (BMI) is a known risk factor for cardiovascular disease and cancer. It is also related to white blood count (WBC) and inflammation. The effects of age and gender on these associations have not been explored. Here we have examined the relationships between BMI and inflammatory parameters/cardiovascular risk factors including WBC/neutrophil count (NC), CRP and mean arterial blood pressure (MAP), in young (20-35 years) and older (60-85 years) healthy donors with respect to gender and CMV IgG serology. In young but not older people significant associations between BMI and WBC were observed, however, with opposite directions in the two genders. Only in CMV+ older women a positive trend was preserved. Across the population, there was no significant association between NC and MAP; however, among older men we saw a positive correlation between the two parameters. Linear regression confirmed that across the whole population, age group (young versus older) and also the interaction between gender and age group but not gender alone had significant effects on this association. When analysing CMV+ older people separately we established that both NC and its interaction with gender had a significant effect on MAP. This study reveals that the correlations between common inflammatory markers/cardiovascular risk factors depend on age, gender, and CMV status in a complex fashion. Our findings support the need to evaluate risk factors independently in men and women and to take into account CMV infection status. More focused studies will be required to shed light on these novel findings. Copyright © 2014 Elsevier B.V. All rights reserved.
Dahle, Arthur J.; And Others
Audiological assessment of 86 children (mean age 38 months at last evaluation time) with congenital cytomegalovirus infection revealed progressive hearing loss in four of 12 Ss with sensorineural hearing impairments. Case descriptions documented the progression of the hearing loss. (Author)
Preconceptual administration of an alphavirus replicon UL83 (pp65 homolog) vaccine induces humoral and cellular immunity and improves pregnancy outcome in the guinea pig model of congenital cytomegalovirus infection.
Schleiss, Mark R; Lacayo, Juan C; Belkaid, Yasmine; McGregor, Alistair; Stroup, Greg; Rayner, Jon; Alterson, Kimberly; Chulay, Jeffrey D; Smith, Jonathan F
Development of a vaccine against congenital cytomegalovirus (CMV) infection is a major public health priority. We report the use of a propagation-defective, single-cycle, RNA replicon vector system, derived from an attenuated strain of the alphavirus Venezuelan equine encephalitis virus, to produce virus-like replicon particles (VRPs) expressing GP83, the guinea pig CMV (GPCMV) homolog of the human CMV pp65 phosphoprotein. Vaccination with VRP-GP83 induced antibodies and CD4(+) and CD8(+) T cell responses in GPCMV-seronegative female guinea pigs. Guinea pigs immunized with VRP-GP83 vaccine or with a VRP vaccine expressing influenza hemagglutinin (VRP-HA) were bred for pregnancy and subsequent GPCMV challenge during the early third trimester. Dams vaccinated with VRP-GP83 had improved pregnancy outcomes, compared with dams vaccinated with the VRP-HA control. For VRP-GP83-vaccinated dams, there were 28 live pups and 4 dead pups (13% mortality) among 10 evaluable litters, compared with 9 live pups and 12 dead pups (57% mortality) among 8 evaluable litters in the VRP-HA-vaccinated group (P<.001, Fisher's exact test). Improved pregnancy outcome was accompanied by reductions in maternal blood viral load, measured by real-time polymerase chain reaction. These results indicate that cell-mediated immune responses directed against a CMV matrix protein can protect against congenital CMV infection and disease.
Sorichetti, Brendan; Goshen, Oran; Pauwels, Julie; Kozak, Frederick K; Tilley, Peter; Krajden, Mel; Gantt, Soren
Records were reviewed from all infants tested for congenital cytomegalovirus infection in British Columbia, Canada from 2006 to June 2014. Fourteen of 701 infants, or approximately 4.2 per 100,000 live births, had a positive test, indicating that >90% of expected symptomatic congenital cytomegalovirus infection cases were not diagnosed using clinician-initiated testing. Copyright © 2016 Elsevier Inc. All rights reserved.
Antona, D; Lepoutre, A; Fonteneau, L; Baudon, C; Halftermeyer-Zhou, F; LE Strat, Y; Lévy-Bruhl, D
Cytomegalovirus (CMV) infection remains the leading cause of congenital virus infection in developed countries. Measuring the national prevalence of this infection, especially among women of childbearing age, is of great value to estimate the risk of congenital CMV infection, as well as to identify risk groups that should be targeted for behavioural interventions and/or vaccination once a CMV vaccine finally becomes available. In order to fulfil these objectives, a seroprevalence survey was conducted in 2010, using a nationally representative, population-based sample of 2536 people aged between 15 and 49 years, living in metropolitan France and attending private microbiological laboratories for blood testing. All blood samples were analysed in the same laboratory and screened for CMV-specific IgG using an enzyme-linked immunoassay technique (Elisa PKS Medac Enzyme immunoassay). The overall point estimate of CMV infection seroprevalence for individuals aged 15-49 years was 41.9%. The estimates were higher in women than in men (respectively 45.6% and 39.3%), and people born in a non-Western country were more likely to be CMV seropositive than those born in France or in another Western country (93.7% vs. 37.7%). Our results showed that a substantial percentage of women of childbearing age in France are CMV seronegative and therefore at risk of primary CMV infection during pregnancy. Educational measures and future vaccine are key issues to prevent infection in pregnant women and congenital CMV disease.
Fowler, Karen B; McCollister, Faye P; Sabo, Diane L; Shoup, Angela G; Owen, Kris E; Woodruff, Julie L; Cox, Edith; Mohamed, Lisa S; Choo, Daniel I; Boppana, Suresh B
Congenital cytomegalovirus (cCMV) infection remains a leading cause of childhood hearing loss. Currently universal CMV screening at birth does not exist in the United States. An alternative approach could be testing infants who do not pass their newborn hearing screening (NHS) for cCMV. This study was undertaken to evaluate whether a targeted approach will identify infants with CMV-related sensorineural hearing loss (SNHL). Infants born at 7 US medical centers received NHS and were also screened for cCMV while in the newborn nursery. Infants who tested positive for CMV received further diagnostic audiologic evaluations to identify or confirm hearing loss. Between 2007 and 2012, 99 945 newborns were screened for both hearing impairment and cCMV. Overall, 7.0% of CMV-positive infants did not pass NHS compared with 0.9% of CMV-negative infants (P < .0001). Among the cCMV infants who failed NHS, diagnostic testing confirmed that 65% had SNHL. In addition, 3.6% of CMV-infected infants who passed their NHS had SNHL confirmed by further evaluation during early infancy. NHS in this cohort identified 57% of all CMV-related SNHL that occurred in the neonatal period. A targeted CMV approach that tests newborns who fail their NHS identified the majority of infants with CMV-related SNHL at birth. However, 43% of the infants with CMV-related SNHL in the neonatal period and cCMV infants who are at risk for late onset SNHL were not identified by NHS. Copyright © 2017 by the American Academy of Pediatrics.
Case report: persistent cytomegalovirus (CMV) infection after haploidentical hematopoietic stem cell transplantation using in vivo alemtuzumab: emergence of resistant CMV due to mutations in the UL97 and UL54 genes.
Oshima, Kumi; Kanda, Yoshinobu; Kako, Shinichi; Asano-Mori, Yuki; Watanabe, Takuro; Motokura, Toru; Chiba, Shigeru; Shiraki, Kimiyasu; Kurokawa, Mineo
Addition of in vivo alemtuzumab to the conditioning regimen enabled 2- or 3-locus-mismatched hematopoietic stem cell transplantation with an acceptable incidence of graft-versus-host-disease. However, the procedure was associated with a high incidence of cytomegalovirus (CMV) reactivation. Although preemptive therapy with ganciclovir prevented successfully severe CMV diseases and CMV-related mortality, a patient developed persistent positive CMV antigenemia for more than 1 year after transplantation and CMV disease, despite the use of ganciclovir and foscarnet. The in vitro susceptibility assay showed that the clinical isolate was resistant to foscarnet, moderately resistant to ganciclovir, but sensitive to cidofovir. Therefore, cidofovir was administered. CMV antigenemia became negative within 2 weeks and never developed again. Nucleotide sequence of the UL54 and UL97 of the clinical isolate showed 4 amino acid substitutions (V11L, Q578H, S655L, and G874R) in UL54 and 2 mutations (A140V and A594V) in UL97 compared with the Towne and AD169 strains. Ganciclovir resistance was suspected to be caused by both A594V of UL97 and Q578H of UL54, whereas foscarnet resistance was due mainly to Q578H of UL54. In conclusion, the in vitro susceptibility assay as well as nucleotide sequence of clinical isolate is important to choose appropriate antiviral agents for patients who have persistent CMV reactivation after stem cell transplantation.
Berardi, Alberto; Spaggiari, Eugenio; Cattelani, Chiara; Roversi, Maria Federica; Pecorari, Monica; Lazzarotto, Tiziana; Ferrari, Fabrizio
The optimal threshold for neonatal platelet transfusions in sick newborns is still uncertain. We report a congenital cytomegalovirus (CMV) infection in a premature neonate with severe thrombocytopenia who subsequently presented with necrotizing enterocolitis and intestinal bleeding. The baby recovered after platelet transfusions were discontinued and the therapy was switched from intravenous ganciclovir to oral valganciclovir. We discuss both measures, speculating on the key role of platelet transfusions.
Lupo, Julien; Germi, Raphaële; Jean, Dominique; Baccard-Longère, Monique; Casez, Olivier; Besson, Gérard; Rougé, Alain; Boutonnat, Jean; Schwebel, Carole; Hoffmann, Pascale; Morand, Patrice
Guillain-Barré syndrome (GBS) is an immune-mediated disorder which can be triggered by cytomegalovirus (CMV) infection. GBS following CMV primary infection is a rare event during pregnancy, which raises the question of maternal and fetal management. We describe an unusual case of GBS after CMV primary infection in a pregnant woman. The mother was successfully treated with standard immunoglobulins but in utero fetal death caused by CMV congenital infection unfortunately occurred. Similar cases have rarely been reported in the literature.
Pietersma, Floor L; van Dorp, Suzanne; Minnema, Monique C; Kuball, Jürgen; Meijer, Ellen; Schuurman, Rob; van Baarle, Debbie
We investigated the role of donor cytomegalovirus (CMV) serostatus on reactivation of CMV infection in CMV-infected transplant recipients. Reactivation of CMV infection occurred more frequently in patients receiving a CMV-positive graft but was less severe than in patients receiving a CMV-negative graft. These data suggest roles for both virus as well as CMV-specific immunity present in the graft. © The Author 2011. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved.
Shang, Jing; Xi, De-Hui; Yuan, Shu; Xu, Fei; Xu, Mo-Yun; Qi, Hai-Long; Wang, Shao-Dong; Huang, Qing-Rong; Wen, Lin; Lin, Hong-Hui
Dark green islands (DGIs) are a common symptom of plants systemically infected with the mosaic virus. DGIs are clusters of green leaf cells that are free of virus but surrounded by yellow leaf tissue that is full of virus particles. In Cucumber mosaic virus (CMV)-infected Nicotiana tabacum leaves, the respiration and photosynthesis capabilities of DGIs and yellow leaf tissues were measured. The results showed that the cyanide-resistant respiration was enhanced in yellow leaf tissue and the photosynthesis was declined, while in DGIs they were less affected. The activities of the oxygen-scavenging enzymes catalase (CAT), peroxidase (POD), and superoxide dismutase (SOD) in infected leaves were significantly higher than those in the healthy leaves, and the enzyme activities in DGIs were always lower than in the yellow leaf tissues. Reactive oxygen species (ROS) staining showed that the hydrogen peroxide content in yellow leaf tissues was apparently higher than that in DGIs, while the superoxide content was on the contrary. Formation of DGIs may be a strategy of the host plants resistance to the CMV infection.
McElhaney, Janet E.; Zhou, Xin; Talbot, H. Keipp; Soethout, Ernst; Bleackley, R. Chris; Granville, David; Pawelec, Graham
Influenza remains the single most important cause of excess disability and mortality during the winter months. In spite of widespread influenza vaccination programs leading to demonstrated cost-savings in the over 65 population, hospitalization and death rates for acute respiratory illnesses continue to rise. As a person ages, increased serum levels of inflammatory cytokines are commonly recorded (TNF-α, IL-1, IL-6). Termed “inflammaging”, this has been linked to persistent cytomegalovirus (CMV) infection and immune senescence, while increased anti-inflammatory cytokines (IL-10, TGF-β) are possibly associated with more healthy aging. Paradoxically, a shift with aging toward an anti-inflammatory (IL-10) response and decline in the IFN-γ:IL-10 ratio in influenza-challenged peripheral blood mononuclear cells is associated with a decline in the cytolytic capacity of CD8+ T cells responsible for clearing influenza virus from infected lung tissue. Thus, it is seemingly counter intuitive that the immune phenotype of healthy aging predicts a poor cell-mediated immune response and more serious outcomes of influenza. Herein we postulate a mechanistic link between the accumulation of late-stage, potentially terminally-differentiated T cells, many or most of which result from CMV infection, and the immunopathogenesis of influenza infection, mediated by granzyme B in older adults. Further, adjuvanted influenza vaccines that stimulate inflammatory cytokines and suppress the IL-10 response to influenza challenge, would be expected to enhance protection in the 65+ population. PMID:22289511
Segura, Elsa L.; Cohen, Joel E.
Trypanosoma cruzi, the causative agent of Chagas disease, infects 10–18 million people and may be transmitted to the newborn. Using various data sources, we estimated that nearly 850 congenital cases occurred in Argentina in 1993, or 6.3 expected cases per each reported case in 1994 and in 1994–2001. The congenital transmission of T. cruzi constitutes a sizeable public health problem in the region. PMID:12533278
Cruz, Maria Letícia Santos; Cardoso, Claudete Araújo; Saavedra, Mariza C; Santos, Eliane Dos; Melino, Tatiana
We report the occurrence of congenital toxoplasmosis in an infant born to an HIV infected mother who had high anti-toxoplasma IgG and negative IgM at nine weeks of gestation. We briefly review available literature and discuss the possible mechanisms of transmission of congenital toxoplasmosis among HIV infected pregnant women.
Dos Santos, Thaís Rabelo; Faria, Gabriela da Silva Magalhães; Guerreiro, Bruna Martins; Dal Pietro, Nathalia Helena Pereira da Silva; Lopes, Welber Daniel Zanetti; da Silva, Helenara Machado; Garcia, João Luis; Luvizotto, Maria Cecília Rui; Bresciani, Katia Denise Saraiva; da Costa, Alvimar José
This experiment studied congenital transmission in sheep experimentally infected with oocysts of Toxoplasma gondii and reinfected at one of three stages of pregnancy. Twenty ewes were experimentally infected with T. gondii strain ME49 (day 0). After the T. gondii infection became chronic (IFAT≤512), the ewes were allocated with rams for coverage. After the diagnosis of pregnancy, these ewes were allocated into four experimental groups (n = 5): I-reinfected with T. gondii on the 40th day of gestation (DG); II-reinfected on DG 80; III-reinfected on DG 120; and IV-saline solution on DG 120 (not reinfected). Five ewes (IFAT<64) were kept as negative controls (uninfected, group V), therefore in groups I-III were infected prior to pregnancy and re-infected during pregnancy, group IV was only infected prior to pregnancy, and group V was not infected. Parasitism by T. gondii was investigated (histopathology, immunohistochemistry, mouse bioassay and PCR) in mothers and lambs tissue. All ewes produced lambs serologically positive for T. gondii. The results of the mouse bioassay, immunohistochemistry and PCR assays revealed the presence of T. gondii in all 20 sheep and their lambs. The congenital transmission of T. gondii was associated with fetal loss and abnormalities in persistently infected sheep and in ewes infected and subsequently reinfected by this protozoan. Therefore, congenital T. gondii infection was common when ewes were chronically infected prior to pregnancy, with or without reinfection during at various stages of gestation.
dos Santos, Thaís Rabelo; Faria, Gabriela da Silva Magalhães; Guerreiro, Bruna Martins; dal Pietro, Nathalia Helena Pereira da Silva; Lopes, Welber Daniel Zanetti; da Silva, Helenara Machado; Garcia, João Luis; Luvizotto, Maria Cecília Rui; Bresciani, Katia Denise Saraiva; da Costa, Alvimar José
This experiment studied congenital transmission in sheep experimentally infected with oocysts of Toxoplasma gondii and reinfected at one of three stages of pregnancy. Twenty ewes were experimentally infected with T. gondii strain ME49 (day 0). After the T. gondii infection became chronic (IFAT≤512), the ewes were allocated with rams for coverage. After the diagnosis of pregnancy, these ewes were allocated into four experimental groups (n = 5): I-reinfected with T. gondii on the 40th day of gestation (DG); II-reinfected on DG 80; III-reinfected on DG 120; and IV-saline solution on DG 120 (not reinfected). Five ewes (IFAT<64) were kept as negative controls (uninfected, group V), therefore in groups I-III were infected prior to pregnancy and re-infected during pregnancy, group IV was only infected prior to pregnancy, and group V was not infected. Parasitism by T. gondii was investigated (histopathology, immunohistochemistry, mouse bioassay and PCR) in mothers and lambs tissue. All ewes produced lambs serologically positive for T. gondii. The results of the mouse bioassay, immunohistochemistry and PCR assays revealed the presence of T. gondii in all 20 sheep and their lambs. The congenital transmission of T. gondii was associated with fetal loss and abnormalities in persistently infected sheep and in ewes infected and subsequently reinfected by this protozoan. Therefore, congenital T. gondii infection was common when ewes were chronically infected prior to pregnancy, with or without reinfection during at various stages of gestation. PMID:27788185
Tsai, T F; Paul, R; Lynberg, M C; Letson, G W
To determine whether yellow fever (YF) vaccine administered in pregnancy causes fetal infection, women who were vaccinated during unrecognized pregnancy in a mass campaign in Trinidad were studied retrospectively. Maternal and cord or infant blood were tested for IgM and neutralizing antibodies to YF and dengue viruses. One of 41 infants had IgM and elevated neutralizing antibodies to YF virus, indicating congenital infection. The infant, the first reported case of YF virus infection after immunization in pregnancy, was delivered after an uncomplicated full-term pregnancy and appeared normal. Congenital dengue 1 infection may have occurred in another case. The frequency of fetal infection and adverse events after such exposure could not be estimated; however, the neurotropism of YF virus for the developing nervous system and the now documented possibility of transplacental infection underscores the admonition that YF vaccination in pregnancy should be avoided.
Tanimura, Kenji; Tairaku, Shinya; Deguchi, Masashi; Sonoyama, Ayako; Morizane, Mayumi; Ebina, Yasuhiko; Morioka, Ichiro; Yamada, Hideto
The aim of this trial study was to assess the preventive efficacy of immunoglobulin with a high titer of anti-CMV antibody for mother-to-fetus cytomegalovirus (CMV) transmission among pregnant women with primary/acute CMV infection. The primary CMV infection in mothers was diagnosed by a positive test for CMV IgM and/or low IgG avidity. Intact type immunoglobulin with a high titer of anti-CMV antibody was injected intravenously at a dosage of 2.5-5.0 g/day for consecutive 3 days to mothers with primary CMV infection. Four pregnant women were enrolled. One pregnancy ended in no congenital infection, while two pregnancies ended in congenital CMV infection. The other one pregnancy was terminated. The mother-to-fetus CMV transmission rate was found to be high as 66.7% (2/3). This preliminary result suggests that intravenous immunoglobulin injections are not effective for the prevention of mother-to-fetus CMV transmission in the present protocol.
Bell, Susan Givens
Our understanding of the effects of maternal Zika virus infection on the newborn continues to evolve. First discovered in 1947 in the Zika Forest in Uganda, the world became more aware of the virus in 2015, with reports of hundreds of cases of microcephaly in Brazilian newborns whose mothers reported symptoms related to Zika viral infection during pregnancy. This article reviews the current guidelines for laboratory evaluation of newborns with possible congenital Zika virus infection.
Huygens, Ariane; Lecomte, Sandra; Tackoen, Marie; Olislagers, Véronique; Delmarcelle, Yves; Burny, Wivine; Van Rysselberge, Michel; Liesnard, Corinne; Larsen, Martin; Appay, Victor; Donner, Catherine; Marchant, Arnaud
Cytomegalovirus (CMV) infection during fetal life causes severe symptoms and is associated with prolonged viral excretion. Previous studies reported low CD4(+) T-cell responses to CMV infection in early life, contrasting with large responses of effector CD8(+) T cells. The mechanisms underlying the defective CD4(+) T-cell responses and the possible dissociation with CD8(+) T-cell responses have not been clarified. The magnitude and the quality of the fetal CD8(+) and CD4(+) T-cell responses to CMV infection were compared to those of adults with primary or chronic infection. In utero CMV infection induced oligoclonal expansions of fetal CD4(+) and CD8(+) T lymphocytes expressing a T-helper type 1 or Tc1 effector phenotype similar to that of adult CMV-specific cells. However, the effector cytokine responses and the polyfunctionality of newborn CD4(+) and CD8(+) T cells were markedly lower than those of adult cells. This reduced functionality was associated with a higher expression of the programmed death 1 inhibitory receptor, and blockade of this receptor increased newborn T-cell responses. Functional exhaustion limits effector CD4(+) and CD8(+) T-lymphocyte responses to CMV during fetal life. © The Author 2015. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: firstname.lastname@example.org.
Wagner, Norbert; Kagan, Karl Oliver; Haen, Susanne; Schmidt, Sybille; Yerlikaya, Gülen; Maden, Zerrin; Jahn, Gerhard; Hamprecht, Klaus
Human Cytomegalovirus (CMV) infection during pregnancy is the most frequent viral cause of intrauterine infection and responsible for various cerebral and other ultrasound abnormalities of the fetus. It is the leading infectious cause of mental retardation and sensorineural deafness in affected newborns and infants. We present three cases of primary cytomegalovirus infection in pregnancy and demonstrate three different scenarios of the disease with regard to clinical outcome and therapy options. We first report on CMV related phospho- and glycoprotein-specific antibody reactivities in amnion fluid that have not been reported earlier in literature. Case 1: A 33-year-old Gravida II Para I was referred for primary CMV infection at 15 weeks gestation presenting with a history of fever. HIG therapy was performed resulting in good neonatal outcome. Case 2: A 23-year-old Gravida I was referred for targeted ultrasound at 23 weeks of gestation presenting with intrauterine growth retardation, multiple fetal hepatic echodensities and thickened placenta. Termination of pregnancy was initiated. Case 3: A 29-year-old Gravida II Para I was referred for primary CMV infection at 16 weeks gestation presenting with no clinical symptoms of CMV. HIG therapy was performed, resulting in good neonatal outcome. We want to stress the potential benefit of an off label use of CMV-specific hyperimmune globulin (HIG) therapy, present an algorithm for the management of affected pregnancies and review current literature on this issue.
Pedrosa, Cristina; Lage, Maria João; Virella, Daniel
Enteroviral infection in pregnancy is common and there is growing evidence relating it to congenital anomalies and neonatal mortality. Neonatal disease may range from unapparent infection to overwhelming systemic illness. Passively acquired maternal serotype specific antibodies determine the severity of the disease in the newborn. A fatal case of congenital echovirus 21 infection, confirmed by PCR in the patient's blood and positive culture of the mother's stools, is reported. A sibling had symptoms of respiratory tract infection and their mother had fever, which prompted iatrogenic delivery that same day. The newborn presented with bradycardia and hypotonia in the first minutes of life and later developed respiratory distress, disseminated intravascular coagulopathy, fulminant hepatitis, acute renal failure and necrotising enterocolitis. Death occurred on the 8 day of life. This case highlights the potential severity of Enteroviral infection in the newborn. Since only supportive treatment is available, prevention is paramount. PMID:23576650
Bialas, Kristy M.; Tanaka, Takayuki; Tran, Dollnovan; Varner, Valerie; Cisneros De La Rosa, Eduardo; Chiuppesi, Flavia; Wussow, Felix; Kattenhorn, Lisa; Macri, Sheila; Kunz, Erika L.; Estroff, Judy A.; Kirchherr, Jennifer; Yue, Yujuan; Fan, Qihua; Lauck, Michael; O’Connor, David H.; Hall, Allison H. S.; Xavier, Alvarez; Diamond, Don J.; Barry, Peter A.; Kaur, Amitinder; Permar, Sallie R.
Elucidation of maternal immune correlates of protection against congenital cytomegalovirus (CMV) is necessary to inform future vaccine design. Here, we present a novel rhesus macaque model of placental rhesus CMV (rhCMV) transmission and use it to dissect determinants of protection against congenital transmission following primary maternal rhCMV infection. In this model, asymptomatic intrauterine infection was observed following i.v. rhCMV inoculation during the early second trimester in two of three rhCMV-seronegative pregnant females. In contrast, fetal loss or infant CMV-associated sequelae occurred in four rhCMV-seronegative pregnant macaques that were CD4+ T-cell depleted at the time of inoculation. Animals that received the CD4+ T-cell–depleting antibody also exhibited higher plasma and amniotic fluid viral loads, dampened virus-specific CD8+ T-cell responses, and delayed production of autologous neutralizing antibodies compared with immunocompetent monkeys. Thus, maternal CD4+ T-cell immunity during primary rhCMV infection is important for controlling maternal viremia and inducing protective immune responses that prevent severe CMV-associated fetal disease. PMID:26483473
Bate, Sheri Lewis; Cannon, Michael J
Congenital cytomegalovirus (CMV) is the most common congenital infection in the United States, causing permanent disabilities in more than 5,500 children born each year. In the absence of a vaccine, a promising means of prevention is through a behavioral intervention that educates women about CMV and promotes adherence to hygiene guidelines during pregnancy. Although effective behavioral interventions have been identified for other infectious diseases with similar transmission modes, current research has not yet identified an effective intervention for CMV. One way to gather evidence and identify key elements of a successful CMV intervention is through a social marketing approach. This article describes a five-step process for applying social marketing principles to the research and development, implementation, and evaluation of a CMV behavioral intervention.
Reina, J; Weber, I; Riera, E; Busquets, M; Morales, C
Cytomegalovirus (CMV) is the main virus causing congenital and postnatal infections in the pediatric population. The aim of this study is to evaluate the usefulness of a quantitative real-time PCR in the diagnosis of these infections using urine as a single sample. We studied all the urine samples of newborns (< 7 days) with suspected congenital infection, and urine of patients with suspected postnatal infection (urine negative at birth). Urines were simultaneously studied by cell culture, qualitative PCR (PCRc), and quantitative real-time PCR (PCRq). We analyzed 332 urine samples (270 to rule out congenital infection and 62 postnatal infections). Of the first, 22 were positive in the PCRq, 19 in the PCRc, and 17 in the culture. PCRq had a sensitivity of 100%, on comparing the culture with the rest of the techniques. Using the PCRq as a reference method, culture had a sensitivity of 77.2%, and PCRc 86.3%. In cases of postnatal infection, PCRq detected 16 positive urines, the PCRq 12, and the cell culture 10. The urines showed viral loads ranging from 2,178 to 116,641 copies/ml. The genomic amplification technique PCRq in real time was more sensitive than the other techniques evaluated. This technique should be considered as a reference (gold standard), leaving the cell culture as a second diagnostic level. The low cost and the automation of PCRq would enable the screening for CMV infection in large neonatal and postnatal populations. Copyright © 2013 Asociación Española de Pediatría. Published by Elsevier Espana. All rights reserved.
In human cytomegalovirus (HCMV), tropism to epithelial and endothelial cells is dependent upon a pentameric complex (PC). Given the structure of the placenta, the PC is potentially an important neutralizing antibody target antigen against congenital infection. The guinea pig is the only small animal model for congenital CMV. Guinea pig cytomegalovirus (GPCMV) potentially encodes a UL128-131 HCMV PC homolog locus (GP128-GP133). In transient expression studies, GPCMV gH and gL glycoproteins interacted with UL128, UL130 and UL131 homolog proteins (designated GP129 and GP131 and GP133 respectively) to form PC or subcomplexes which were determined by immunoprecipitation reactions directed to gH or gL. A natural GP129 C-terminal deletion mutant (aa 107–179) and a chimeric HCMV UL128 C-terminal domain swap GP129 mutant failed to form PC with other components. GPCMV infection of a newly established guinea pig epithelial cell line required a complete PC and a GP129 mutant virus lacked epithelial tropism and was attenuated in the guinea pig for pathogenicity and had a low congenital transmission rate. Individual knockout of GP131 or 133 genes resulted in loss of viral epithelial tropism. A GP128 mutant virus retained epithelial tropism and GP128 was determined not to be a PC component. A series of GPCMV mutants demonstrated that gO was not strictly essential for epithelial infection whereas gB and the PC were essential. Ectopic expression of a GP129 cDNA in a GP129 mutant virus restored epithelial tropism, pathogenicity and congenital infection. Overall, GPCMV forms a PC similar to HCMV which enables evaluation of PC based vaccine strategies in the guinea pig model. PMID:27387220
Revello, Maria Grazia; Tibaldi, Cecilia; Masuelli, Giulia; Frisina, Valentina; Sacchi, Alessandra; Furione, Milena; Arossa, Alessia; Spinillo, Arsenio; Klersy, Catherine; Ceccarelli, Manuela; Gerna, Giuseppe; Todros, Tullia
Cytomegalovirus (CMV) is the leading infectious agent causing congenital sensorineural hearing loss and psychomotor retardation. CMV vaccine is currently unavailable and treatment options in pregnancy are limited. Susceptible pregnant women caring for children are at high risk for primary infection. CMV educational and hygienic measures have the potential to prevent primary maternal infection. A mixed interventional and observational controlled study was conducted to investigate the effectiveness of hygiene information among pregnant women at risk for primary CMV infection for personal/occupational reasons. In the intervention arm, CMV-seronegative women, identified at the time of maternal serum screening for fetal aneuploidy at 11-12 weeks of gestation, were given hygiene information and prospectively tested for CMV until delivery. The comparison arm consisted of women enrolled at delivery who were neither tested for nor informed about CMV during pregnancy, and who had a serum sample stored at the screening for fetal aneuploidy. By design, groups were homogeneous for age, parity, education, and exposure to at least one risk factor. The primary outcome was CMV seroconversion. Acceptance of hygiene recommendations was a secondary objective and was measured by a self-report. Four out of 331 (1.2%) women seroconverted in the intervention group compared to 24/315 (7.6%) in the comparison group (delta = 6.4%; 95% CI 3.2-9.6; P < 0.001). There were 3 newborns with congenital infection in the intervention group and 8 in the comparison group (1 with cerebral ultrasound abnormalities at birth). Ninety-three percent of women felt hygiene recommendations were worth suggesting to all pregnant women at risk for infection. This controlled study provides evidence that an intervention based on the identification and hygiene counseling of CMV-seronegative pregnant women significantly prevents maternal infection. While waiting for CMV vaccine to become available, the
Zare Mehrjardi, Mohammad; Poretti, Andrea; Huisman, Thierry A G M; Werner, Heron; Keshavarz, Elham; Araujo Júnior, Edward
Zika virus (ZIKV) is a mosquito-borne arbovirus from the Flaviviridae family. It had caused several epidemics since its discovery in 1947, but there was no significant attention to this virus until the recent outbreak in Brazil in 2015. The main concern is the causal relationship between prenatal ZIKV infection and congenital microcephaly, which has been confirmed recently. Moreover, ZIKV may cause other central nervous system abnormalities such as brain parenchymal atrophy with secondary ventriculomegaly, intracranial calcification, malformations of cortical development (such as polymicrogyria, and lissencephaly-pachygyria), agenesis/hypoplasia of the corpus callosum, cerebellar and brainstem hypoplasia, sensorineural hearing-loss, and ocular abnormalities as well as arthrogryposis in the infected fetuses. Postnatal (acquired) ZIKV infection usually has an asymptomatic or mildly symptomatic course, while prenatal (congenital) ZIKV infection has a more severe course and may cause severe brain anomalies that are described as congenital Zika syndrome. In this pictorial essay, we aim to illustrate the prenatal and postnatal neuroimaging findings that may be seen in fetuses and neonates with congenital Zika syndrome, and will discuss possible radiological differential diagnoses. A detailed knowledge of these findings is paramount for an early correct diagnosis, prognosis determination, and counseling of the affected children and families.
Booiman, Thijs; Wit, Ferdinand W.; Girigorie, Arginell F.; Maurer, Irma; De Francesco, Davide; Sabin, Caroline A.; Harskamp, Agnes M.; Prins, Maria; Franceschi, Claudio; Deeks, Steven G.; Winston, Alan; Reiss, Peter
HIV-1-positive individuals on successful antiretroviral therapy (ART) are reported to have higher rates of age-associated non-communicable comorbidities (AANCCs). HIV-associated immune dysfunction has been suggested to contribute to increased AANCC risk. Here we performed a cross-sectional immune phenotype analysis of T cells in ART-treated HIV-1-positive individuals with undetectable vireamia (HIV-positives) and HIV-1-negative individuals (HIV-negatives) over 45 years of age. In addition, two control groups were studied: HIV negative adults selected based on lifestyle and demographic factors (Co-morBidity in Relation to AIDS, or COBRA) and unselected age-matched donors from a blood bank. Despite long-term ART (median of 12.2 years), HIV-infected adults had lower CD4+ T-cell counts and higher CD8+ T-cell counts compared to well-matched HIV-negative COBRA participants. The proportion of CD38+HLA-DR+ and PD-1+ CD4+ T-cells was higher in HIV-positive cohort compared to the two HIV-negative cohorts. The proportion CD57+ and CD27−CD28− cells of both CD4+ and CD8+ T-cells in HIV-positives was higher compared to unselected adults (blood bank) as reported before but this difference was not apparent in comparison with well-matched HIV-negative COBRA participants. Multiple regression analysis showed that the presence of an increased proportion of terminally differentiated T cells was strongly associated with CMV infection. Compared to appropriately selected HIV-negative controls, HIV-positive individuals on ART with long-term suppressed viraemia exhibited incomplete immune recovery and increased immune activation/exhaustion. CMV infection rather than treated HIV infection appears to have more consistent effects on measures of terminal differentiation of T cells. PMID:28806406
Pass, Robert F.; Zhang, Changpin; Evans, Ashley; Simpson, Tina; Andrews, William; Huang, Meei-Li; Corey, Lawrence; Hill, Janie; Davis, Elizabeth; Flanigan, Cynthia; Cloud, Gretchen
BACKGROUND Congenital infection with cytomegalovirus (CMV) is an important cause of hearing, cognitive, and motor impairments in newborns. METHODS In this phase 2, placebo-controlled, randomized, double-blind trial, we evaluated a vaccine consisting of recombinant CMV envelope glycoprotein B with MF59 adjuvant, as compared with placebo. Three doses of the CMV vaccine or placebo were given at 0, 1, and 6 months to CMV-seronegative women within 1 year after they had given birth. We tested for CMV infection in the women in quarterly tests during a 42-month period, using an assay for IgG antibodies against CMV proteins other than glycoprotein B. Infection was confirmed by virus culture or immunoblotting. The primary end point was the time until the detection of CMV infection. RESULTS We randomly assigned 234 subjects to receive the CMV vaccine and 230 subjects to receive placebo. A scheduled interim analysis led to a stopping recommendation because of vaccine efficacy. After a minimum of 1 year of follow-up, there were 49 confirmed infections, 18 in the vaccine group and 31 in the placebo group. Kaplan-Meier analysis showed that the vaccine group was more likely to remain uninfected during a 42-month period than the placebo group (P = 0.02). Vaccine efficacy was 50% (95% confidence interval, 7 to 73) on the basis of infection rates per 100 person-years. One congenital infection among infants of the subjects occurred in the vaccine group, and three infections occurred in the placebo group. There were more local reactions (pain, erythema, induration, and warmth) and systemic reactions (chills, arthralgias, and myalgias) in the vaccine group than in the placebo group. CONCLUSIONS CMV glycoprotein B vaccine has the potential to decrease incident cases of maternal and congenital CMV infection. (ClinicalTrials.gov number, NCT00125502.) PMID:19297572
Tomasoni, Lina R; Meroni, Valeria; Bonfanti, Carlo; Bollani, Lina; Lanzarini, Paolo; Frusca, Tiziana; Castelli, Francesco
Italy provides a free voluntary serological screening for toxoplasmosis in pregnancy supported by public health system, as there is an estimated congenital toxoplasmosis rate of 1-2/10,000. The aim of this study was to make an inventory of diagnostic and therapeutic protocols in use in Italy in the absence of a national guideline. A semistructured questionnaire was distributed to AMCLI (Italian Association of Clinical Microbiologists) members who were asked to involve other specialists to fill in the form. Data from 26 centers show: a) a general use of the IgG avidity test to solve diagnosis in IgG/IgM positive, pregnant women; b) a widespread attitude to spyramicin antenatal treatment in suspected, unconfirmed maternal infection; c) avoidance of invasive antenatal diagnosis only in suspected early or late (>24 weeks), even confirmed, maternal infection d) fetal diagnosis performed by PCR assays on amniotic fluid; e) variability of both indications and dosage of pyrimethamine-sulfadiazine (P-S) as fetal treatment; f) use of comparative mother and newborn IgG/IgM Immuneblot in most centers; g) no diagnostic tests performed on placenta and cord blood; h) spyramicin is no longer used in congenital infections; i) no P-S-based treatment for children at high risk of congenital infection (late maternal infection) in the absence of diagnosis. As there is the opportunity to test pregnant women for Toxoplasma gondii infection in Italy free of charge, standardized diagnostic and therapeutic national guidelines would focus on a more uniform approach.
Mosca, F; Pugni, L
Cytomegalovirus (CMV) is the leading cause of congenital infection in humans and constitutes a major public health problem. Congenitally infected infants, both symptomatic and asymptomatic at birth, may develop sequelae, particularly sensorineural hearing loss (SNHL) and brain damage. Transmission of the virus from mother to fetus can occur during either primary or recurrent maternal infection; however it is much higher in primary infected mothers than in mothers with preconceptional immunity. Routine CMV screening for primary infection during pregnancy constitutes a controversial issue, because of the lack of prenatal recommended therapy for congenital CMV infection. Ganciclovir may be used to treat neonates with symptoms at birth. Despite advances in antiviral therapy, congenitally infected infants, both symptomatic and asymptomatic at birth, need a follow up evaluation to detect sequelae. Congenital CMV infection cna be diagnosed at birth by using a test based on detection of viral DNA by PCR in dried blood spots (Guthrie card) collected on filter paper in the first days of life. Therefore, universal newborn screening for CMV by using DBS test should be recommended to detect sequelae as early as possible, so that infants can receive intervention promptly.
Bergevin, Anna; Zick, Cathleen D; McVicar, Stephanie Browning; Park, Albert H
In this study, we estimate an ex ante cost-benefit analysis of a Utah law directed at improving early cytomegalovirus (CMV) detection. We use a differential cost of treatment analysis for publicly insured CMV-infected infants detected by a statewide hearing-directed CMV screening program. Utah government administrative data and multi-hospital accounting data are used to estimate and compare costs and benefits for the Utah infant population. If antiviral treatment succeeds in mitigating hearing loss for one infant per year, the public savings will offset the public costs incurred by screening and treatment. If antiviral treatment is not successful, the program represents a net cost, but may still have non-monetary benefits such as accelerated achievement of diagnostic milestones. The CMV education and treatment program costs are modest and show potential for significant cost savings. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.
Congenital transmission of Trypanosoma cruzi infection in Argentina has being increasing its relative importance with control of vectorial and transfusional transmission growth. It is for this reason that vertical transmission is seen, in the future, as a continuous source of infected newborns, even with vectorial and transfusional transmission completely controlled. Preventing vertical transmission of T.cruzi is not possible, but it can be precociously detected, permitting mother and child to be incorporated into the medical attention system, and so allowing the newbornś treatment with practically 100% efficacy. It is estimated that between 800 and 1700 children infected with T. cruzi by congenital transmission are born in Argentina, per year. The implementation of an early strategy of detection for an effective and opportune treatment acquires great relevance as a Public Health measure.
Seel, K; Guschmann, M; van Landeghem, F; Grosch-Wörner, I
CMV infection is common in pediatric HIV-1 infected patients. We present a case report, to our knowledge the first pediatric patient, in which Addison-disease due to CMV was suspected during lifetime. We want to point out the importance of routine clinical and laboratory follow up once a HIV-1 infected child is shown to be infected with CMV.
Revello, Maria Grazia; Lazzarotto, Tiziana; Guerra, Brunella; Spinillo, Arsenio; Ferrazzi, Enrico; Kustermann, Alessandra; Guaschino, Secondo; Vergani, Patrizia; Todros, Tullia; Frusca, Tiziana; Arossa, Alessia; Furione, Milena; Rognoni, Vanina; Rizzo, Nicola; Gabrielli, Liliana; Klersy, Catherine; Gerna, Giuseppe
Congenital infection with human cytomegalovirus (CMV) is a major cause of morbidity and mortality. In an uncontrolled study published in 2005, administration of CMV-specific hyperimmune globulin to pregnant women with primary CMV infection significantly reduced the rate of intrauterine transmission, from 40% to 16%. We evaluated the efficacy of hyperimmune globulin in a phase 2, randomized, placebo-controlled, double-blind study. A total of 124 pregnant women with primary CMV infection at 5 to 26 weeks of gestation were randomly assigned within 6 weeks after the presumed onset of infection to receive hyperimmune globulin or placebo every 4 weeks until 36 weeks of gestation or until detection of CMV in amniotic fluid. The primary end point was congenital infection diagnosed at birth or by means of amniocentesis. A total of 123 women could be evaluated in the efficacy analysis (1 woman in the placebo group withdrew). The rate of congenital infection was 30% (18 fetuses or infants of 61 women) in the hyperimmune globulin group and 44% (27 fetuses or infants of 62 women) in the placebo group (a difference of 14 percentage points; 95% confidence interval, -3 to 31; P=0.13). There was no significant difference between the two groups or, within each group, between the women who transmitted the virus and those who did not, with respect to levels of virus-specific antibodies, T-cell-mediated immune response, or viral DNA in the blood. The clinical outcome of congenital infection at birth was similar in the two groups. The number of obstetrical adverse events was higher in the hyperimmune globulin group than in the placebo group (13% vs. 2%). In this study involving 123 women who could be evaluated, treatment with hyperimmune globulin did not significantly modify the course of primary CMV infection during pregnancy. (Funded by Agenzia Italiana del Farmaco; CHIP ClinicalTrials.gov number, NCT00881517; EudraCT no. 2008-006560-11.).
Arce-Estrada, Gabriel Emmanuel; Gómez-Toscano, Valeria; Cedillo-Peláez, Carlos; Sesman-Bernal, Ana Luisa; Bosch-Canto, Vanessa; Mayorga-Butrón, José Luis; Vargas-Villavicencio, José Antonio; Correa, Dolores
We present one unusual case of anophthalmia and craniofacial cleft, probably due to congenital toxoplasmosis only. A two-month-old male had a twin in utero who disappeared between the 7(th) and the 14(th) week of gestation. At birth, the baby presented anophthalmia and craniofacial cleft, and no sign compatible with genetic or exposition/deficiency problems, like the Wolf-Hirschhorn syndrome or maternal vitamin A deficiency. Congenital toxoplasmosis was confirmed by the presence of IgM abs and IgG neo-antibodies in western blot, as well as by real time PCR in blood. CMV infection was also discarded by PCR and IgM negative results. Structures suggestive of T. gondii pseudocysts were observed in a biopsy taken during the first functional/esthetic surgery. We conclude that this is a rare case of anophthalmia combined with craniofacial cleft due to congenital toxoplasmosis, that must be considered by physicians. This has not been reported before.
... daily (D), monthly (M), quarterly (Q), and yearly (Y) time scales and regional maps associated with field campaigns at daily and monthly time scales. The CMV product provides conveniently organized, high quality ...
Zhang, Jian; Yuan, Yan; Li, Peiling; Wang, Tuanjie; Gao, Jun; Yao, Jinhua; Li, Shujun
Objective: To study the pathogen distribution, antimicrobial susceptibility and risk factors of postoperative nosocomial infections among children with congenital heart disease. Methods: Three hundreds children with congenital heart disease admitted to our hospital to receive surgeries from February 2010 to February 2013 were selected. Results: A total of 120 children were tested as positive by sputum culture, with the infection rate of 40.0%. The top five most common pathogenic microorganisms included Staphylococcus epidermidis, Staphylococcus aureus, Enterococcus, Pseudomonas aeruginosa, and Candida albicans. S. epidermidis, S. aureus and Enterococcus were highly resistant to penicillin, azithromycin and erythromycin, moderately susceptible to levofloxacin and cefazolin, and completely susceptible to vancomycin. Multivariate Logistic regression analysis showed that hospitalization stay length, combined use of antibiotics, systemic use of hormones, mechanical ventilation and catheter indwelling were the independent risk factors of postoperative nosocomial infections (P<0.05). Conclusion: Nosocomial infection, which was the most frequent postoperative complication of pediatric congenital heart disease, was predominantly induced by Gram-positive bacteria that were highly susceptible to cephalosporins and vancomycin. Particular attention should be paid to decrease relevant risk factors to improve the prognosis. PMID:24948978
Bachmeyer, C; Mouchnino, G; Thulliez, P; Blum, L
Congenital toxoplasmosis usually results from acquired infection in non-immune pregnant women. However, severely HIV-infected women with a latent Toxoplasma infection can transmit the parasite as a result of reactivation. We report a case of toxoplasmic reactivation in an HIV-infected woman with moderate immunosuppression resulting in a severe congenital toxoplasmosis.
Alarcon, Ana; Martinez-Biarge, Miriam; Cabañas, Fernando; Hernanz, Angel; Quero, Jose; Garcia-Alix, Alfredo
To evaluate clinical, biochemical, and neuroimaging findings as predictors of neurodevelopmental outcome in patients with symptomatic congenital cytomegalovirus (CMV). The study cohort comprised 26 patients with symptomatic congenital CMV born between 1993 and 2009 in a single center. Absolute and weight deficit-adjusted head circumference were considered. Cerebrospinal fluid (CSF) investigations included standard cytochemical analysis, determination of beta2-microglobulin (β2-m), neuron-specific enolase, and CMV DNA detection. Neuroimaging was classified according to a validated scoring system comprising calcifications, ventriculomegaly, and atrophy, with findings graded from 0 to 3. Systematic long-term neurodevelopmental assessment included motor function, cognition, behavior, hearing, vision, and epilepsy. Sequelae were graded as mild/absent, moderate, or severe; adverse outcome was defined as death or moderate to severe disability. Three children died. The mean age at follow-up of the survivors was 8.7 ± 5.3 years (range, 19 months to 18.0 years). Neonatal findings showing a significant association with adverse outcome were relative microcephaly, CSF β2-m concentrations, and grade 2-3 neuroimaging abnormalities (P < .05). Receiver operator characteristic curve analysis indicated that the most accurate single factor for predicting unfavorable outcome was CSF β2-m >7.9 mg/L (area under the curve, 0.84 ± 0.08; sensitivity, 69%; specificity, 100%). The combination of CSF β2-m >7.9 mg/L and moderate-severe neuroimaging alterations improved predictive ability (area under the curve, 0.92 ± 0.06; sensitivity, 87%; specificity, 100%). Adjusted head circumference, CSF β2-m level, and neuroimaging studies have prognostic significance for neurodevelopmental outcome in newborns with congenital CMV. A combination of early findings improves the predictive value. Copyright © 2013 Mosby, Inc. All rights reserved.
Iwasenko, Jenna M; Howard, Jonathan; Arbuckle, Susan; Graf, Nicole; Hall, Beverley; Craig, Maria E; Rawlinson, William D
Human cytomegalovirus (CMV) is the most common congenital infection in developed countries and is a known cause of intrauterine fetal death. We examined CMV infection in stillbirths and the relationship with histopathological findings at autopsy. We collected liver, kidney, and placenta specimens from 130 stillbirths. CMV DNA and protein were detected using polymerase chain reaction and immunohistochemistry, along with routine autopsy of stillborn infants. Overall, CMV DNA was detected in 15% of singleton, >20-week stillborn infants. CMV DNA was detected in kidney (9%), liver (11%), and placenta (5%) specimens, with 75% of infections confirmed by immunohistochemistry. Fetal thrombotic vasculopathy was the only histopathological abnormality associated with CMV infection (in 60% CMV-infected vs 28% uninfected stillbirths P = .010). Stillbirth has multiple etiologies. However, the detection of CMV DNA in 15% of fetal tissues or placentae suggests a strong association between CMV infection in pregnancy and stillbirth. Molecular testing during postmortem investigation has an important role to determine the contribution of CMV infection.
Goodwin, T. J.; McCarthy, M.; Albrecht, T.; Cohrs, R.
The old adage we are our own worst enemies may perhaps be the most profound statement ever made when applied to man s desire for extraterrestrial exploration and habitation of Space. Consider the immune system protects the integrity of the entire human physiology and is comprised of two basic elements the adaptive or circulating and the innate immune system. Failure of the components of the adaptive system leads to venerability of the innate system from opportunistic microbes; viral, bacteria, and fungal, which surround us, are transported on our skin, and commonly inhabit the human physiology as normal and imunosuppressed parasites. The fine balance which is maintained for the preponderance of our normal lives, save immune disorders and disease, is deregulated in microgravity. Thus analogue systems to study these potential Risks are essential for our progress in conquering Space exploration and habitation. In this study we employed two known physiological target tissues in which the reactivation of hCMV and VZV occurs, human neural and lung systems created for the study and interaction of these herpes viruses independently and simultaneously on the innate immune system. Normal human neural and lung tissue analogues called tissue like assemblies (TLAs) were infected with low MOIs of approximately 2 x 10(exp -5) pfu hCMV or VZV and established active but prolonged low grade infections which spanned .7-1.5 months in length. These infections were characterized by the ability to continuously produce each of the viruses without expiration of the host cultures. Verification and quantification of viral replication was confirmed via RT_PCR, IHC, and confocal spectral analyses of the respective essential viral genomes. All host TLAs maintained the ability to actively proliferate throughout the entire duration of the experiments as is analogous to normal in vivo physiological conditions. These data represent a significant advance in the ability to study the triggering
Zika virus (ZIKV) is an arbovirus belonging to flaviviridae family that includes Dengue, West Nile, and Yellow Fever among others. Zika virus was first discovered in 1947 in Zika forest of Uganda. It is a vector borne disease, which has been sporadically reported mostly from Africa, Pacific islands and Southeast Asia since its discovery. ZIKV infection presents as a mild illness with symptoms lasting for several days to a week after the bite of an infected mosquito. Majority of the patients have low grade fever, rash, headaches, joints pain, myalgia, and flu like symptoms. Pregnant women are more vulnerable to ZIKV infection and serious congenital anomalies can occur in foetus through trans-placental transmission. The gestation at which infection is acquired is important. Zika virus infection acquired in early pregnancy poses greater risk. There is no evidence so far about transmission through breast milk. Foetal microcephaly, Gillian Barre syndrome and other neurological and autoimmune syndromes have been reported in areas where Zika outbreaks have occurred. As infection is usually very mild no specific treatment is required. Pregnant women may be advised to take rest, get plenty of fluids. For fever and pain they can take antipyretics like paracetamol. So far no specific drugs or vaccines are available against Zika Virus Infection so prevention is the mainstay against this diseases. As ZIKV infection is a vector borne disease, prevention can be a multi-pronged strategy. These entail vector control interventions, personal protection, environmental sanitation and health education among others.
Contopoulos-Ioannidis, Despina; Wheeler, Kelsey M.; Ramirez, Raymund; Press, Cindy; Mui, Ernest; Zhou, Ying; Van Tubbergen, Christine; Prasad, Sheela; Maldonado, Yvonne; Withers, Shawn; Boyer, Kenneth M.; Noble, A. Gwendolyn; Rabiah, Peter; Swisher, Charles N.; Heydemann, Peter; Wroblewski, Kristen; Karrison, Theodore; Grigg, Michael E.; Montoya, Jose G.; McLeod, Rima
Background. Family clusters and epidemics of toxoplasmosis in North, Central, and South America led us to determine whether fathers of congenitally infected infants in the National Collaborative Chicago-Based Congenital Toxoplasmosis Study (NCCCTS) have a high incidence of Toxoplasma gondii infection. Methods. We analyzed serum samples collected from NCCCTS families between 1981 and 2013. Paternal serum samples were tested for T. gondii antibodies with immunoglobulin (Ig) G dye test and IgM enzyme-linked immunosorbent assay. Additional testing of paternal serum samples was performed with differential-agglutination and IgG avidity tests when T. gondii IgG and IgM results were positive and serum samples were collected by the 1-year visit of the congenitally infected child. Prevalence of paternal seropositivity and incidence of recent infection were calculated. We analyzed whether certain demographics, maternal parasite serotype, risk factors, or maternal/infant clinical manifestations were associated with paternal T. gondii infection status. Results. Serologic testing revealed a high prevalence (29 of 81; 36%) of T. gondii infection in fathers, relative to the average seropositivity rate of 9.8% for boys and men aged 12–49 years in the United States between 1994 and 2004 (P < .001). Moreover, there was a higher-than-expected incidence of recent infections among fathers with serum samples collected by the 1-year visit of their child (6 of 45; 13%; P < .001). No demographic patterns or clinical manifestations in mothers or infants were associated with paternal infections, except for sandbox exposure. Conclusions. The high prevalence of chronic and incidence of recent T. gondii infections in fathers of congenitally infected children indicates that T. gondii infections cluster within families in North America. When a recently infected person is identified, family clustering and community risk factors should be investigated for appropriate clinical management
Fouts, Ashley E; Chan, Pamela; Stephan, Jean-Philippe; Vandlen, Richard; Feierbach, Becket
Anti-cytomegalovirus (anti-CMV) hyperimmune globulin (HIG) has demonstrated efficacy in preventing CMV disease in solid-organ transplant patients as well as congenital disease when administered to pregnant women. To identify the neutralizing component of cytomegalovirus hyperimmune globulin (CMV-HIG), we performed serial depletions of CMV-HIG on cell-surface-expressed CMV antigens as well as purified antigens. Using this approach, we demonstrate that the major neutralizing antibody response is directed at the gH/gL/UL128/UL130/UL131 complex, suggesting little role for anti-gB antibodies in CMV-HIG neutralization.
Balcells, Carla; Botet, Francesc; Gayete, Sònia; Marcos, M Ángeles; Dorronsoro, Izaskun; de Alba, Concepción; Figueras-Aloy, Josep
To determine the epidemiology of congenital and acquired cytomegalovirus (CMV) infections in preterm infants and to analyze the efficacy of breast milk freezing in decreasing the vertical transmission rate of CMV. During 2013 and 2014, preterm newborns who weighed ≤1500 g and were admitted to 22 Spanish neonatal units were included and screened for CMV infection according to the Spanish Neonatology Society recommendations. Each hospital treated the breast milk according to its own protocols. Among the 1236 preterm neonates included, 10 had a congenital infection (0.8%) and 49 had an acquired infection (4.0%) (82% demonstrated positive PCR-CMV in breast milk). The neonates who received only frozen milk presented less frequently with acquired infection (1.2%) than those fed fresh milk (5.5%) (RR=0.22; 95% CI 0.05-0.90; P=0.017). The newborns who received bank milk followed by frozen or fresh breast milk more frequently had an acquired infection (2.1% or 2.2%, respectively) than those fed only frozen breast milk. The incidence of congenital CMV infection in our sample is low, as described in the literature. To reduce acquired CMV infection, freezing breast milk might be an advisable procedure for preterm neonates born from seropositive mothers, either from the beginning of lactation or after a period of bank milk administration.
Alarcón Allen, A; Baquero-Artigao, F
Postnatal cytomegalovirus (CMV) infection in the newborn can occur from exposure to maternal cervical secretions during birth, ingestion of breast milk, transfusion of blood products or transmission by body fluids of infected people. Breast milk is the main source of infection, given the high rate of CMV-positive mothers excreting CMV in milk. Freezing reduces the risk of CMV transmission by breastfeeding, although it does not eliminate it completely. Pasteurisation prevents such transmission, but it can alter the immunological properties of breast milk. Postnatal CMV infection is usually asymptomatic, as it normally results from viral reactivation in the mother, and the neonate is born with protective antibodies. However, in the very low birth weight premature infant the amount of transferred antibodies is smaller and a symptomatic infection can occur. Symptomatic post-natal CMV infection in the newborn typically causes hepatitis, neutropenia, thrombocytopenia or sepsis-like syndrome. Pneumonitis and enteritis are less common, but very characteristic. Diagnosis is based on urine virus detection at the time of onset of symptoms. Postnatal CMV infection in the newborn generally resolves spontaneously without antiviral treatment. Ganciclovir should be reserved for severe cases. Unlike congenital CMV disease, post-natal CMV infection in the preterm infant does not seem to be associated with hearing loss or abnormal neuro-development in long term follow-up.
Dammermann, Werner; Bochmann, David; Bentzien, Frank; Komorowski, Lars; Steinhagen, Katja; Ullrich, Sebastian; van Lunzen, Jan; Lüth, Stefan
Interferon gamma release assays (IGRAs) are widely used to detect pathogen specific cellular immunity. Cytomegalovirus (CMV) is the foremost problematic viral infection in immunocompromised patients such as transplant or HIV infected patients. CMV antibody ELISAs are not able to predict CMV specific cellular immunity during immunosuppression. We developed a CMV specific IGRA comparing synthetic CMV peptides, native lysate and recombinant antigen. In addition, TLR agonists were tested to enhance CMV antigen immunogenicity. 397 healthy controls (HC) were stratified according to CMV IgM and IgG serostatus and subsequently tested for IFNγ- and IL2-secretion in whole blood after challenge with synthetic, native or recombinant CMV antigens and TLR agonists by ELISA. The selected TLR agonists were lipopolysaccharide (LPS), lipoteichoic acid (LTA), peptidoglycan (PGN), zymosan (Zym), polyinosinic-polycytidylic acid (Poly(I:C)), flagellin (Fla), R848, loxoribine (Lox) and bropirimine (Bro). Synthetic pp65 peptides elicited strong IFNγ responses in CMV seropositive, but not seronegative HC (6418 vs. 13 pg/ml). Native lysates and recombinant pp65 induced equally high IFNγ responses in seropositive (35,877 and 26,428 pg/ml) and increased background IFNγ expression in seronegative HC (43 and 1148 pg/ml). Diagnostic sensitivity and specificity with regard to anti-CMV serology reached 100% for synthetic pp65 and native CMV lysate, but 57% and 100% for recombinant pp65, respectively. TLR agonists LTA and Poly(I:C) augmented IFNγ responses after challenge with synthetic pp65 peptide, native lysate or recombinant pp65 in seropositive HC. Seronegative HC remained unaffected. IL2 production was negligible compared to IFNγ. IGRAs using synthetic CMV peptides or native lysate showed the best cytokine signal to noise ratio compared to recombinant antigen and TLR agonists LTA and Poly(I:C) constitute potential costimulating reagents. Copyright © 2014 Elsevier B.V. All rights
Lanzieri, Tatiana M; Chung, Winnie; Flores, Marily; Blum, Peggy; Caviness, A Chantal; Bialek, Stephanie R; Grosse, Scott D; Miller, Jerry A; Demmler-Harrison, Gail
To assess the prevalence, characteristics, and risk of sensorineural hearing loss (SNHL) in children with congenital cytomegalovirus infection identified through hospital-based newborn screening who were asymptomatic at birth compared with uninfected children. We included 92 case-patients and 51 controls assessed by using auditory brainstem response and behavioral audiometry. We used Kaplan-Meier survival analysis to estimate the prevalence of SNHL, defined as ≥25 dB hearing level at any frequency and Cox proportional hazards regression analyses to compare SNHL risk between groups. At age 18 years, SNHL prevalence was 25% (95% confidence interval [CI]: 17%-36%) among case-patients and 8% (95% CI: 3%-22%) in controls (hazard ratio [HR]: 4.0; 95% CI: 1.2-14.5; P = .02). Among children without SNHL by age 5 years, the risk of delayed-onset SNHL was not significantly greater for case-patients than for controls (HR: 1.6; 95% CI: 0.4-6.1; P = .5). Among case-patients, the risk of delayed-onset SNHL was significantly greater among those with unilateral congenital/early-onset hearing loss than those without (HR: 6.9; 95% CI: 2.5-19.1; P < .01). The prevalence of severe to profound bilateral SNHL among case-patients was 2% (95% CI: 1%-9%). Delayed-onset and progression of SNHL among children with asymptomatic congenital cytomegalovirus infection continued to occur throughout adolescence. However, the risk of developing SNHL after age 5 years among case-patients was not different than in uninfected children. Overall, 2% of case-patients developed SNHL that was severe enough for them to be candidates for cochlear implantation. Copyright © 2017 by the American Academy of Pediatrics.
Leng, Sean X.; Li, Huifen; Xue, Qian-Li; Tian, Jing; Yang, Xi; Ferrucci, Luigi; Fedarko, Neal; Fried, Linda P.; Semba, Richard D.
In immunocompetent persons, cytomegalovirus (CMV) is thought to persist primarily in monocytes and myeloid progenitor cells, establishing a chronic infection. In older adults, chronic CMV infection is typically diagnosed by a positive IgG serology. While many studies have shown CMV-specific T-cell expansion in CMV seropositive older individuals, significant heterogeneity has also been observed in this elderly population. In a study of 71 community-dwelling older adults, we assessed CMV viral DNA in peripheral monocytes by nested PCR and compared the relationships of detectable CMV DNA and IgG serology with serum levels of neopterin, a marker for monocyte/macrophage-mediated immune activation. The results showed that 52 (73.2%) participants were CMV seropositive, of whom 30 (57.5%) had detectable CMV DNA. CMV seropositive and seronegative participants did not differ in their neopterin levels, but individuals with detectable CMV DNA had higher neopterin than those without (10.6±4.4 vs 8.0±1.9nM, respectively, p<.0001) adjusting for demographic and clinical covariates and interferon (IFN)-γ levels. In addition, there was no association between IgG titers and neopterin. These findings suggest that detection of CMV viral DNA in monocytes may be an informative tool to evaluate chronic CMV infection and its potential role in monocyte/macrophage-mediated immune activation in the elderly. PMID:21513787
Kocher, Alfred A; Bonaros, Nikolaos; Dunkler, Daniela; Ehrlich, Marek; Schlechta, Bernhard; Zweytick, Barbara; Grimm, Michael; Zuckermann, Andreas; Wolner, Ernst; Laufer, Guenther
Cytomegalovirus (CMV) has emerged as the most important pathogen to affect the post-operative course after heart transplantation. We performed a retrospective analysis to evaluate the efficiency of CMV hyperimmune globulin (CMVIG) prophylaxis in preventing CMV disease in aggressively immunosuppressed patients after heart transplantation. We studied 377 heart transplant recipients who received quadruple-immunosuppressive therapy and CMVIG as sole CMV prophylaxis. The study population was categorized into 4 groups according to donor and recipient CMV serology at the time of transplantation (D+/R+, D+/R-, D-/R+, D-/R-) and was monitored for CMV immediate early antigen in peripheral blood cells, in urine sediments, and in throat washings; for the presence of serum CMV immunoglobulin M and CMV immunoglobulin G; and for clinical evidence of CMV-related symptoms. In addition, we compared the incidence of cardiac allograft vasculopathy and infection among the groups. During the first 5 years after transplantation, CMV disease developed in 79 patients (20.96%). Comparison among the groups showed significantly increased risk for CMV disease in allograft recipients of organs from seropositive donors (D+, 27.31%; D-, 11.33%; p = 0.0003). We observed 6 CMV-associated deaths, all in CMV-antibody-negative recipients. Additionally CMV-positive recipients had a greater incidence of cardiac allograft vasculopathy (p = 0.048), and a greater overall infection rate (p = 0.0034). Cytomegalovirus hyperimmune globulin administration prevents CMV disease and infection in aggressively immunosuppressed heart transplant recipients. Because fatal CMV disease in CMV-negative recipients of organs from seropositive donors could not be prevented with CMVIG alone, we recommend the additional use of prophylactic ganciclovir in this CMV-mismatched population.
Villamil-Gómez, Wilmer; Alba-Silvera, Luz; Menco-Ramos, Antonio; Gonzalez-Vergara, Alfonso; Molinares-Palacios, Tatiana; Barrios-Corrales, María; Rodríguez-Morales, Alfonso J
Congenital chikungunya virus (CHIK) infection has been infrequently reported, even more so during the current 2013-15 outbreak in Latin America. In this study, the consequences of CHIK on pregnancy outcomes and particularly consequences in infants born to infected women were assessed in a case series from a single private institution in the north of Colombia. During September 2014 to February 2015, seven pregnant women with serological and reverse transcription-polymerase chain reaction-positive test for CHIK delivered eight infants with CHIK. These newborns required admission to pediatric intensive care, and related support, owing to severe clinical manifestations, which included respiratory distress, sepsis, necrotizing enterocolitis, meningoencephalitis, myocarditis, edema, bullous dermatitis and pericarditis. There were three deaths (case fatality rate of 37.5%). Pregnant women and newborns with CHIK long term should be followed up, given the implications of chronic sequelae (e.g. chronic inflammatory rheumatism in women) as well as recently described neurocognitive impairment in infants.
Price, Simani M; Bonilla, Erika; Zador, Paul; Levis, Denise M; Kilgo, Christina L; Cannon, Michael J
Congenital cytomegalovirus (CMV) is the most common congenital infection in the U.S. and can result in permanent disabilities, such as hearing and vision loss, intellectual disability, and psychomotor and language impairments. Women can adopt prevention behaviors in an attempt to reduce their exposure to CMV. Currently, few women are familiar with CMV. To increase awareness of CMV, the Centers for Disease Control and Prevention (CDC) developed draft health education materials. The purpose of this study was to pilot test two health education materials to gauge their appeal and to determine if they increase knowledge about CMV and motivate audiences to seek additional information on CMV and adopt CMV prevention behaviors. African-American (n = 404) and Caucasian women (n = 405), who had a young child and were either pregnant or planning a pregnancy, were recruited to participate in a 15-minute web survey. Participants were randomly assigned to view one of two CMV health education materials, either a factsheet or video. Pre and post survey measures were used to assess changes in knowledge of CMV and motivation to adopt prevention behaviors. We also examined audience preferences regarding materials and motivation. CMV knowledge score increased significantly after presentation of either the video or factsheet (from 3.7 out of 10 to 9.1 out of 10, p <0.001). The average materials appeal score was high, with a mean of 3.6 on a four-point scale, indicating women responded very positively to both materials. Regression analyses indicated that appeal, message involvement (e.g., information seeking, discussing with others), post materials knowledge score, and viewing the video (vs. factsheet) were significantly positively associated with increased support for CMV prevention behaviors. Overall, we found that the health education materials improved women's knowledge of CMV and encouraged them to adopt prevention behaviors. Given the low awareness levels among women
Natale, Fabio; Bizzarri, Bianca; Cardi, Veronica; Gaeta, Aurelia; Villani, Paola; Liuzzi, Giuseppina; De Curtis, Mario
Currently, there is no evidence whether ganciclovir, or its oral prodrug valganciclovir, penetrates into the cerebrospinal fluid of human infants treated for congenital cytomegalovirus infection. Here, we report a case study providing evidence that ganciclovir, administered as valganciclovir, reaches the infant's cerebrospinal fluid when used at the currently recommended dose for congenital cytomegalovirus infection.
Calamy, L; Goudjil, F; Godineau, N; Bolot, P
Congenital toxoplasmosis is a potentially serious fetal infection associated with maternal seroconversion or a reactivation of toxoplasmosis during pregnancy. We report the case of congenital toxoplasmosis with severe neurological injury with normal prenatal obstetric ultrasounds in a mother infected with HIV at the AIDS stage and previously immunized against toxoplasmosis.
Bernstein, David I
Despite the clear need, progress toward a vaccine for congenital cytomegalovirus (CMV) has been slow. However, recent events have provided new interest, and several vaccine candidates are either in clinical trials or the trials are close to starting. In this issue of Clinical and Vaccine Immunology, Schleiss and colleagues show that a nonreplicating lymphocytic choriomeningitis virus (rLCMV)-vectored vaccine expressing CMV glycoprotein B (gB) and/or pp65 induces B and T cells and improves pup survival in a guinea pig model of congenital CMV infection (Clin Vaccine Immunol 24:e00300-16, 2017, https://doi.org/10.1128/CVI.00300-16). The combination vaccine appeared to be the most effective.
dela Pena, Myra G; Strelow, Lisa; Barry, Peter A; Abel, Kristina
Congenital human cytomegalovirus (HCMV) infection can result in lifelong neurological deficits. Seronegative pregnant woman often acquire primary HCMV from clinically asymptomatic, but HCMV-shedding children. Potential age-related differences in viral and immune parameters of primary RhCMV infection were examined in an oral rhesus CMV infection model in specific pathogen free macaques. RhCMV shedding was measured by real time PCR in plasma, saliva and urine. Immune parameters, including neutralizing and binding antibodies and RhCMV-specific T cell responses, were assessed in longitudinally collected blood samples. The oral RhCMV infection model in infant SPF rhesus macaques demonstrated that (i) the susceptibility to oral RhCMV infection declines with age, and (ii) infant macaques shed RhCMV more persistently and at higher titers compared to adult macaques. (iii) The oral infant RhCMV infection model appears to reflect viral pathogenesis in human HCMV-infected children. Larger studies are needed to define immune parameters associated with better control of RhCMV in adult compared to young animals. © 2012 John Wiley & Sons A/S.
Sanbonmatsu Gámez, Sara; Ruiz, Mercedes Pérez; Navarro Marí, José María
Prevalence of human cytomegalovirus infection is very high worldwide. Following primary infection, the virus remains latent, being able to cause recurrences either by reinfection with a new strain or by reactivation of the replication of the latent virus. The most severe disease is seen in congenital infection and in immunosuppressed patients, in whom the virus act as an opportunistic pathogen. Serological techniques are the methods of choice in primary infection and to determine the immune status against CMV in organ donor and receptor. Although well-standardized studies are lacking, the recent commercial availability of methods that measure cellular immune response are promising to predict the risk of CMV disease in immunosuppressed individuals. Molecular assays, that have gradually been substituting viral culture and/or antigen detection, are the most widely used methods for the diagnosis and control of CMV infection. Copyright © 2014 Elsevier España, S.L. All rights reserved.
Zin, Andrea A; Tsui, Irena; Rossetto, Julia; Vasconcelos, Zilton; Adachi, Kristina; Valderramos, Stephanie; Halai, Umme-Aiman; Pone, Marcos Vinicius da Silva; Pone, Sheila Moura; Silveira Filho, Joel Carlos Barros; Aibe, Mitsue S; da Costa, Ana Carolina C; Zin, Olivia A; Belfort, Rubens; Brasil, Patricia; Nielsen-Saines, Karin; Moreira, Maria Elisabeth Lopes
nervous system abnormalities (OR, 4.3; 95% CI, 1.6-11.2), arthrogryposis (OR, 29.0; 95% CI, 3.3-255.8), and maternal trimester of infection (first trimester OR, 5.1; 95% CI, 1.9-13.2; second trimester OR, 0.5; 95% CI, 0.2-1.2; and third trimester OR, 0.3; 95% CI, 0.1-1.2). Eye abnormalities may be the only initial finding in congenital Zika virus infection. All infants with potential maternal Zika virus exposure at any time during pregnancy should undergo screening eye examinations regardless of the presence or absence of central nervous system abnormalities.
Kato, Ken; Otake, Hironao; Tagaya, Mitsuhiko; Takahashi, Yoshiyuki; Ito, Yoshinori; Hama, Asahito; Muramatsu, Hideki; Kojima, Seiji; Naganawa, Shinji; Nakashima, Tsutomu
We report a rare case of progressive hearing loss after acquired CMV infection in a child with Langerhans cell histiocytosis (LCH). A 5-month-old female was diagnosed as having LCH. When she was 14 months old, she received an unrelated donor umbilical cord blood transfusion for the treatment of intractable LCH. CMV infection was confirmed after the blood transfusion. Because her own umbilical cord had no CMV, the CMV infection was not congenital. When she was 7 years old, mixed hearing loss was noted with bilateral otitis media with effusion. After that time, the sensorineural hearing loss progressed to bilateral profound hearing loss over 3 years. Three-dimensional fluid-attenuated inversion recovery magnetic resonance imaging with gadolinium contrast enhancement revealed a high intensity area in the inner ear that suggested bilateral labyrinthitis. This case demonstrates the possibility that, under the immunodeficiency, the acquired CMV infection causes progressive sensorineural hearing loss. Copyright © 2013 Elsevier Inc. All rights reserved.
Background Aim of our study is to analyze the immunological status in pregnancy for two main TORCH agents, Toxoplasma and Cytomegalovirus (CMV), and the results of group B streptococcus (GBS) screening, assessing the risk for congenital infection in a population from Palermo, Italy. Methods We retrospectively analyzed the medical records of all inborn live newborns who were born in our division during 2012, gathering information about the mother, the pregnancy and neonatal hospitalization at birth. Whenever data were available, we categorized the serologic status of the mothers for Toxoplasma and CMV. We also considered the results of rectal and vaginal swabs for GBS. We compared the results in Italian and immigrant mothers. The neonatal outcome was evaluated in all cases at risk. Results Prevalence of anti-Toxo IgG antibodies was 17.97%, and was significantly higher in immigrant women (30% vs 16.4% in Italian women; p = 0.0008). Prevalence of anti-CMV IgG antibodies was 65.87%. Again, it was significantly higher in immigrant women (91.4% vs 62.5%, p = 3.31e-08). We compared those data with a previous study performed in our hospital in 2005–2006, and found that the prevalence of anti-Toxoplasma and anti-CMV antibodies in our population has remained stable, both in the immigrant and in the local population. Seroconversion rates and neonatal infections were rare: no seroconversions were observed for Toxoplasma, 4 seroconversions for CMV. One neonatal Toxoplasma infection and two neonatal CMV infections were documented. In some cases with dubious patterns or probable persistence of IgM, we performed additional tests and follow-up. Vaginal and rectal swabs were positive for GBS in 7.98% of cases, with no significant difference between the Italian and the immigrant population. No GBS neonatal sepsis was documented. Conclusions The prevalence of Toxoplasma IgG antibodies in pregnant women was low in our population, if compared with European countries and with
Hutchinson, M. Katherine; Sandall, Susan R.
This article describes TORCH infections, a congenital cluster of infections including toxoplasmosis, syphilis, rubella, cytomegalovirus, and herpes which often results in developmental disabilities for infected children. Methods of transmission, incidence, and developmental outcomes for common TORCH infections are described, as are program…
Hutchinson, M. Katherine; Sandall, Susan R.
This article describes TORCH infections, a congenital cluster of infections including toxoplasmosis, syphilis, rubella, cytomegalovirus, and herpes which often results in developmental disabilities for infected children. Methods of transmission, incidence, and developmental outcomes for common TORCH infections are described, as are program…
Ducournau, Céline; Nguyen, Thi Tl; Carpentier, Rodolphe; Lantier, Isabelle; Germon, Stéphanie; Précausta, Flavien; Pisella, Pierre-Jean; Leroux, Hervé; Van Langendonck, Nathalie; Betbeder, Didier; Dimier-Poisson, Isabelle
Development of protein vaccine to prevent congenital infection is a major public health priority. Our goal is the design of mucosal synthetic pathogen inducing protective immune responses against congenital toxoplasmosis. Mice were immunized intranasally, establishing pregnancy and challenging orally. Placental immune response, congenital infection, pup growth, parasitic load rates were studied. Pups born to vaccinated infected dams had significantly fewer brain cysts, no intraocular inflammation and normal growth. Protection was associated with a placental cellular Th1 response downregulated by IL-6 and correlated with persistence of vaccine for few hours in the nose before being totally eliminated. Our vaccine conferred high protection against congenital toxoplasmosis. These results provide support for future studies of other congenital vaccine.
Hutson, Samuel L.; Wheeler, Kelsey M.; McLone, David; Frim, David; Penn, Richard; Swisher, Charles N.; Heydemann, Peter T.; Boyer, Kenneth M.; Noble, A. Gwendolyn; Rabiah, Peter; Withers, Shawn; Montoya, Jose G.; Wroblewski, Kristen; Karrison, Theodore; Grigg, Michael E.; McLeod, Rima
Four anatomical patterns of hydrocephalus secondary to congenital Toxoplasma gondii infection were identified and characterized for infants enrolled in the National Collaborative Chicago-based Congenital Toxoplasmosis Study. Analysis of parasite serotype revealed that different anatomical patterns associate with Type-II vs Not-Exclusively Type-II strains (NE-II) (P = .035). PMID:26405147
Laccourreye, L; Ettienne, V; Prang, I; Couloigner, V; Garabedian, E-N; Loundon, N
To analyze speech in children with profound hearing loss following congenital cytomegalovirus (cCMV) infection with cochlear implantation (CI) before the age of 3 years. In a cohort of 15 children with profound hearing loss, speech perception, production and intelligibility were assessed before and 3 years after CI; variables impacting results were explored. Post-CI, median word recognition was 74% on closed-list and 48% on open-list testing; 80% of children acquired speech production; and 60% were intelligible for all listeners or listeners attentive to lip-reading and/or aware of the child's hearing loss. Univariate analysis identified 3 variables (mean post-CI hearing threshold, bilateral vestibular areflexia, and brain abnormality on MRI) with significant negative impact on the development of speech perception, production and intelligibility. CI showed positive impact on hearing and speech in children with post-cCMV profound hearing loss. Our study demonstrated the key role of maximizing post-CI hearing gain. A few children had insufficient progress, especially in case of bilateral vestibular areflexia and/or brain abnormality on MRI. This led us to suggest that balance rehabilitation and speech therapy should be intensified in such cases. Copyright © 2015 Elsevier Masson SAS. All rights reserved.
Sánchez Negrette, Olga; Mora, María Celia; Basombrío, Miguel Angel
Trypanosoma cruzi, the causative agent of Chagas' disease, is transmitted mainly by insect vectors, but congenital and transfusion-borne infections occasionally occur. The factors that are involved in transmission from mother to offspring are not well understood. The objective of this study was to study the presence of T cruzi infection in children who were born to infected mothers and in the children's siblings to evaluate the epidemiologic risk factors associated with congenital transmission of Chagas' disease. Congenital T cruzi infection was studied in 340 children who were born to chronically infected mothers in Salta, Argentina. Infection was detected in 31 children, who were selected for additional study as infected index cases (IIC). Of the 309 noninfected children, 31 were taken as noninfected index cases (NIIC). We compared the prevalence of congenital T cruzi transmission in the remaining siblings of the IIC and NIIC. Data and blood samples were collected in house-to-house visits. Diagnosis of infection was established mainly by serologic methods, indirect hemmagglutination, and enzyme-linked immunosorbent assay. The prevalence was 31.4% (32 of 102 children) for IIC siblings, whereas no infected siblings were found in families with NIIC (0 of 112). Clustering of congenital infection was found in 14 families, in which >1 child was infected. Second-generation congenital transmission (from grandmother to mother to newborn) was established in 4 families. The association among low weight at birth, prematurity, and congenital transmission was highly significant. An important observation was the absence of pathologic findings in a high proportion of infected children. The detection of asymptomatic infections was a consequence of population screening, as opposed to hospital-based diagnosis, for which symptomatic cases predominate. Congenital transmission was associated with the geographic origin of mothers: women from areas where insect vectors proliferate were
Melnick, Michael; Jaskoll, Tina
Congenital human cytomegalovirus (CMV) infection is the leading nongenetic etiology of sensorineural hearing loss (SNHL) at birth and prelingual SNHL not expressed at birth. The paucity of temporal bone autopsy specimens from infants with congenital CMV infection has hindered the critical correlation of histopathology with pathogenesis. Here, we present an in vitro embryonic mouse model of CMV-infected cochleas that mimics the human sites of viral infection and associated pathology. There is a striking dysplasia/hyperplasia in mouse CMV-infected cochlear epithelium and mesenchyme, including organ of Corti hair and supporting cells and stria vascularis. This is concomitant with significant dysregulation of p19, p21, p27, and Pcna gene expression, as well as proliferating cell nuclear antigen (PCNA) protein expression. Other pathologies similar to those arising from known deafness gene mutations include downregulation of KCNQ1 protein expression in the stria vascularis, as well as hypoplastic and dysmorphic melanocytes. Thus, this model provides a relevant and reliable platform within which the detailed cell and molecular biology of CMV-induced deafness may be studied.
Melnick, Michael; Jaskoll, Tina
Congenital human cytomegalovirus (CMV) infection is the leading nongenetic etiology of sensorineural hearing loss (SNHL) at birth and prelingual SNHL not expressed at birth. The paucity of temporal bone autopsy specimens from infants with congenital CMV infection has hindered the critical correlation of histopathology with pathogenesis. Here, we present an in vitro embryonic mouse model of CMV-infected cochleas that mimics the human sites of viral infection and associated pathology. There is a striking dysplasia/hyperplasia in mouse CMV-infected cochlear epithelium and mesenchyme, including organ of Corti hair and supporting cells and stria vascularis. This is concomitant with significant dysregulation of p19, p21, p27, and Pcna gene expression, as well as proliferating cell nuclear antigen (PCNA) protein expression. Other pathologies similar to those arising from known deafness gene mutations include downregulation of KCNQ1 protein expression in the stria vascularis, as well as hypoplastic and dysmorphic melanocytes. Thus, this model provides a relevant and reliable platform within which the detailed cell and molecular biology of CMV-induced deafness may be studied. PMID:23281115
Willame, Alexia; Blanchard-Rohner, Geraldine; Combescure, Christophe; Irion, Olivier; Posfay-Barbe, Klara; Martinez de Tejada, Begoña
Background: Cytomegalovirus (CMV) is the most frequent cause of congenital infection and commonly associated with sensorineural deficit. At present, there is neither prophylaxis nor treatment during pregnancy. The objective of this study was to evaluate the level of awareness regarding CMV infection and its consequences in women delivering at the University of Geneva Hospitals (Geneva, Switzerland). Methods: The study consisted of a validated questionnaire completed by women in the immediate postpartum period. Results: The questionnaire was completed by 59% (314/528) of delivering women. Only 39% (123/314) knew about CMV and 19.7% (62/314) had received information about preventive measures. Women were more aware about other congenital diseases, such as toxoplasmosis (87%); human immunodeficiency virus (99%); syphilis (85.5%); rubella (92.3%); and group B Streptococcus (63%). Factors associated with CMV awareness were Swiss nationality, high education level, employment in health care or with children, and being followed by an obstetrician. Regarding quality of information, few were aware of the main CMV complications (deafness, 25.2%; mental retardation, 34.5%). Among those informed about CMV, most (74.6%) knew about preventive measures. Among these, 82.5% thought that these were easily applicable. Conclusions: Most women are unaware of CMV infection and its potential risks during pregnancy. It is crucial to improve CMV information given to pregnant women to prevent the risks for the fetus/newborn. PMID:26633451
Frasca, Daniela; Blomberg, Bonnie B
Influenza vaccination is less effective in elderly as compared to young individuals. Several studies have identified immune biomarkers able to predict a protective humoral immune response to the vaccine. In this review, we summarize current knowledge on the effects of aging on influenza vaccine responses and on biomarkers so far identified, and we discuss the relevance of latent cytomegalovirus (CMV) infection on these vaccine responses.
Picone, O; Grangeot-Keros, L; Senat, Mv; Fuchs, F; Bouthry, E; Ayoubi, Jm; Benachi, A; Vauloup-Fellous, C
Diagnosis of cytomegalovirus (CMV) primary infection is reliable, but diagnosis of CMV non-primary infection (NPI) is questionable. Our aim is to highlight the difficulties met in diagnosis of CMV NPI. We illustrate that in proven cases of CMV NPI, very different serologic and molecular patterns may be observed and that routine serologic testing may fail to help with diagnosis. These results point out that many data available in literature concerning the prevalence of NPI, materno-fetal transmission rates and consequences of NPI may be wrong. We need to know how frequently they occur, are transmitted and cause fetal damages. Diagnosis of NPI must be improved, along with our understanding of the mechanisms leading to intrauterine CMV transmission and congenital infection in babies born to women with preexisting immunity.
Stadler, Laura Patricia; Bernstein, David I.; Callahan, S. Todd; Turley, Christine B.; Munoz, Flor M.; Ferreira, Jennifer; Acharya, Mekhala; Simone, Gina A. Gorgone; Patel, Shital M.; Edwards, Kathryn M.; Rosenthal, Susan L.
Background Congenital cytomegalovirus (CMV) is a leading cause of disability, including sensorineural hearing loss, developmental delay, and mental retardation. Understanding risk factors for acquisition of CMV infection in adolescent females will help determine vaccine strategies. Methods Females (12–17 years) were recruited from primary care settings in Cincinnati, Galveston, Houston, and Nashville from June 2006 to July 2010 for a seroepidemiologic study, from which seronegative participants were recruited for a CMV vaccine trial. Participants (n = 1585) responded to questions regarding potential exposures. For those with young children in the home (n = 859), additional questions were asked about feeding and changing diapers, and for those > 14 years of age (n = 1162), questions regarding sexual activity were asked. Serum was evaluated for CMV antibody using a commercial immunoglobulin G assay. Results Cytomegalovirus antibody was detected in 49% of participants. In the univariate analyses, CMV seroprevalence was significantly higher among African Americans, those with children < 3 years of age in the home, and those with a history of oral, anal, or vaginal intercourse. Among those with young children in the home, feeding children and changing diapers further increased the association with CMV infection. However, in the final multivariate analysis, only African Americans and household contact with young children were associated with CMV infection. Conclusions By age 12, evidence of CMV infection was common. Multiple factors regarding race and personal behaviors likely contribute to seroconversion earlier in life. PMID:23687583
Distéfano, Angélica L; González, Cecilia A; Pardón, Fabián; Sarubi, María A; Canero Velazco, Cristina
Laboratories play a crucial role in the diagnosis of congenital and perinatal cytomegalovirus infection, considering that other viral infections in newborn infants have similar clinical characteristics. The objectives of this work are to compare the results of the polymerase reaction in blood spots and urine as well as point out the relevance of the result in the Guthrie cards to differentiate congenital from perinatal infection. A total of 148 patients suspicious of CMVH infections were studied in the Congenital Perinatal Infections and Sexual Transmission Laboratory, at the National Institute "Carlos G. Malbrán". The dry blood samples (Guthrie cards) and urine of all patients were studied through the polymerase chain reaction. From the 148 patients, 3 presented other infections, 95 tested negative and 50 positive for cytomegalovirus: 35 had congenital infection and 15 perinatal. In the congenital cases, the polymerase reaction in dry blood was positive (sensitivity 100%, specificity 98.9%, VPP 98% and VPN 100%). Four of them with tardive symptoms were studied retrospectively. The urine specimens from the remaining 15 patients that were taken 15 days after birth were analyzed through the same methods, showing a sensitivity of 100%, the retrospective analysis of this dry blood group yielded negative results, so the infection was considered perinatal. Thus, the dry blood polymerase reaction of the newborn infants makes it a reliable assay for diagnosing congenital cytomegalovirus infection and could be used as an alternative method to urine polymerase reaction. In addition, this test is able to reveal whether the infection is congenital or perinatal in those cases of late symptom or other cases of controversial origin.
Couvreur, J; Desmonts, G; Thulliez, P
The results of parasitological investigation of the placenta for toxoplasma in 223 cases with documented congenital toxoplasmosis were analysed according to whether the mother had been treated, or not, with spiramycin during pregnancy. The investigation was negative in 10-11% of the cases when the mother had not been treated or had been inadequately treated; in 25% of the cases with a treatment of 3 g spiramycin day; and in 50% with spiramycin plus the combination of pyrimethamine with sulphonamide. This series is compared with a previous group of 321 women whose placental investigation was negative in 50% of untreated cases and 81% of treated women. The treatment categories are not directly comparable, because it is not possible to have a randomly assigned 'no treatment' group, for ethical reasons. Correlation between spiramycin treatment and negative results of mouse inoculation of placental material suggests that spiramycin might decrease the risk of materno-fetal transmission of toxoplasma by reducing the severity and duration of toxoplasmic placentitis. Current use of spiramycin in infected pregnant women is recommended because of its activity and lack of side effects. The dosage must not be lower than 3 g/day. Additional pyrimethamine plus sulphonamide should be restricted to selected cases with fetal abnormality diagnosed during pregnancy. Some data on pharmacology of spiramycin in mothers, placentas and fetuses are reviewed. They suggest that monitoring of maternal serum antibody titres for a dosage more adapted to individual cases may be desirable.
Kim, J M; Kim, S J; Joh, J-W; Shin, M; Kim, E Y; Moon, J I; Jung, G O; Choi, G-S; Kwon, C H D; Lee, S-K
Cytomegalovirus (CMV) infection is not only a common complication after liver transplantation but also a significant contributing factor to morbidity and mortality. We investigated whether preemptive therapy can prevent CMV syndrome or tissue-invasive CMV disease in an endemic area. Preemptive therapy was initiated when more than 10 positive CMV pp65 antigen-positive cells per 400,000 white blood cells were detected, regardless of clinical manifestations. Intravenous ganciclovir as preemptive therapy was administered daily for 10 to 14 days until negative results were achieved. The incidence of initial CMV antigenemia and CMV syndrome during the posttransplantation period was 49.7% (353/710) and 5.2% (37/710), respectively. One hundred eight-two patients (51.6%) received ganciclovir as preemptive therapy. Patients with CMV antigenemia who received preemptive therapy had high Model for End-Stage Liver Disease score, repeat operation, renal dysfunction, infection, low hemoglobin concentration, low platelet count, low albumin concentration, high international normalized ratio, high total bilirubin value, high aspartate transaminase concentration, and high CMV peak titer. Cytomegalovirus syndrome and tissue-invasive CMV disease were more common in these patients. The survival curve in patients without CMV syndrome was better than that in those with CMV syndrome (P=.000). Patients with more than 10 pp65 antigen-positive cells per 400,000 white blood cells should be treated aggressively with an antiviral agent as preemptive therapy because CMV infection is common in CMV-endemic areas and patients with CMV syndrome demonstrate poor survival rates. Copyright (c) 2010 Elsevier Inc. All rights reserved.
Revello, Maria Grazia; Tibaldi, Cecilia; Masuelli, Giulia; Frisina, Valentina; Sacchi, Alessandra; Furione, Milena; Arossa, Alessia; Spinillo, Arsenio; Klersy, Catherine; Ceccarelli, Manuela; Gerna, Giuseppe; Todros, Tullia
Background Cytomegalovirus (CMV) is the leading infectious agent causing congenital sensorineural hearing loss and psychomotor retardation. CMV vaccine is currently unavailable and treatment options in pregnancy are limited. Susceptible pregnant women caring for children are at high risk for primary infection. CMV educational and hygienic measures have the potential to prevent primary maternal infection. Methods A mixed interventional and observational controlled study was conducted to investigate the effectiveness of hygiene information among pregnant women at risk for primary CMV infection for personal/occupational reasons. In the intervention arm, CMV-seronegative women, identified at the time of maternal serum screening for fetal aneuploidy at 11–12 weeks of gestation, were given hygiene information and prospectively tested for CMV until delivery. The comparison arm consisted of women enrolled at delivery who were neither tested for nor informed about CMV during pregnancy, and who had a serum sample stored at the screening for fetal aneuploidy. By design, groups were homogeneous for age, parity, education, and exposure to at least one risk factor. The primary outcome was CMV seroconversion. Acceptance of hygiene recommendations was a secondary objective and was measured by a self-report. Findings Four out of 331 (1.2%) women seroconverted in the intervention group compared to 24/315 (7.6%) in the comparison group (delta = 6.4%; 95% CI 3.2–9.6; P < 0.001). There were 3 newborns with congenital infection in the intervention group and 8 in the comparison group (1 with cerebral ultrasound abnormalities at birth). Ninety-three percent of women felt hygiene recommendations were worth suggesting to all pregnant women at risk for infection. Interpretation This controlled study provides evidence that an intervention based on the identification and hygiene counseling of CMV-seronegative pregnant women significantly prevents maternal infection. While waiting for
Mallimaci, María Cristina; Sosa-Estani, Sergio; Russomando, Graciela; Sanchez, Zunilda; Sijvarger, Carina; Alvarez, Isabel Marcela; Barrionuevo, Lola; Lopez, Carlos; Segura, Elsa Leonor
Chagas' disease, or American trypanosomiasis, is caused by the protozoan parasite Trypanasoma cruzi. It is estimated that 15,000 new cases of congenital T. cruzi transmission occur in the Americas each year. The aim of this study was to estimate the rate of congenital T. cruzi infection in infants born to infected women living in Ushuaia, Argentina, as well to assess a serologic test using Shed Acute Phase Antigen (SAPA) for a timely diagnosis of congenital infection. The rate of congenital infection among children in the study was 4.4% (3/68). Our results show that for infants younger than 30 days of age, matched blood samples from mother and infant were capable of identifying congenital transmission of infection using an enzyme-linked immunosorbent assay with SAPA. For infants older than 3 months, congenital infection could be ruled out using the same procedure.
Mallimaci, María Cristina; Sosa-Estani, Sergio; Russomando, Graciela; Sanchez, Zunilda; Sijvarger, Carina; Alvarez, Isabel Marcela; Barrionuevo, Lola; Lopez, Carlos; Segura, Elsa Leonor
Chagas' disease, or American trypanosomiasis, is caused by the protozoan parasite Trypanasoma cruzi. It is estimated that 15,000 new cases of congenital T. cruzi transmission occur in the Americas each year. The aim of this study was to estimate the rate of congenital T. cruzi infection in infants born to infected women living in Ushuaia, Argentina, as well to assess a serologic test using Shed Acute Phase Antigen (SAPA) for a timely diagnosis of congenital infection. The rate of congenital infection among children in the study was 4.4% (3/68). Our results show that for infants younger than 30 days of age, matched blood samples from mother and infant were capable of identifying congenital transmission of infection using an enzyme-linked immunosorbent assay with SAPA. For infants older than 3 months, congenital infection could be ruled out using the same procedure. PMID:20064996
Lipka, Bozena; Milewska-Bobula, Bogumiła; Idzik, Mirosława; Marciński, Paweł; Dunin-Wasowicz, Dorota; Kassur-Siemieńska, Barbara; Bauer, Anna; Sebiguli Marishekome, Augustin; Hautz, Wojciech; Radziszewska, Marzanna
Intrauterine infections are an important cause of hearing and visual impairment in children. The aim of this paper was to evaluate the character and frequency of hearing and visual disturbances in children with congenital toxoplasmosis and cytomegalovirus infection. 38 out of 54 children with congenital toxoplasmosis as well as 34 out of 403 children with congenital human cytomegalovirus disease, with visual/auditory impairment, hospitalized in Infant Department in Children's Memorial Health Institute between 1995-2001 were enrolled in this study. Visual impairment was observed in all children with toxoplasmosis (with visual dysfunction rate of 74%), but there was no deafness found. Vision impairment had been observed in 18% of children with congenital cytomegalovirus infection compared to 35% of children with auditory impairment (bilateral deafness had been found in half of them). Neurological deficits' rate was much higher in children with toxoplasmosis (52% vs. 4%). Because of common hearing impairment in children with congenital cytomegalovirus infection and vision impairment in children with congenital toxoplasmosis, it is essential to start the prophylaxis to decrease the percentage of handicapped children.
Blázquez-Gamero, Daniel; Galindo Izquierdo, A; Del Rosal, T; Baquero-Artigao, F; Izquierdo Méndez, N; Soriano-Ramos, M; Rojo Conejo, P; González-Tomé, M I; García-Burguillo, A; Pérez Pérez, N; Sánchez, V; Ramos-Amador, J T; De la Calle, M
Cytomegalovirus (CMV) is the leading cause of congenital infection worldwide. Data about the management of CMV infection in pregnant women are scarce, and treatment options are very limited. The aim of the study is to investigate the effectiveness of cytomegalovirus hyperimmune globulin (CMV-HIG) for the prevention and treatment of congenital CMV (cCMV) infection. A retrospective observational study was conducted in three tertiary hospitals in Madrid. In the period 2009-2015, CMV-HIG (Cytotect® CP Biotest, Biotest) treatment was offered to all pregnant women with primary CMV infection and/or detection of CMV-DNA in amniotic fluid in participating centers. Women were divided into prevention and treatment groups (PG and TG, respectively). Those with primary CMV infection who had not undergone amniocentesis comprised the PG and received monthly CMV-HIG (100 UI/kg). If CMV-DNA was subsequently detected in amniotic fluid, one extra dose of CMV-HIG (200 UI/kg) was given 4 weeks after the last dose. Those women were considered to be part of the PG group despite detection of CMV-DNA in amniotic fluid. In the case of a negative result in CMV-DNA detection in amniotic fluid or if amniocentesis was not performed, monthly HIG was given up to the end of the pregnancy. Thirty-six pregnant women were included. Median gestational age at birth was 39 weeks [interquartile range (IQR): 38-40] and 2 children (5.5%) were premature (born at 28 and 34 weeks' gestation). Amniocentesis was performed in 30/36 (83.4%) pregnancies and CMV PCR was positive in 21 of them (70%). One fetus with a positive PCR in amniotic fluid that received one dose of HIG after amniocentesis presented a negative CMV-PCR in urine at birth, and was asymptomatic at 12 months of age. Twenty-four children were infected at birth, and 16/21 (76.2%) presented no sequelae at 12 months, while 2 (9.5%) had mild unilateral hearing loss and three (14.3%) severe hearing loss or neurological sequelae. Seventeen women
Rea, Federico; Potena, Luciano; Yonan, Nizar; Wagner, Florian; Calabrese, Fiorella
Cytomegalovirus (CMV) infection negatively influences both short- and long-term outcomes after cardiothoracic transplantation. In heart transplantation, registry analyses have shown that CMV immunoglobulin (CMVIG) with or without virostatic prophylaxis is associated with a significant reduction in mortality and graft loss versus no prophylaxis, particularly in high-risk donor (D)+/recipient (R)- transplants. Randomized comparative trials are lacking but retrospective data suggest that addition of CMVIG to antiviral prophylaxis may reduce rates of CMV-related events after heart transplantation, including the incidence of acute rejection or chronic allograft vasculopathy. However, available data consistently indicate that when CMVIG is used, it should be administered with concomitant antiviral therapy, and that evidence concerning preemptive management with CMVIG is limited, but promising. In lung transplantation, CMVIG should again only be used with concomitant antiviral therapy. Retrospective studies have shown convincing evidence that addition of CMVIG to antiviral prophylaxis lowers CMV endpoints and mortality. The current balance of evidence suggests that CMVIG prophylaxis reduces the risk of bronchiolitis obliterans syndrome, but a controlled trial is awaited. Overall, the relatively limited current data set suggests that prophylaxis with CMVIG in combination with antiviral therapy appears effective in D+/R- heart transplant patients, whereas in lung transplantation, addition of CMVIG in recipients of a CMV-positive graft may offer an advantage in terms of CMV infection and disease.
Rittà, Massimo; Costa, Cristina; Sidoti, Francesca; Ballocco, Cinzia; Ranghino, Andrea; Messina, Maria; Biancone, Luigi; Cavallo, Rossana
Cytomegalovirus (CMV) primary infection or re-activation in solid organ transplant (SOT) recipients is associated with increased morbidity and mortality, with patients with IgG-CMV D+/R- sero-matching at greater risk. The impact of pre-transplant CMV-specific host cellular immunity on the long-term risk of CMV replication in kidney transplants (KT) was prospectively evaluated in eighty patients by CMV-EliSpot assay. The study population included 54 male and 26 female recipients, with CMV-IgG distribution: 60 D+/R+, 11 D-/R+, 7 D+/R-, 2 D-/R-. At pre-transplantation, 49 KT (61.3%) were CMV-responders by EliSpot. At 3-month follow up, 16 (32.7%) out of 49 CMV-responders showed CMV blood infection, compared to 8 (25.8%) out of 31 non-responders. No further episode of CMV viraemia was reported in the responder group, in comparison to 15 out 31 non-responders (48.4%) showing at least one episode of CMV-DNAemia at 12-month follow-up. Baseline CMV-IgG serology showed a strong correlation with EliSpot determinations; KT recipients exhibiting at least one episode of CMV viraemia at 12-month follow-up showed lower baseline CMV-EliSpot values than those without signs of CMV replication. The study suggests that monitoring CMV-specific T-cell responses at pre-transplantation by EliSpot assay may be useful for predicting the post-transplantation risk of CMV infection and reactivation.
Di Nardo, Walter; Cattani, Paola; Scorpecci, Alessandro; Giannantonio, Sara; D'Onghia, Sara; Fadda, Giovanni; Paludetti, Gaetano
In the present article we report cytomegalovirus (CMV) DNA localization in the inner ear of a 15-month-old deaf boy 1 month after a virologically documented primary infection. CMV DNA retrieval was possible thanks to polymerase chain reaction analysis of the perilymph collected at cochlear implant surgery. To the authors' knowledge this is the first demonstration of CMV persistence in the cochlea of an immunocompetent subject after an acquired infection. Copyright © 2011 The American Laryngological, Rhinological, and Otological Society, Inc., Rhinological, and Otological Society, Inc.
Al Jabbari, Odeaa; Abu Saleh, Walid K.; Ramchandani, Mahesh; Scheinin, Scott
Unilateral agenesis of the pulmonary artery (UAPA) is a rare congenital anomaly. This report describes a 52-year-old female who gave a long history of chronic, recurrent, left-sided pulmonary infections related to UAPA. For many years, she was managed medically but the infection continued to recur. She eventually underwent left pneumonectomy and made a good recovery. PMID:27127564
Al Jabbari, Odeaa; Abu Saleh, Walid K; Ramchandani, Mahesh; Scheinin, Scott
Unilateral agenesis of the pulmonary artery (UAPA) is a rare congenital anomaly. This report describes a 52-year-old female who gave a long history of chronic, recurrent, left-sided pulmonary infections related to UAPA. For many years, she was managed medically but the infection continued to recur. She eventually underwent left pneumonectomy and made a good recovery.
Özkarata, Emre; Özkarataş, Emre; Özbek, Ö Alpay; Avkan Oğuz, Vildan; Sayıner, A Arzu
Cytomegalovirus (CMV) infection is among the most common important viral infections in solid organ transplant (SOT) recipients. Diagnostic tests for detecting CMV replication are widely used for this group of patients, however there is no clear agreement on the cut-off levels for interpretation of clinical decisions especially when the low level of viral load is detected. In this study, CMV pp65 antigenemia test results were compared with plasma CMV-DNA levels detected by quantitative real-time polymerase chain reaction (qPCR) in samples of kidney and liver transplant recipients in the Central Laboratory of Dokuz Eylul University Hospital between 2011 and 2013, and the correlation between these two tests and viral load equivalent to antigenemia positivity were determined. In the study, pp65 antigenemia and CMV-DNA qPCR results were evaluated retrospectively. The samples from the same patients were included if the time between antigenemia and CMV-DNA qPCR tests were less than 48 hours. SPSS v15.0 was used for correlation, regression and ROC curve analysis. The results of the 217 samples collected from 100 patients (59 male, 41 female; age range: 16-71, mean age: 46 ± 13 years), 36 liver and 64 kidney recipients were evaluated in the study. Of the patients 80% were CMV IgM negative, IgG positive; 1% was CMV IgG and IgM positive; 2% were CMV IgM and IgG negative, while for 17 patients serological results could not be reached. CMV pp65 antigenemia and CMV-DNA were both negative in 102 (47%) samples, while both were positive in 37 (17%) samples. The single sample from a case with CMV IgM and IgG positivity yielded negative results for both antigenemia and CMV-DNA tests. In 78 samples antigenemia were negative and CMV-DNA qPCR were positive, while there were no samples with antigenemia positive and qPCR negative. Mean values of antigenemia and qPCR tests were 23 positive cells/200.000 leukocytes (range: 1 to 230 positive cells) and 12.595 copies/ml (range: 180 to 106
García-Bermejo, Isabel; de Ory-Manchón, Fernando
Congenital infection is those transmitted by the mother to the fetus before delivery. It can occur transplacentally or by direct contact with the pathogen during birth or in the immediate postnatal period. Congenital infection can be due to viruses (rubella, cytomegalovirus, herpes simplex, varicella-zoster, hepatitis B and C virus, human inunodeficiencia, erythrovirus B19) as bacteria (Treponema pallidum) and parasites (Toxoplasma gondii and Trypanosoma cruzi). Serological diagnosis of congenital infection is based on both the knowledge of infectious serology in the mother, including the systematic serological screening and diagnostic aspects of the determination of IgM and confirmatory methods, IgG avidity tests, establishment of antibody profiles, and in the diagnosis the neonate. Serological diagnosis of congenital infection in the newborn is mainly based on the detection of specific IgM usually by immunoenzymatic assays or immunochemiluminescence techniques. In some instances it is important to perform the serological follow up of the newborn to confirm the congenital infection. Copyright © 2015 Elsevier España, S.L.U. All rights reserved.
Frenkel, L D; Gomez, F; Sabahi, F
The emergence of Zika-virus-associated congenital microcephaly has engendered renewed interest in the pathogenesis of microcephaly induced by infectious agents. Three of the original "TORCH" agents are associated with an appreciable incidence of congenital microcephaly: cytomegalovirus, rubella virus, and Toxoplasma gondii. The pathology of congenital microcephaly is characterized by neurotropic infectious agents that involve the fetal nervous system, leading to brain destruction with calcifications, microcephaly, sensorineural hearing loss, and ophthalmologic abnormalities. The inflammatory reaction induced by these four agents has an important role in pathogenesis. The potential role of "strain differences" in pathogenesis of microcephaly by these four pathogens is examined. Specific epidemiologic factors, such as first and early second trimester maternal infection, and the manifestations of congenital infection in the infant, shed some light on the pathogenesis. Immune aspects of normal pregnancy and their role in congenital infections is examined. In this review, we integrate all these findings to create a unified hypothesis of the pathogenesis of congenital microcephaly induced by these infectious agents.
Li, Huifen; Mao, Genxiang; Carlson, Joshua; Leng, Sean X
Human cytomegalovirus (hCMV) is a ubiquitous pathogen that causes congenital infection and severe infections in immunocompromised patients. Chronic hCMV infection may also play an important role in immunosenescence and adverse health outcomes in older adults. THP-1, a human monocytic cell line and its derived macrophages serve as a useful cell culture model for mechanistic studies of hCMV infection and its underlying biology. A major methodological challenge is the lack of a quick and reliable tool to accurately determine the efficiency of hCMV infection in THP-1 derived macrophages. In this study, we developed a flow cytometry based method using commercially available monoclonal antibody (MAb) against hCMV immediate early (IE) antigen that can accurately determine infection efficiency. We used 0.5% formaldehyde for fixation, 90% methanol for permeabilization, and incubation with FITC conjugated MAb at 37°C. The method was tested by hCMV infection with laboratory Towne strain in the presence or absence of hydrocortisone. It was also compared with the routine flow cytometry protocol using Cytofix/Cytoperm solution and with immunofluorescence. The results indicate that this new method is reliable and time saving for accurate determination of infection efficiency. It may facilitate further investigations into the underlying biological mechanisms of hCMV infection.
Kanik-Yuksek, Saliha; Gülhan, Belgin; Tezer, Hasan; Ozkaya-Parlakay, Aslinur
Cytomegalovirus (CMV) infection is the most common viral infection of newborns in all periods worldwide. Perinatal form of infection is usually less severe than the congenital form because of having a lower rate for serious organ involvement like central nervous system. In this article, we report a 3-month-old immunocompetent patient who was diagnosed as having perinatal CMV infection with a scar of chorioretinitis after presenting with gastroenteritis and hepatitis. © The Author . Published by Oxford University Press. All rights reserved. For Permissions, please email: email@example.com.
Prevention of CMV disease in pediatric kidney transplant recipients: evaluation of pp67 NASBA-based pre-emptive ganciclovir therapy combined with CMV hyperimmune globulin prophylaxis in high-risk patients.
Renoult, Edith; Clermont, Marie-José; Phan, Véronique; Buteau, Chantal; Alfieri, Carolina; Tapiero, Bruce
A new prevention strategy for CMV infection was evaluated in our pediatric kidney transplant unit. This approach comprises a pre-emptive therapy, based upon the monitoring of CMV pp67 mRNA in whole blood by the qualitative NASBA, combined with prophylactic CMV-IG in high risk (R-/D+) children. Thirty-one kidney transplant children were followed for six months with serial measurements of CMV pp67 mRNA in the blood. The R-/D+ patients were given prophylactic CMV-IG for the first 16 wk after transplantation. I.v. ganciclovir was administered upon CMV detection by NASBA and was discontinued after two consecutive negative results. CMV infection, detected by NASBA, developed in 11 (35%) recipients: one (33%) of the R+/D- patients and 10 (72%) of the R-/D+ patients. CMV disease developed in 9.6% of the patients (3/31), exclusively in the R-/D+ group. These three patients presented concurrently with CMV viremia and disease. It is noteworthy that two of the three patients could not receive a complete course of CMV-IG, and one of the latter two subjects had been treated for acute rejection 15 days before CMV infection. Ganciclovir was given for the 11 cases of primary infection, and for three cases of relapsed CMV infection. pp67 NASBA-based pre-emptive ganciclovir therapy, combined with prophylactic CMV-IG in high-risk patients leads to a lower rate of CMV disease, as long as a complete course of CMV-IG has been administered and ganciclovir is given during the period of treatment for acute rejection in high-risk populations.
Alvarado-Esquivel, Cosme; Hernández-Tinoco, Jesús; Sánchez-Anguiano, Luis Francisco; Ramos-Nevárez, Agar; Cerrillo-Soto, Sandra Margarita; Estrada-Martínez, Sergio; Martínez-Ramírez, Lucio; Pérez-Álamos, Alma Rosa; Guido-Arreola, Carlos Alberto
Cytomegalovirus causes congenital infections all around the world. The seroepidemiology of cytomegalovirus infection in pregnant women in Mexico is largely unknown. We sought to determine the seroprevalence of cytomegalovirus infection in pregnant women in Durango City, Mexico; and to determine seroprevalence association with socio-demographic, clinical and behavioral characteristics of pregnant women. Through a cross-sectional study design, 343 pregnant women were examined for anti-cytomegalovirus IgG and IgM antibodies in Durango City, Mexico. We used a standardized questionnaire to obtain the general characteristics of the pregnant women. Multivariate analysis was performed to determine the association of cytomegalovirus infection with the characteristics of the pregnant women. Anti-CMV IgG and IgM antibodies were detected in 225 (65.6%) and in none of the 343 pregnant women studied, respectively. Multivariate analysis showed that CMV exposure was associated with increasing age (OR = 1.67; 95% CI: 1.01-2.76; P = 0.04). Other women characteristics including socioeconomic status, education, blood transfusion, transplantation, sexual promiscuity and number of previous pregnancies or deliveries did not show an association with CMV exposure. This is the first seroepidemiology study of CMV infection in pregnant women in Mexico. A number of known factors associated with CMV infection were not associated with CMV exposure in the women studied. Further studies to determine routes of CMV infection in pregnant women in Mexico are needed.
Ornaghi, Sara; Davis, John N; Gorres, Kelly L; Miller, George; Paidas, Michael J; van den Pol, Anthony N
Cytomegalovirus (CMV) infection can generate debilitating disease in immunocompromised individuals and neonates. It is also the most common infectious cause of congenital birth defects in infected fetuses. Available anti-CMV drugs are partially effective but are limited by some toxicity, potential viral resistance, and are not recommended for fetal exposure. Valproate, valpromide, and valnoctamide have been used for many years to treat epilepsy and mood disorders. We report for the first time that, in contrast to the virus-enhancing actions of valproate, structurally related valpromide and valnoctamide evoke a substantial and specific inhibition of mouse and human CMV in vitro. In vivo, both drugs safely attenuate mouse CMV, improving survival, body weight, and developmental maturation of infected newborns. The compounds appear to act by a novel mechanism that interferes with CMV attachment to the cell. Our work provides a novel potential direction for CMV therapeutics through repositioning of agents already approved for use in psychiatric disorders. Copyright © 2016 Elsevier Inc. All rights reserved.
Knight, Andrea; Arnouk, Hilal; Britt, William; Gillespie, G. Yancey; Cloud, Gretchen A.; Harkins, Lualhati; Su, Yun
Vδ2neg γδ T cells, of which Vδ1+ γδ T cells are by far the largest subset, are important effectors against CMV infection. Malignant gliomas often contain CMV genetic material and proteins, and evidence exists that CMV infection may be associated with initiation and/or progression of glioblastoma multiforme (GBM). We sought to determine if Vδ1+ γδ T cells were cytotoxic to GBM and the extent to which their cytotoxicity was CMV dependent. We examined the cytotoxic effect of ex vivo expanded/activated Vδ1+ γδ T cells from healthy CMV seropositive and CMV seronegative donors on unmanipulated and CMV-infected established GBM cell lines and cell lines developed from short- term culture of primary tumors. Expanded/activated Vδ1+ T cells killed CMV-negative U251, U87, and U373 GBM cell lines and two primary tumor explants regardless of the serologic status of the donor. Experimental CMV infection did not increase Vδ1+ T cell - mediated cytotoxicity and in some cases the cell lines were more resistant to lysis when infected with CMV. Flow cytometry analysis of CMV-infected cell lines revealed down-regulation of the NKG2D ligands ULBP-2, and ULBP-3 as well as MICA/B in CMV-infected cells. These studies show that ex vivo expanded/activated Vδ1+ γδ T cells readily recognize and kill established GBM cell lines and primary tumor-derived GBM cells regardless of whether CMV infection is present, however, CMV may enhance the resistance GBM cell lines to innate recognition possibly contributing to the poor immunogenicity of GBM. PMID:23950874
Lyra, Priscila Pinheiro Ribeiro; Campos, Gúbio Soares; Bandeira, Igor Dórea; Sardi, Silvia Ines; Costa, Lilian Ferreira de Moura; Santos, Flávia Rocha; Ribeiro, Carlos Alexandre Santos; Jardim, Alena Maria Barreto; Santiago, Ana Cecília Travassos; de Oliveira, Patrícia Maria Ribeiro; Moreira, Lícia Maria Oliveira
There is little information about the congenital chikungunya virus (CHIKV) transmission. We describe two cases of well-documented congenital CHIKV infection in Salvador-Brazil, where CHIKV has been identified since 2014. The outbreak in the city led to the clinical CHIKV diagnoses of both pregnant women 2 days before delivery. Urine and blood samples from the mothers and newborns were collected and tested for reverse transcription-polymerase chain reaction (PCR) analysis for Zika, dengue, and CHIKV. Both neonates and mothers had positive urine and serum PCR results for CHIKV. The newborns had significant perinatal complications and were admitted to the neonatal intensive care unit. The purpose of our case report is to show how severe congenital CHIKV infection can be and the importance to include CHIKV infection in the differential diagnosis of neonatal sepsis when mothers have clinical signs of the disease and live in an affected area. PMID:27555980
Murcia, Laura; Simón, Marina; Carrilero, Bartolomé; Roig, Mercedes; Segovia, Manuel
We evaluated the effectiveness of treating women of childbearing age with benznidazole to prevent congenital Chagas disease (CCD), as well as the usefulness of polymerase chain reaction (PCR) as a tool to predict the risk of transmission. Prospective study involving 144 T. cruzi seropositive pregnant women. The parasitological status was studied by PCR in 159 pregnancies, 38 of which involved a cohort of previously treated mothers. One hundred sixty children were examined by PCR and serologically studied at 0-6, 9 and 12 months and annually after treatment. PCR was seen to be useful for predicting the risk of congenital transmission: 18.8% of mothers with a positive PCR result transmitted the infection (16 infected children out of 85 pregnancies). No infected infants were detected among 74 pregnancies when PCR was negative. Of the treated mothers, 92.1% had negative PCR results, compared with 32.2% of untreated mothers. No infected infants were detected from previously treated mothers, compared with 13.2% among untreated mothers (P = .019; χ2). All infants treated before the first year of life were cured. Treating infected women of childbearing age prevents congenital Chagas disease. Polymerase chain reaction screening of T. cruzi-infected pregnant women is a useful tool for predicting the risk of congenital transmission.
Hematopoietic/Lymphoid Cancer; Accelerated Phase Chronic Myelogenous Leukemia; Acute Undifferentiated Leukemia; Adult Acute Lymphoblastic Leukemia in Remission; Adult Acute Myeloid Leukemia in Remission; Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities; Adult Acute Myeloid Leukemia With Del(5q); Adult Acute Myeloid Leukemia With Inv(16)(p13;q22); Adult Acute Myeloid Leukemia With t(15;17)(q22;q12); Adult Acute Myeloid Leukemia With t(16;16)(p13;q22); Adult Acute Myeloid Leukemia With t(8;21)(q22;q22); Adult Grade III Lymphomatoid Granulomatosis; Adult Nasal Type Extranodal NK/T-cell Lymphoma; Anaplastic Large Cell Lymphoma; Angioimmunoblastic T-cell Lymphoma; Aplastic Anemia; Atypical Chronic Myeloid Leukemia, BCR-ABL Negative; Blastic Phase Chronic Myelogenous Leukemia; Chronic Eosinophilic Leukemia; Chronic Myelomonocytic Leukemia; Chronic Neutrophilic Leukemia; Chronic Phase Chronic Myelogenous Leukemia; Contiguous Stage II Adult Burkitt Lymphoma; Contiguous Stage II Adult Diffuse Large Cell Lymphoma; Contiguous Stage II Adult Diffuse Mixed Cell Lymphoma; Contiguous Stage II Adult Diffuse Small Cleaved Cell Lymphoma; Contiguous Stage II Adult Immunoblastic Large Cell Lymphoma; Contiguous Stage II Adult Lymphoblastic Lymphoma; Contiguous Stage II Grade 1 Follicular Lymphoma; Contiguous Stage II Grade 2 Follicular Lymphoma; Contiguous Stage II Grade 3 Follicular Lymphoma; Contiguous Stage II Mantle Cell Lymphoma; Contiguous Stage II Marginal Zone Lymphoma; Contiguous Stage II Small Lymphocytic Lymphoma; Cutaneous B-cell Non-Hodgkin Lymphoma; Cytomegalovirus Infection; de Novo Myelodysplastic Syndromes; Essential Thrombocythemia; Extramedullary Plasmacytoma; Extranodal Marginal Zone B-cell Lymphoma of Mucosa-associated Lymphoid Tissue; Intraocular Lymphoma; Isolated Plasmacytoma of Bone; Mast Cell Leukemia; Meningeal Chronic Myelogenous Leukemia; Myelodysplastic/Myeloproliferative Neoplasm, Unclassifiable; Nodal Marginal Zone B-cell Lymphoma
Sen, Amitabh Chanchal; Morrow, Debra Forbes; Balachandran, Rakhi; Du, Xinwei; Gauvreau, Kimberlee; Jagannath, Byalal R; Kumar, Raman Krishna; Kupiec, Jennifer Koch; Melgar, Monica L; Chau, Nguyen Tran; Potter-Bynoe, Gail; Tamariz-Cruz, Orlando; Jenkins, Kathy J
Postoperative infections contribute substantially to morbidity and mortality after congenital heart disease surgery and are often preventable. We sought to identify risk factors for postoperative infection and the impact on outcomes after congenital heart surgery, using data from the International Quality Improvement Collaborative for Congenital Heart Surgery in Developing World Countries. Pediatric cardiac surgical cases performed between 2010 and 2012 at 27 participating sites in 16 developing countries were included. Key variables were audited during site visits. Demographics, preoperative, procedural, surgical complexity, and outcome data were analyzed. Univariate and multivariable logistic regression were used to identify risk factors for infection, including bacterial sepsis and surgical site infection, and other clinical outcomes. Standardized infection ratios were computed to track progress over time. Of 14 545 cases, 793 (5.5%) had bacterial sepsis and 306 (2.1%) had surgical site infection. In-hospital mortality was significantly higher among cases with infection than among those without infection (16.7% versus 5.3%; P<0.001), as were postoperative ventilation duration (80 versus 14 hours; P<0.001) and intensive care unit stay (216 versus 68 hours; P<0.001). Younger age at surgery, higher surgical complexity, lower oxygen saturation, and major medical illness were independent risk factors for infection. The overall standardized infection ratio was 0.65 (95% confidence interval, 0.58-0.73) in 2011 and 0.59 (95% confidence interval, 0.54-0.64) in 2012, compared with that in 2010. Postoperative infections contribute to mortality and morbidity after congenital heart surgery. Younger, more complex patients are at particular risk. Quality improvement targeted at infection risk may reduce morbidity and mortality in the developing world. © 2017 American Heart Association, Inc.
Pass, Robert F.
A vaccine comprised of recombinant cytomegalovirus (CMV) envelope glycoprotein B (gB) with MF59 adjuvant developed in the 1990s recently was recently found to have efficacy for prevention of CMV infection in a phase 2 clinical trial in young mothers. This review briefly considers the rationale for gB as a vaccine antigen, the history of this CMV gB vaccine and the data supporting vaccine efficacy. PMID:19647480
Botet, F; Figueras Aloy, J; Álvarez, E; de Alba, C; Dorronsolo, I; Echaniz Urcelay, I; Rite, S; Moreno, J; Fernández Lorenzo, J R; Herranz Carrillo, G; Salguero, E; Sánchez Luna, M
Cytomegalovirus (CMV) infection is endemic, and children who attend day care are the most important source of infection. To establish recommendations based on the medical evidence on the vertical transmission of cytomegalovirus in preterm infants weighing less than 1500g at birth. Infection in pregnant women may be primary or secondary. Although there is fetal infection, 85% of newborn infants are asymptomatic. Symptoms of infection include low birth weight, hepatosplenomegaly, thrombocytopenia, microcephaly and neurological disorders. The prognosis of symptomatic children is very poor, with high mortality and neurological disorders. The virus can be reactivated during breast feeding, and early infection is possible through breast milk, probably with little impact in term infants, although the long-term neurological outcome worsens in preterm infants. The diagnostic method of choice is the identification of CMV in urine; the determination in the first two weeks of life suggests congenital infection; later it can be acquired at birth or through breast milk or contaminated blood transfusion. Determine viral DNA at 4-6 weeks of life by protease chain reaction. If it is positive, monitoring of samples from the first days of life and breast milk are mandatory. This should allow the newborn to be classified into three states: "Without CMV infection", "Congenital CMV infection", "Acquired CMV infection". Copyright © 2014 Asociación Española de Pediatría. Published by Elsevier Espana. All rights reserved.
Slavuljica, Irena; Kveštak, Daria; Huszthy, Peter Csaba; Kosmac, Kate; Britt, William J; Jonjić, Stipan
Congenital human cytomegalovirus infection is a leading infectious cause of long-term neurodevelopmental sequelae, including mental retardation and hearing defects. Strict species specificity of cytomegaloviruses has restricted the scope of studies of cytomegalovirus infection in animal models. To investigate the pathogenesis of congenital human cytomegalovirus infection, we developed a mouse cytomegalovirus model that recapitulates the major characteristics of central nervous system infection in human infants, including the route of neuroinvasion and neuropathological findings. Following intraperitoneal inoculation of newborn animals with mouse cytomegalovirus, the virus disseminates to the central nervous system during high-level viremia and replicates in the brain parenchyma, resulting in a focal but widespread, non-necrotizing encephalitis. Central nervous system infection is coupled with the recruitment of resident and peripheral immune cells as well as the expression of a large number of pro-inflammatory cytokines. Although infiltration of cellular constituents of the innate immune response characterizes the early immune response in the central nervous system, resolution of productive infection requires virus-specific CD8(+) T cells. Perinatal mouse cytomegalovirus infection results in profoundly altered postnatal development of the mouse central nervous system and long-term motor and sensory disabilities. Based on an enhanced understanding of the pathogenesis of this infection, prospects for novel intervention strategies aimed to improve the outcome of congenital human cytomegalovirus infection are proposed.
La Rosa, Corinna; Longmate, Jeff; Martinez, Joy; Zhou, Qiao; Kaltcheva, Teodora I; Tsai, Weimin; Drake, Jennifer; Carroll, Mary; Wussow, Felix; Chiuppesi, Flavia; Hardwick, Nicola; Dadwal, Sanjeet; Aldoss, Ibrahim; Nakamura, Ryotaro; Zaia, John A; Diamond, Don J
Attenuated poxvirus modified vaccinia Ankara (MVA) is a useful viral-based vaccine for clinical investigation, because of its excellent safety profile and property of inducing potent immune responses against recombinant (r) antigens. We developed Triplex by constructing an rMVA encoding 3 immunodominant cytomegalovirus (CMV) antigens, which stimulates a host antiviral response: UL83 (pp65), UL123 (IE1-exon4), and UL122 (IE2-exon5). We completed the first clinical evaluation of the Triplex vaccine in 24 healthy adults, with or without immunity to CMV and vaccinia virus (previous DryVax smallpox vaccination). Three escalating dose levels (DL) were administered IM in 8 subjects/DL, with an identical booster injection 28 days later and 1-year follow-up. Vaccinations at all DL were safe with no dose-limiting toxicities. No vaccine-related serious adverse events were documented. Local and systemic reactogenicity was transient and self-limiting. Robust, functional, and durable Triplex-driven expansions of CMV-specific T cells were detected by measuring T-cell surface levels of 4-1BB (CD137), binding to CMV-specific HLA multimers, and interferon-γ production. Marked and durable CMV-specific T-cell responses were also detected in Triplex-vaccinated CMV-seronegatives, and in DryVax-vaccinated subjects. Long-lived memory effector phenotype, associated with viral control during CMV primary infection, was predominantly found on the membrane of CMV-specific and functional T cells, whereas off-target vaccine responses activating memory T cells from the related herpesvirus Epstein-Barr virus remained undetectable. Combined safety and immunogenicity results of MVA in allogeneic hematopoietic stem cell transplant (HCT) recipients and Triplex in healthy adults motivated the initiation of a placebo-controlled multicenter trial of Triplex in HCT patients. This trial was registered at www.clinicaltrials.gov as #NCT02506933. © 2017 by The American Society of Hematology.
Maingi, Zakayo; Nyamache, Anthony Kebira
The fetal consequences of CMV infection have made it one of the most serious infections contracted during pregnancy. Despite the posed teratogenic risk during pregnancy, there is no national screening test for CMV infection is available during pregnancy in Kenya. Thus little is known on its epidemiological data that is necessary for health planners and care providers. A cross sectional study was conducted at Thika district level 5 hospital, Kenya to investigate seroprevalence of CMV infections and associated possible risk factors among pregnant women. Structured questionnaires were used to gather socio-demographic data and ELISA was used to detect CMV infections using IgG and IgM. Out of 260 pregnant women, 201 (77.3%) were CMV IgG 21(8.1%) CMV IgM being on acute stage of the disease. Marital status (OR = 3.7533, 95% CI =3.0231-6.9631, P < 0.0001), parity (OR = 3.7533, 95% CI = 3.0231-6.9631, P < 0.0001), and education (OR = 3.7533, 95% CI = 3.0231-6.9631, P < 0.0001), history of blood transfusion (OR = 0.0374, 95% CI = 0.00120-0.1168, OR = 0.3804) were found to significantly influence seropostivity in univariate analysis. The 88.4% CMV prevalence rate being detected among pregnant women calls for vaccine and routine screening for CMV infections and its associated risk factors in this kind of settings.
Jenkins, Kathy J; Castañeda, Aldo R; Cherian, K M; Couser, Chris A; Dale, Emily K; Gauvreau, Kimberlee; Hickey, Patricia A; Koch Kupiec, Jennifer; Morrow, Debra Forbes; Novick, William M; Rangel, Shawn J; Zheleva, Bistra; Christenson, Jan T
There is little information about congenital heart surgery outcomes in developing countries. The International Quality Improvement Collaborative for Congenital Heart Surgery in Developing World Countries uses a registry and quality improvement strategies with nongovernmental organization reinforcement to reduce mortality. Registry data were used to evaluate impact. Twenty-eight sites in 17 developing world countries submitted congenital heart surgery data to a registry, received annual benchmarking reports, and created quality improvement teams. Webinars targeted 3 key drivers: safe perioperative practice, infection reduction, and team-based practice. Registry data were audited annually; only verified data were included in analyses. Risk-adjusted standardized mortality ratios (SMRs) and standardized infection ratios among participating sites were calculated. Twenty-seven sites had verified data in at least 1 year, and 1 site withdrew. Among 15,049 cases of pediatric congenital heart surgery, unadjusted mortality was 6.3% and any major infection was 7.0%. SMRs for the overall International Quality Improvement Collaborative for Congenital Heart Surgery in Developing World Countries were 0.71 (95% confidence interval [CI] 0.62-0.81) in 2011 and 0.76 (95% CI 0.69-0.83) in 2012, compared with 2010 baseline. SMRs among 7 sites participating in all 3 years were 0.85 (95% CI 0.71-1.00) in 2011 and 0.80 (95% CI 0.66-0.96) in 2012; among 14 sites participating in 2011 and 2012, the SMR was 0.80 (95% CI 0.70-0.91) in 2012. Standardized infection ratios were similarly reduced. Congenital heart surgery risk-adjusted mortality and infections were reduced in developing world programs participating in the collaborative quality improvement project and registry. Similar strategies might allow rapid reduction in global health care disparities. Copyright © 2014 by the American Academy of Pediatrics.
Rawlinson, William D; Boppana, Suresh B; Fowler, Karen B; Kimberlin, David W; Lazzarotto, Tiziana; Alain, Sophie; Daly, Kate; Doutré, Sara; Gibson, Laura; Giles, Michelle L; Greenlee, Janelle; Hamilton, Stuart T; Harrison, Gail J; Hui, Lisa; Jones, Cheryl A; Palasanthiran, Pamela; Schleiss, Mark R; Shand, Antonia W; van Zuylen, Wendy J
Congenital cytomegalovirus is the most frequent, yet under-recognised, infectious cause of newborn malformation in developed countries. Despite its clinical and public health importance, questions remain regarding the best diagnostic methods for identifying maternal and neonatal infection, and regarding optimal prevention and therapeutic strategies for infected mothers and neonates. The absence of guidelines impairs global efforts to decrease the effect of congenital cytomegalovirus. Data in the literature suggest that congenital cytomegalovirus infection remains a research priority, but data are yet to be translated into clinical practice. An informal International Congenital Cytomegalovirus Recommendations Group was convened in 2015 to address these questions and to provide recommendations for prevention, diagnosis, and treatment. On the basis of consensus discussions and a review of the literature, we do not support universal screening of mothers and the routine use of cytomegalovirus immunoglobulin for prophylaxis or treatment of infected mothers. However, treatment guidelines for infected neonates were recommended. Consideration must be given to universal neonatal screening for cytomegalovirus to facilitate early detection and intervention for sensorineural hearing loss and developmental delay, where appropriate. The group agreed that education and prevention strategies for mothers were beneficial, and that recommendations will need continual updating as further data become available. Copyright © 2017 Elsevier Ltd. All rights reserved.
Schleiss, Mark R.
Fetal and neonatal infections caused by human cytomegalovirus (CMV) are important causes of morbidity and occasional mortality. Development of a vaccine against congenital CMV infection is a major public health priority. Vaccine design is currently focused on strategies that aim to elicit neutralizing antibody and T-cell responses, toward the goal of preventing primary or recurrent infection in women of child-bearing age. However, there has been relatively little attention given to understanding the mechanisms of immune protection against acquisition of CMV infection in the fetus and newborn and how this information might be exploited for vaccine design. There has similarly been an insufficient study of what deficits in the immune response to CMV, both for mother and fetus, may increase susceptibility to congenital infection and disease. Protection of the fetus against vertical transmission can likely be achieved by protection of the placenta, which has its own unique immunological milieu, further complicating the analysis of the correlates of protective immunity. In this review, the current state of knowledge about immune effectors of protection against CMV in the maternal, placental, and fetal compartments is reviewed. A better understanding of immune responses that prevent and/or predispose to infection will help in the development of novel vaccine strategies. PMID:24023565
Mujtaba, Ghulam; Khurshid, Adnan; Sharif, Salmaan; Alam, Muhammad Masroor; Aamir, Uzma Bashir; Shaukat, Shahzad; Angez, Mehar; Rana, Muhammad Suleman; Umair, Massab; Shah, Aamer Ali; Zaidi, Syed Sohail Zahoor
Background Congenital cytomegalovirus (cCMV) infection contributes to considerable long-term sequelae in neonates and children all over the world. The association between viral genotypes and severity of clinical cytomegalovirus (CMV) infection is yet to be defined. The objective of this study was to find the impact of active CMV infection during pregnancy and the clinical significance of genotypes in neonates with congenital cytomegalovirus infections in Pakistan. Methods A total of 409 blood samples from pregnant women seeking health care services at the two antenatal hospitals of Islamabad during January to December 2012 were tested by ELISA and nested-PCR. Pregnant women with active infection (detected as IgM positive, PCR positive or positive on both assays) were followed until delivery, to detect the outcome of overt cCMV infection in neonates. Genetic characterization of CMV strains was performed by sequence analysis of envelope glycoproteins: gB, gN and gH to detect the contributing CMV genotypes. Results The seroprevalence of anti-CMV IgG and IgM was 97.5% (399 out of 409) and 12.7% (52 out of 409), respectively, while 20% (82/409) pregnant women were found positive for CMV DNA by PCR. Logistic regression analysis showed a significant association of active infection with parity [OR = 2.56, 95% CI = 1.82–2.62, p = 0.04], febrile illness [OR = 1.84, 95% CI = 1.76–3.65, p = 0.01] and jaundice [OR = 22.5, 95% CI = 4.53–85.02, p = 0.002]. We were able to isolate virus in 41 out of 70 neonates; 36.6% (15 out of 41) of them were symptomatic at birth while 63.4% (26 out of 41) were asymptomatic. The most prominent clinical feature observed in symptomatic neonates was hepatosplenomegaly (26.6%; 4 out of 15). All three genotypes gB, gN and gH were found with the highest frequency of gB1 genotype, found in 75% infants with hepatic damage. Phylogenetic analysis of Pakistani strains showed 96%-100% homology to their prototype strains. Conclusions Active CMV
Mujtaba, Ghulam; Khurshid, Adnan; Sharif, Salmaan; Alam, Muhammad Masroor; Aamir, Uzma Bashir; Shaukat, Shahzad; Angez, Mehar; Rana, Muhammad Suleman; Umair, Massab; Shah, Aamer Ali; Zaidi, Syed Sohail Zahoor
Congenital cytomegalovirus (cCMV) infection contributes to considerable long-term sequelae in neonates and children all over the world. The association between viral genotypes and severity of clinical cytomegalovirus (CMV) infection is yet to be defined. The objective of this study was to find the impact of active CMV infection during pregnancy and the clinical significance of genotypes in neonates with congenital cytomegalovirus infections in Pakistan. A total of 409 blood samples from pregnant women seeking health care services at the two antenatal hospitals of Islamabad during January to December 2012 were tested by ELISA and nested-PCR. Pregnant women with active infection (detected as IgM positive, PCR positive or positive on both assays) were followed until delivery, to detect the outcome of overt cCMV infection in neonates. Genetic characterization of CMV strains was performed by sequence analysis of envelope glycoproteins: gB, gN and gH to detect the contributing CMV genotypes. The seroprevalence of anti-CMV IgG and IgM was 97.5% (399 out of 409) and 12.7% (52 out of 409), respectively, while 20% (82/409) pregnant women were found positive for CMV DNA by PCR. Logistic regression analysis showed a significant association of active infection with parity [OR = 2.56, 95% CI = 1.82-2.62, p = 0.04], febrile illness [OR = 1.84, 95% CI = 1.76-3.65, p = 0.01] and jaundice [OR = 22.5, 95% CI = 4.53-85.02, p = 0.002]. We were able to isolate virus in 41 out of 70 neonates; 36.6% (15 out of 41) of them were symptomatic at birth while 63.4% (26 out of 41) were asymptomatic. The most prominent clinical feature observed in symptomatic neonates was hepatosplenomegaly (26.6%; 4 out of 15). All three genotypes gB, gN and gH were found with the highest frequency of gB1 genotype, found in 75% infants with hepatic damage. Phylogenetic analysis of Pakistani strains showed 96%-100% homology to their prototype strains. Active CMV infection during pregnancy is a major cause of
de la Cámara, Rafael
Due to its negative impact on the outcome of stem cell transplant (SCT) and solid organ transplant patients (SOT) CMV has been called “the troll of transplantation”. One of the greatest advances in the management of SCT has been the introduction of the preemptive strategy. Since its introduction, the incidence of the viremia, as expected, remains unchanged but there has been a marked decline in the incidence of early CMV disease. However, in spite of the advances in prevention of CMV disease, CMV is still today an important cause of morbidity and mortality. Late CMV disease is still occurring in a significant proportion of patients and the so-called indirect effects of CMV are causing significant morbidity and mortality. Fortunately there have been several advances in the development of new antivirals, adoptive immunotherapy and DNA-CMV vaccines that might transform the management of CMV in the near future. PMID:27413524
Glass, Hannah C; Bowman, Chelsea; Chau, Vann; Moosa, Alisha; Hersh, Adam L; Campbell, Andrew; Poskitt, Kenneth; Azakie, Anthony; Barkovich, A James; Miller, Steven P; McQuillen, Patrick S
More than 60% of newborns with severe congenital cardiac disease develop perioperative brain injuries. Known risk factors include: pre-operative hypoxemia, cardiopulmonary bypass characteristics, and post-operative hypotension. Infection is an established risk factor for white matter injury in premature newborns. In this study, we examined term infants with congenital cardiac disease requiring surgical repair to determine whether infection is associated with white matter injury. Acquired infection was specified by site - bloodstream, pneumonia, or surgical site infection - according to strict definitions. Infection was present in 23 of 127 infants. Pre- and post-operative imaging was evaluated for acquired injury by a paediatric neuroradiologist. Overall, there was no difference in newly acquired post-operative white matter injury in infants with infection (30%), compared to those without (31%). When stratified by anatomy, infants with transposition of the great arteries, and bloodstream infection had an estimated doubling of risk of white matter injury that was not significant, whereas those with single ventricle anatomy had no apparent added risk. When considering only infants without stroke, the estimated association was higher, and became significant after adjusting for duration of inotrope therapy. In this study, nosocomial infection was not associated with white matter injury. Nonetheless, when controlling for risk factors, there was an association between bloodstream infection and white matter injury in selected sub-populations. Infection prevention may have the potential to mitigate long-term neurologic impairment as a consequence of white matter injury, which underscores the importance of attention to infection control for these patients.
Yachie, A.; Tosato, G.; Straus, S.E.; Blaese, R.M.
Cytomegalovirus (CMV) is the cause of a number of different diseases ranging from self-limited benign infections in healthy adults to life threatening illnesses among immunocompromised hosts and newborns. Suppression of cell-mediated immunity is often found in cases of acute CMV infection, and in addition, the virus may also be a potent stimulant of lymphoid cells in vivo. The authors studied cellular proliferation and immunoglobulin (Ig) production induced by CMV to determine its effect on human lymphocytes in vitro. The CMV that was added to cultures of lymphocytes from CMV-seronegative donors failed to induce either significant cellular proliferation or Ig production. By contrast, CMV-stimulated cultures from CMV-seropositive donors induced both prominent cellular proliferation and Ig production. B cell differentiation into Ig-secreting cells required the presence of T cells, and this T cell help was sensitive to irradiation with 2000 rad and to treatment with cyclosporin A. When T cells were depleted of OKT4+ cells with monoclonal antibody and complement, the co-cultured B cells failed to produce Ig, whereas the depletion of OKT8+ cells had no effect on the Ig-secreting cell response. Inactivation of CMV before culture did not result in a reduction of either cellular proliferation or Ig production. Thus, infection of target cells is not required for in vitro lymphocyte activation by CMV. These results demonstrate that CMV is a potent activator of B cells inducing Ig production in vitro, and that this process requires the presence of virus-specific memory T cells.
Katchanov, J; Branding, G; Stocker, H
We report a very rare case of a combined CMV- and HSV-1 isolated brainstem encephalitis restricted to medulla oblongata in a patient with advanced HIV disease. Neither limbic nor general ventricular involvement was detected on neuroimaging. The case highlights the importance of testing for HSV-1 and CMV in HIV-infected patients presenting with an isolated brainstem syndrome.
van den Brom, R; Luttikholt, S J M; Lievaart-Peterson, K; Peperkamp, N H M T; Mars, M H; van der Poel, W H M; Vellema, P
Epizootic outbreaks of congenital malformations in sheep are rare and have, to the best of our knowledge, never been reported before in Europe. This paper describes relevant preliminary findings from the first epizootic outbreak of ovine congenital malformations in the Netherlands. Between 25 November and 20 December 2011, congenital malformations in newborn lambs on sheep farms throughout the country were reported to the Animal Health Service in Deventer. Subsequently, small ruminant veterinary specialists visited these farms and collected relevant information from farmers by means of questionnaires. The deformities varied from mild to severe, and ewes were reported to have given birth to both normal and deformed lambs; both male and female lambs were affected. Most of the affected lambs were delivered at term. Besides malformed and normal lambs, dummy lambs, unable to suckle, were born also on these farms. None of the ewes had shown clinical signs during gestation or at parturition. Dystocia was common, because of the lambs' deformities. Lambs were submitted for post-mortem examination, and samples of brain tissue were collected for virus detection. The main macroscopic findings included arthrogryposis, torticollis, scoliosis and kyphosis, brachygnathia inferior, and mild-to-marked hypoplasia of the cerebrum, cerebellum and spinal cord. Preliminary data from the first ten affected farms suggest that nutritional deficiencies, intoxication, and genetic factors are not likely to have caused the malformations. Preliminary diagnostic analyses of precolostral serum samples excluded border disease virus, bovine viral diarrhoea virus, and bluetongue virus. In December 2011, samples of brain tissue from 54 lambs were sent to the Central Veterinary Institute of Wageningen University Research, Lelystad. Real-time PCR detected the presence of a virus, provisionally named the Schmallenberg virus, in brain tissue from 22 of the 54 lambs, which originated from seven of eight
Abras, Alba; Muñoz, Carmen; Ballart, Cristina; Berenguer, Pere; Llovet, Teresa; Herrero, Mercedes; Tebar, Silvia; Pinazo, María-Jesús; Posada, Elizabeth; Martí, Carmen; Fumadó, Victoria; Bosch, Jordi; Coll, Oriol; Juncosa, Teresa; Ginovart, Gemma; Armengol, Josep; Gascón, Joaquim; Portús, Montserrat; Gállego, Montserrat
The immigration of Latin American women of childbearing age has spread the congenital transmission of Chagas disease to non-endemic areas, and the disease is now a worldwide problem. Some European health authorities have implemented screening programs to prevent vertical transmission, but the lack of a uniform protocol calls for the urgent establishment of a new strategy, common for all laboratories. Our aims were (i) to analyze the trend of passive IgG antibodies in the newborn by means of five serological tests for the diagnosis and follow-up of congenital Trypanosoma cruzi infection, (ii) to assess the utility of these techniques for diagnosing a congenital transmission, and (iii) to propose a strategy for a prompt, efficient and cost-effective diagnosis of T. cruzi infection. In non-infected newborns, a continuous decreasing trend of passive IgG antibodies was observed, but none of the serological assays seroreverted in all the infants before 12 months. From 12 months onwards, serological tests achieved negative results in all the samples analyzed, with the exception of the highly sensitive chemiluminescent microparticle immunoassay (CMIA). In contrast, in congenitally infected infants, the antibody decline was only detected after treatment initiation. In order to improve the diagnosis of congenital T. cruzi infection, we propose a new strategy involving fewer tests that allows significant cost savings. The protocol could start 1 month after birth with a parasitological test and/or a PCR. If negative, a serological test would be carried out at 9 months, which if positive, would be followed by another at around 12 months for confirmation.
van der Linden, Vanessa; Pessoa, André; Dobyns, William; Barkovich, A James; Júnior, Hélio van der Linden; Filho, Epitacio Leite Rolim; Ribeiro, Erlane Marques; Leal, Mariana de Carvalho; Coimbra, Pablo Picasso de Araújo; Aragão, Maria de Fátima Viana Vasco; Verçosa, Islane; Ventura, Camila; Ramos, Regina Coeli; Cruz, Danielle Di Cavalcanti Sousa; Cordeiro, Marli Tenório; Mota, Vivian Maria Ribeiro; Dott, Mary; Hillard, Christina; Moore, Cynthia A
Congenital Zika virus infection can cause microcephaly and severe brain abnormalities (1). Congenital Zika syndrome comprises a spectrum of clinical features (2); however, as is the case with most newly recognized teratogens, the earliest documented clinical presentation is expected to be the most severe. Initial descriptions of the effects of in utero Zika virus infection centered prominently on the finding of congenital microcephaly (3). To assess the possibility of clinical presentations that do not include congenital microcephaly, a retrospective assessment of 13 infants from the Brazilian states of Pernambuco and Ceará with normal head size at birth and laboratory evidence of congenital Zika virus infection was conducted. All infants had brain abnormalities on neuroimaging consistent with congenital Zika syndrome, including decreased brain volume, ventriculomegaly, subcortical calcifications, and cortical malformations. The earliest evaluation occurred on the second day of life. Among all infants, head growth was documented to have decelerated as early as 5 months of age, and 11 infants had microcephaly. These findings provide evidence that among infants with prenatal exposure to Zika virus, the absence of microcephaly at birth does not exclude congenital Zika virus infection or the presence of Zika-related brain and other abnormalities. These findings support the recommendation for comprehensive medical and developmental follow-up of infants exposed to Zika virus prenatally. Early neuroimaging might identify brain abnormalities related to congenital Zika infection even among infants with a normal head circumference (4).
Inaba, Yuji; Motobayashi, Mitsuo; Nishioka, Makoto; Kaneko, Tomoki; Yamauchi, Shoko; Kawasaki, Yoichiro; Shiba, Naoko; Nishio, Shin-ya; Moteki, Hideaki; Miyagawa, Maiko; Takumi, Yutaka; Usami, Shin-ichi; Koike, Kenichi
It is well known that congenital cytomegalovirus infection exhibits white matter and other types of lesions in magnetic resonance imaging (MRI), but little is known on the clinical significance of white matter lesions because they are also present in asymptomatic congenital cytomegalovirus infection. We investigated for relationships among white matter lesions, intelligence quotient, and other neurodevelopmental features. Nine children (five boys and four girls; mean age: 87.4 months, range: 63-127 months) with sensorineural hearing loss (five bilateral and four unilateral) had been diagnosed as having congenital cytomegalovirus infection by positive polymerase chain reaction findings of dried umbilical cords. They were evaluated for the presence of autistic features, tested using Wechsler Intelligence Scale for Children-Fourth Edition for intelligence quotient, and underwent brain MRI to measure white matter lesion localization and volume. At the time of MRI examination (mean age: 69.4 months, range: 19-92 months), white matter lesions were detected in eight of nine patients. Five subjects were diagnosed as having autism spectrum disorders. We observed increased white matter lesion volume was associated with lower intelligence quotient scores (R(2) = 0.533, P = 0.026) but not with autism spectrum disorders. In individuals with congenital cytomegalovirus, an increased white matter lesion volume is associated with lower intelligence quotient scores but not with an increased likelihood of autistic behavior. Copyright © 2016 Elsevier Inc. All rights reserved.
Vaccination with a Live Attenuated Cytomegalovirus Devoid of a Protein Kinase R Inhibitory Gene Results in Reduced Maternal Viremia and Improved Pregnancy Outcome in a Guinea Pig Congenital Infection Model.
Schleiss, Mark R; Bierle, Craig J; Swanson, Elizabeth C; McVoy, Michael A; Wang, Jian Ben; Al-Mahdi, Zainab; Geballe, Adam P
against virion proteins but have yielded disappointing results. The advent of bacterial artificial chromosome technologies has enabled engineering of recombinant cytomegaloviruses (CMVs) from which virus genome-encoded immune modulation genes have been deleted, toward the goal of developing a safe and potentially more efficacious live attenuated vaccine. Here we report the findings of studies of such a vaccine against congenital CMV infection based on a virus with a targeted deletion in gp145, a virus genome-encoded inhibitor of protein kinase R, using the guinea pig model of vertical CMV transmission. The deletion virus was attenuated for dissemination in immunocompromised guinea pigs but elicited ELISA and neutralizing responses. The vaccine conferred protection against maternal DNAemia and congenital transmission and resulted in reduced viral loads in newborn guinea pigs. These results provide support for future studies of attenuated CMV vaccines. Copyright © 2015, American Society for Microbiology. All Rights Reserved.
Ikram, H; Prince, A M; Baker, L N
Male homosexuals have been found to have an extraordinarily high prevalence, and high titers, of antibodies to cytomegalovirus (CMV), as determined by complement-fixation and passive hemagglutination tests. These findings support other data suggesting that CMV may be sexually transmitted. The high titers of CMV antibody found in this population suggest that the homosexual population may be a valuable source of plasma for preparations of CMV immune globulins. CMV immune globulins may be useful in passive immunoprophylaxis or immunotherapy in immunosuppressed patients.
Fila, M; Dechartes, A; Maisin, A; Dossier, C; Zhao, W; Deschênes, G; Baudouin, V
Prophylaxis has dramatically decreased the occurrence of cytomegalovirus (CMV) infection after renal transplantation. Optimal regimens of treatment remain controversial, especially in pediatric recipients. The aim of this study was to evaluate the effectiveness of valganciclovir (VGC) versus aciclovir/valaciclovir (ACV) in a pediatric renal transplant population. Data from 101 renal transplantations were retrospectively analyzed. Except those with R-/Dstatus, all patients received prophylaxis either with ACV, n = 39 or VGC, n = 38. Incidences of positive CMV antigenemia and disease, as well as the delay in relation to the prophylaxis, were collected during at least 12 months after the end of treatment. Positive CMV antigenemia was reported in 34 patients (ACV: 16, VGC: 16, no prophylaxis: 2). CMV disease occurred in 15 patients (ACV: 5; VGC: 8) (ns). For the majority of patients under VGC, positive CMV antigenemia occurred within the year following the withdrawal of prophylaxis (VGC: 14; ACV: 5, P <0.05), whereas it occurred during prophylaxis in 11 patients under ACV versus two under VGC (P <0.05). The over-all incidence of positive CMV antigenemia was similar between ACV and VGC prophylaxis. However, VGC was more efficient to prevent early CMV infection while patients treated with ACV had less CMV infection or disease after the end of the prophylaxis.
Intracranial dermoid cysts commonly present as a discharging sinus, local swelling, mass lesion, or abscess formation. These can sometimes be found in association with congenital anomalies. The author presents two original cases of infected posterior fossa dermoid associated with congenital heart diseases (CHDs) that is very rare. The embryologic basis for this unique occurrence is reviewed, and a new hypothesis proposed. Two infants with CHD presented with infected midline posterior fossa dermoid. Excision of the dermoid cyst with the sinus tract was performed. Postoperative period was uneventful. Both the infants had undergone surgery for congenial heart disease a few months prior to the present clinical presentation with uneventful recovery. Infected posterior fossa dermoid cyst without a discharging sinus should prompt a thorough examination to detect CHD. Early diagnosis and timely management results in better outcome. PMID:26557168
Meyer, Lucy; Sharon, Bazak; Huang, Tina C; Meyer, Abby C; Gravel, Kristin E; Schimmenti, Lisa A; Swanson, Elizabeth C; Herd, Hannah E; Hernandez-Alvarado, Nelmary; Coverstone, Kirsten R; McCann, Mark; Schleiss, Mark R
Congenital cytomegalovirus (cCMV) infection is the most common non-genetic cause of sensorineural hearing loss (SNHL). However, accurate diagnosis of cCMV as the etiology of SNHL is problematic beyond the neonatal period. This study therefore examined whether cCMV infection could be identified retrospectively in children presenting with unexplained SNHL to a multidisciplinary diagnostic outpatient otolaryngology clinic at an academic medical center in Minnesota. Over a 4-year period, 57 patients with an age range of 3months to 10years with unexplained SNHL were recruited to participate in this study. Informed consent was obtained to test the archived dried blood spots (DBS) of these patients for cCMV infection by real-time PCR, targeting a highly conserved region of the CMV UL83 gene. Results were normalized to recovery of an NRAS gene control. Chart review was conducted to identify subjects who underwent genetic testing and/or neurodiagnostic imaging to investigate possible genetic, syndromic, or anatomical causes of SNHL. In total, 15 of the 57 children with unexplained SNHL tested positive for CMV DNA in their DBS (26%). A mean viral load of 8.3×10(4) (±4.1×10(4)) [range, 1×10(3)-6×10(5)] copies/μg DNA was observed in subjects retrospectively diagnosed with cCMV. No statistically significant correlation was found between viral load and SNHL severity. A retrospective DBS analysis demonstrated that 26% of patients presenting with unexplained SNHL in childhood had cCMV. DBS testing is useful in the retrospective diagnosis of cCMV, and may provide definitive diagnostic information about the etiology of SNHL. Copyright © 2017. Published by Elsevier Inc.
Davis, Zachary B.; Cooley, Sarah A.; Cichocki, Frank; Felices, Martin; Wangen, Rose; Luo, Xianghua; DeFor, Todd E.; Bryceson, Yenan T.; Diamond, Don J.; Brunstein, Claudio; Blazar, Bruce R.; Wagner, John E.; Weisdorf, Daniel J.; Horowitz, Amir; Guethlein, Lisbeth A.; Parham, Peter; Verneris, Michael R.; Miller, Jeffrey S.
Cytomegalovirus (CMV) reactivates in >30% of CMV seropositive patients after allogeneic hematopoietic cell transplantation (HCT). Previously, we reported an increase of NK cells expressing NKG2C, CD57 and inhibitory killer-cell immunoglobulin-like receptors (KIRs) in response to CMV reactivation post-HCT. These NK cells persist after the resolution of infection and display ‘adaptive’ or memory properties. Despite these findings, the differential impact of persistent/inactive vs. reactivated CMV on NK vs. T cell maturation following HCT from different graft sources has not been defined. We compared the phenotype of NK and T cells from 292 recipients of allogeneic sibling (n = 118) or umbilical cord blood (UCB; n = 174) grafts based on recipient pre-transplant CMV serostatus and post-HCT CMV reactivation. This cohort was utilized to evaluate CMV-dependent increases in KIR-expressing NK cells exhibiting an ‘adaptive’ phenotype (NKG2C+CD57+). Compared to CMV seronegative recipients, those who reactivated CMV (React+) had the highest adaptive cell frequencies, while intermediate frequencies were observed in CMV seropositive recipients harboring persistent/non-replicating CMV. The same effect was observed in T cells and CD56+ T cells. These adaptive lymphocyte subsets were increased in CMV seropositive recipients of sibling, but not UCB grafts, and correlated with lower rates of CMV reactivation (sibling 33% vs. UCB 51%; p<0.01). These data suggest that persistent/non-replicating recipient CMV induces rapid production of adaptive NK and T cells from mature cells from sibling, but not UCB grafts. These adaptive lymphocytes are associated with protection from CMV reactivation. PMID:26055301
Golemac, Mijo; Pugel, Ester Pernjak; Jonjic, Stipan; Britt, William J.
Congenital human cytomegalovirus (HCMV) occurs in 0.5–1% of live births and approximately 10% of infected infants develop hearing loss. The mechanism(s) of hearing loss remain unknown. We developed a murine model of CMV induced hearing loss in which murine cytomegalovirus (MCMV) infection of newborn mice leads to hematogenous spread of virus to the inner ear, induction of inflammatory responses, and hearing loss. Characteristics of the hearing loss described in infants with congenital HCMV infection were observed including, delayed onset, progressive hearing loss, and unilateral hearing loss in this model and, these characteristics were viral inoculum dependent. Viral antigens were present in the inner ear as were CD3+ mononuclear cells in the spiral ganglion and stria vascularis. Spiral ganglion neuron density was decreased after infection, thus providing a mechanism for hearing loss. The lack of significant inner ear histopathology and persistence of inflammation in cochlea of mice with hearing loss raised the possibility that inflammation was a major component of the mechanism(s) of hearing loss in MCMV infected mice. PMID:25875183
Bradford, Russell D; Yoo, Young-Gun; Golemac, Mijo; Pugel, Ester Pernjak; Jonjic, Stipan; Britt, William J
Congenital human cytomegalovirus (HCMV) occurs in 0.5-1% of live births and approximately 10% of infected infants develop hearing loss. The mechanism(s) of hearing loss remain unknown. We developed a murine model of CMV induced hearing loss in which murine cytomegalovirus (MCMV) infection of newborn mice leads to hematogenous spread of virus to the inner ear, induction of inflammatory responses, and hearing loss. Characteristics of the hearing loss described in infants with congenital HCMV infection were observed including, delayed onset, progressive hearing loss, and unilateral hearing loss in this model and, these characteristics were viral inoculum dependent. Viral antigens were present in the inner ear as were CD(3+) mononuclear cells in the spiral ganglion and stria vascularis. Spiral ganglion neuron density was decreased after infection, thus providing a mechanism for hearing loss. The lack of significant inner ear histopathology and persistence of inflammation in cochlea of mice with hearing loss raised the possibility that inflammation was a major component of the mechanism(s) of hearing loss in MCMV infected mice.
Azadi, Pejman; Otang, Ntui Valentaine; Supaporn, Hasthanasombut; Khan, Raham Sher; Chin, Dong Poh; Nakamura, Ikuo; Mii, Masahiro
Lilium cv Acapulco was transformed with a defective cucumber mosaic virus (CMV) replicase gene (CMV2-GDD) construct using Agrobacterium tumefaciens. Four lines were analyzed for gene expression and resistance to CMV-O strain. Expression of the CMV2-GDD gene in the transgenic plants was confirmed by reverse transcription PCR (RT-PCR). When these four lines were mechanically inoculated with CMV-O, no signal of coat protein (CP) messages using RT-PCR was detected in newly produced leaves of two transgenic lines. Dot-immunobinding assay (DIBA) of CP was performed to examine the presence of the CMV in the newly produced leaves of challenged plants. Results, similar to those obtained with RT-PCR of the CP messages, were observed in DIBA. Therefore, our results imply that the two lines show increased levels of resistance to CMV, and CMV-GDD replicase gene is an effective construct that has protection against CMV in Lilium.
Dangel, Volker; Bäder, Ursula; Enders, Gisela
Human cytomegalovirus (CMV) is the most common cause of viral intrauterine infection. Primary CMV infection in early pregnancy bears a high risk of fetal damage. Accurate measurement of CMV-specific IgG avidity may help to improve the serodiagnosis of CMV-infected women by determining the time of infection and fetal outcome. To study the performance of the CMV avidity assay with the fully automated Vidas analyzer (bioMérieux) as a function of the concentration of CMV-specific IgG present in the serum sample. Eighty-two serum samples were investigated from 3 clinical scenarios: 18 individuals with sera negative for CMV-specific IgG and IgM (control group), 20 pregnant women (44 samples) containing CMV-specific IgG- and IgM-antibodies suggesting acute or recent primary infection and 20 patients with evidence of past infection (CMV-IgG positive and CMV-IgM negative). In the group with presumed acute or recent primary infection 12 of 44 sera had CMV-specific IgG values above 100 arbitrary units (AU, bioMérieux)/ml and in these cases an increase in AI was measurable upon dilution of the serum sample. In two cases, AI's were shifted towards or above the cut-off value of AI>or=0.8, indicative of past infection. Dilution of sera which were CMV-specific IgM positive and had specific IgG concentrations of
Sakao-Suzuki, Makiko; Kawasaki, Hideya; Akamatsu, Taisuke; Meguro, Shiori; Miyajima, Hiroaki; Iwashita, Toshihide; Tsutsui, Yoshihiro; Inoue, Naoki; Kosugi, Isao
Objective Congenital cytomegalovirus (CMV) infection is the leading viral cause of neurodevelopmental disorders in humans, with the most severe and permanent sequelae being those affecting the cerebrum. As the fetal immune reactions to congenital CMV infection in the brain and their effects on cerebral development remain elusive, our aim was to investigate primitive innate immunity to CMV infection and its effects on cerebral corticogenesis in a mouse model for congenital CMV infection using a precise intraplacental inoculation method. Methods At 13.5 embryonic days (E13.5), pregnant C57BL/6 mice were intraplacentally infected with murine CMV (MCMV). Placentas and fetal organs were collected at 1, 3, and 5 days postinfection and analyzed. Results MCMV antigens were found frequently in perivascular macrophages, and subsequently in neural stem/progenitor cells (NSPCs). With increased expression of inducible nitric oxide synthase and proinflammatory cytokines, activated macrophages infiltrated into the infectious foci. In addition to the infected area, the numbers of both meningeal macrophages and parenchymal microglia increased even in the uninfected areas of MCMV-infected brain due to recruitment of their precursors from other sites. A bromodeoxyuridine (BrdU) incorporation experiment demonstrated that MCMV infection globally disrupted the self-renewal of NSPCs. Furthermore, BrdU-labeled neurons, particularly Brn2+ neurons of upper layers II/III in the cortical plate, decreased in number significantly in the MCMV-infected E18.5 cerebrum. Interpretation Brain macrophages are crucial for innate immunity during MCMV infection in the fetal brain, while their aberrant recruitment and activation may adversely impact on the stemness of NSPCs, resulting in neurodevelopmental disorders. PMID:25356429
Avettand-Fenoël, Véronique; Marlin, Sandrine; Vauloup-Fellous, Christelle; Loundon, Natalie; François, Martine; Couloigner, Vincent; Rouillon, Isabelle; Drouin-Garraud, Valérie; Laccourreye, Laurence; Denoyelle, Françoise; Guilleminot, Tiffany; Grabar, Sophie; Leruez-Ville, Marianne
To estimate the prevalence of congenital cytomegalovirus (cCMV) among causes of bilateral hearing loss in young French children. Children <3 years old with hearing loss were prospectively included at their first visit to a referral center. Cytomegalovirus polymerase chain reaction was performed on dried blood spots from Guthrie cards. Medical records were reviewed. One hundred children with bilateral hearing loss were included at a median age of 15 months; the prevalence of cCMV was 8% (8/100) (95% CI, 2.7%-13.3%) in this population and 15.4% (8/52) in the subpopulation of children with profound bilateral hearing loss. Delayed neurodevelopment and brain abnormalities on computed tomography scan were found more often in children with cCMV than in children with hearing loss without cCMV (P = .027, P = .005). In 6 of 8 cCMV cases, cCMV infection had not been diagnosed before the study. In a comprehensive study of the causes of bilateral hearing loss in young French children, cCMV is the second most frequent cause of hearing loss after connexin mutations. It underlines that a majority of French children with hearing loss and cCMV are not diagnosed early and therefore may not benefit from early intervention including the possibility of neonatal antiviral treatment. These results make the case for promoting systematic cytomegalovirus screening in neonates with confirmed hearing loss identified through neonatal hearing screening. Copyright © 2013 Mosby, Inc. All rights reserved.
Madden, John F; Burchette, James L; Hale, Laura P
Infection with parainfluenza virus typically produces a mild, self-limited upper respiratory infection. However, parainfluenza infections have become increasingly recognized as a source of severe morbidity and mortality in immunocompromised patients. In this retrospective study we identified 6 patients with congenital immunodeficiency and positive respiratory cultures for parainfluenza virus who died and underwent complete autopsy. Tissues obtained at autopsy were studied using hematoxylin and eosin-stained sections, immunoperoxidase staining for parainfluenza virus, and in selected cases, electron microscopy. All 6 patients exhibited typical cytopathic effects of parainfluenza virus, including giant cell formation, in lung and/or bronchial tissues. Parainfluenza virus infection was also documented by giant cell formation and immunohistochemistry in the pancreas (in 3 of 6 patients) and the kidney or bladder (in 2 of 4 patients). Anti-parainfluenza antibody also specifically reacted with cells in the gastrointestinal tract (in 2 of 4), spleen (in 4 of 6), thymus and/or lymph nodes (in 4 of 4), and small blood vessels in various organs (in 4 of 6). Pancreatic, bladder, colon, and thymic epithelial cell lines were susceptible to experimental infections with clinical isolates of parainfluenza virus type 3 in vitro. Parainfluenza virus infection was serious in patients with congenital immunodeficiencies, contributing directly to death in 5 of the 6 patients studied. Because this virus is capable of infecting tissues in the gastrointestinal and urinary systems as well as in the respiratory tract, body secretions and fluids from each of these locations should be considered potentially infectious.
Ito, Fumitake; Okubo, Tomoharu; Yasuo, Tadahiro; Mori, Taisuke; Iwasa, Koichi; Iwasaku, Kazuhiro; Kitawaki, Jo
Congenital cutaneous candidiasis is a very rare disease with less than 100 cases published in the medical literature. Neonates having this disease present with systemic skin lesions caused by intrauterine Candida infections. We present a case of threatened premature delivery due to Candida chorioamnionitis, which caused both maternal postpartum endometritis and neonatal congenital cutaneous candidiasis. A 34-year-old woman who was admitted for fetal membrane bulging at 20 weeks of gestation underwent McDonald cervical cerclage. We diagnosed threatened premature delivery due to intrauterine infection; therefore, we terminated the gestation by cesarean section at 24 weeks of gestation. Fungi-like yeast was detected in infantile gastric juice. Histopathological findings of the placenta revealed that Candida albicans mycelium invaded the placenta, chorioamniotic membrane and umbilical cord.
Hotez, Peter J
In the United States, there is a largely hidden burden of diseases caused by a group of chronic and debilitating parasitic, bacterial, and congenital infections known as the neglected infections of poverty. Like their neglected tropical disease counterparts in developing countries, the neglected infections of poverty in the US disproportionately affect impoverished and under-represented minority populations. The major neglected infections include the helminth infections, toxocariasis, strongyloidiasis, ascariasis, and cysticercosis; the intestinal protozoan infection trichomoniasis; some zoonotic bacterial infections, including leptospirosis; the vector-borne infections Chagas disease, leishmaniasis, trench fever, and dengue fever; and the congenital infections cytomegalovirus (CMV), toxoplasmosis, and syphilis. These diseases occur predominantly in people of color living in the Mississippi Delta and elsewhere in the American South, in disadvantaged urban areas, and in the US-Mexico borderlands, as well as in certain immigrant populations and disadvantaged white populations living in Appalachia. Preliminary disease burden estimates of the neglected infections of poverty indicate that tens of thousands, or in some cases, hundreds of thousands of poor Americans harbor these chronic infections, which represent some of the greatest health disparities in the United States. Specific policy recommendations include active surveillance (including newborn screening) to ascertain accurate population-based estimates of disease burden; epidemiological studies to determine the extent of autochthonous transmission of Chagas disease and other infections; mass or targeted treatments; vector control; and research and development for new control tools including improved diagnostics and accelerated development of a vaccine to prevent congenital CMV infection and congenital toxoplasmosis.
Hotez, Peter J.
In the United States, there is a largely hidden burden of diseases caused by a group of chronic and debilitating parasitic, bacterial, and congenital infections known as the neglected infections of poverty. Like their neglected tropical disease counterparts in developing countries, the neglected infections of poverty in the US disproportionately affect impoverished and under-represented minority populations. The major neglected infections include the helminth infections, toxocariasis, strongyloidiasis, ascariasis, and cysticercosis; the intestinal protozoan infection trichomoniasis; some zoonotic bacterial infections, including leptospirosis; the vector-borne infections Chagas disease, leishmaniasis, trench fever, and dengue fever; and the congenital infections cytomegalovirus (CMV), toxoplasmosis, and syphilis. These diseases occur predominantly in people of color living in the Mississippi Delta and elsewhere in the American South, in disadvantaged urban areas, and in the US–Mexico borderlands, as well as in certain immigrant populations and disadvantaged white populations living in Appalachia. Preliminary disease burden estimates of the neglected infections of poverty indicate that tens of thousands, or in some cases, hundreds of thousands of poor Americans harbor these chronic infections, which represent some of the greatest health disparities in the United States. Specific policy recommendations include active surveillance (including newborn screening) to ascertain accurate population-based estimates of disease burden; epidemiological studies to determine the extent of autochthonous transmission of Chagas disease and other infections; mass or targeted treatments; vector control; and research and development for new control tools including improved diagnostics and accelerated development of a vaccine to prevent congenital CMV infection and congenital toxoplasmosis. PMID:18575621
Fabbro, Diana L.; Danesi, Emmaria; Olivera, Veronica; Codebó, Maria Olenka; Denner, Susana; Heredia, Cecilia; Streiger, Mirtha; Sosa-Estani, Sergio
With the control of the vectorial and transfusional routes of infection with Trypanosoma cruzi, congenital transmission has become an important source of new cases. This study evaluated the efficacy of trypanocidal therapy to prevent congenital Chagas disease and compared the clinical and serological evolution between treated and untreated infected mothers. We conducted a multicenter, observational study on a cohort of mothers infected with T. cruzi, with and without trypanocidal treatment before pregnancy. Their children were studied to detect congenital infection. Among 354 “chronically infected mother-biological child” pairs, 132 were treated women and 222 were untreated women. Among the children born to untreated women, we detected 34 infected with T. cruzi (15.3%), whose only antecedent was maternal infection. Among the 132 children of previously treated women, no infection with T. cruzi was found (0.0%) (p<0.05). Among 117 mothers with clinical and serological follow up, 71 had been treated and 46 were untreated. The women were grouped into three groups. Group A: 25 treated before 15 years of age; Group B: 46 treated at 15 or more years of age; Group C: untreated, average age of 29.2±6.2 years at study entry. Follow-up for Groups A, B and C was 16.3±5.8, 17.5±9.2 and 18.6±8.6 years respectively. Negative seroconversion: Group A, 64.0% (16/25); Group B, 32.6% (15/46); Group C, no seronegativity was observed. Clinical electrocardiographic alterations compatible with chagasic cardiomyopathy: Group A 0.0% (0/25); B 2.2% (1/46) and C 15.2% (7/46). The trypanocidal treatment of women with chronic Chagas infection was effective in preventing the congenital transmission of Trypanosoma cruzi to their children; it had also a protective effect on the women's clinical evolution and deparasitation could be demonstrated in many treated women after over 10 years of follow up. PMID:25411847
Fabbro, Diana L; Danesi, Emmaria; Olivera, Veronica; Codebó, Maria Olenka; Denner, Susana; Heredia, Cecilia; Streiger, Mirtha; Sosa-Estani, Sergio
With the control of the vectorial and transfusional routes of infection with Trypanosoma cruzi, congenital transmission has become an important source of new cases. This study evaluated the efficacy of trypanocidal therapy to prevent congenital Chagas disease and compared the clinical and serological evolution between treated and untreated infected mothers. We conducted a multicenter, observational study on a cohort of mothers infected with T. cruzi, with and without trypanocidal treatment before pregnancy. Their children were studied to detect congenital infection. Among 354 "chronically infected mother-biological child" pairs, 132 were treated women and 222 were untreated women. Among the children born to untreated women, we detected 34 infected with T. cruzi (15.3%), whose only antecedent was maternal infection. Among the 132 children of previously treated women, no infection with T. cruzi was found (0.0%) (p<0.05). Among 117 mothers with clinical and serological follow up, 71 had been treated and 46 were untreated. The women were grouped into three groups. Group A: 25 treated before 15 years of age; Group B: 46 treated at 15 or more years of age; Group C: untreated, average age of 29.2 ± 6.2 years at study entry. Follow-up for Groups A, B and C was 16.3 ± 5.8, 17.5 ± 9.2 and 18.6 ± 8.6 years respectively. Negative seroconversion: Group A, 64.0% (16/25); Group B, 32.6% (15/46); Group C, no seronegativity was observed. Clinical electrocardiographic alterations compatible with chagasic cardiomyopathy: Group A 0.0% (0/25); B 2.2% (1/46) and C 15.2% (7/46). The trypanocidal treatment of women with chronic Chagas infection was effective in preventing the congenital transmission of Trypanosoma cruzi to their children; it had also a protective effect on the women's clinical evolution and deparasitation could be demonstrated in many treated women after over 10 years of follow up.
... Churchill Livingstone; 2014:chap 140. Swanson EC. Congenital cytomegalovirus infection: new prospects for prevention and therapy. Pediatr Clin ... and the A.D.A.M. Editorial team. Cytomegalovirus Infections Read more Latest Health News Read more Health ...
Sarmiento, E; Fernàndez-Yáñez, J; Muñoz, P; Palomo, J; Rodríguez-Molina, J J; Bermejo, J; Catalan, P; Bouza, E; Fernández-Cruz, E; Carbone, J
Secondary hypogammaglobulinemia after heart transplantation may follow immunosuppressive therapy with the resultant increased risk of infections, including cytomegalovirus (CMV) disease. There is limited information on the use of intravenous immunoglobulin replacement therapy (IVIG) in heart-transplanted patients with hypogammaglobulinemia and CMV disease. We present data on five consecutive heart-transplanted patients with relapsing CMV disease, four of whom developed gastrointestinal disease. The immunosuppressive regimen included prednisone, cyclosporine A, azathioprine, mycophenolate mofetil, tacrolimus and antithymocyte globulin (ATG). Evaluation revealed CMV antigenemia. All the patients had been treated with intravenous ganciclovir. In addition, hyperimmune CMV immunoglobulin was administered in three patients. Significantly reduced levels of immunoglobulin G (IgG) were observed in the patients as compared with 15 heart-transplanted individuals without CMV disease [mean IgG levels: 323+/-18 and 639+/-63 mg/dl, respectively (p=0.003)]. IVIG [FLEBOGAMMA], 200-400 mg/kg every 21 days with the goal of maintaining normal serum IgG levels, was added for the treatment of CMV disease. Selected batches with the highest anti-CMV titers were set apart for the treatment of the patients. IVIG treatment, in combination with antiviral therapy, proved able to control CMV disease. There was a favorable clinical response and the patients became free of gastrointestinal symptoms. Detection of CMV antigens was negative after treatment. During IVIG therapy no immediate or delayed adverse effects were observed. Even if our survey was limited to five cases, the results suggest that addition of IVIG to antiviral chemotherapy might improve outcome in heart-transplanted patients with hypogammaglobulinemia and CMV disease.
Ouellette, Christopher P; Joshi, Sarita; Texter, Karen; Jaggi, Preeti
Two children with congenital heart disease status post surgical correction presented with prolonged constitutional symptoms, hepatosplenomegaly and pancytopenia. Concern for malignancy prompted bone marrow biopsies that were without evidence thereof. In case 1, echocardiography identified a multilobulated vegetation on the conduit valve. In case 2, transthoracic, transesophageal and intracardiac echocardiography were performed and were without evidence of cardiac vegetations; however, pulmonic emboli raised concern for infective endocarditis. Both patients underwent surgical resection of the infected material and had histopathologic evidence of infective endocarditis. Further diagnostics identified elevated cytoplasmic antineutrophil cytoplasmic antibodies and antiproteinase 3 antibodies in addition to acute kidney injury with crescentic glomerulonephritis on renal biopsy. Serologic evidence of infection with Bartonella henselae was observed in both patients. These 2 cases highlight the potential multiorgan involvement that may confound the diagnosis of culture-negative infective endocarditis caused by B. henselae.
González-Sánchez, H M; Monsiváis-Urenda, A; Salazar-Aldrete, C A; Hernández-Salinas, A; Noyola, D E; Jiménez-Capdeville, M E; Martínez-Serrano, A; Castillo, C G
Cytomegalovirus (CMV) is the most common cause of congenital infection in developed countries and a major cause of neurological disability in children. Although CMV can affect multiple organs, the most important sequelae of intrauterine infection are related to lesions of the central nervous system. However, little is known about the pathogenesis and the cellular events responsible for neuronal damage in infants with congenital infection. Some studies have demonstrated that neural precursor cells (NPCs) show the greatest susceptibility to CMV infection in the developing brain. We sought to establish an in vitro model of CMV infection of the developing brain in order to analyze the cellular events associated with invasion by this virus. To this end, we employed two cell lines as a permanent source of NPC, avoiding the continuous use of human fetal tissue, the human SK-N-MC neuroblastoma cell line, and an immortalized cell line of human fetal neural origin, hNS-1. We also investigated the effect of the differentiation stage in relation to the susceptibility of these cell lines by comparing the neuroblastoma cell line with the multipotent cell line hNS-1. We found that the effects of the virus were more severe in the neuroblastoma cell line. Additionally, we induced hNS-1 to differentiate and evaluated the effect of CMV in these differentiated cells. Like SK-N-MC cells, hNS-1-differentiated cells were also susceptible to infection. Viability of differentiated hNS-1 cells decreased after CMV infection in contrast to undifferentiated cells. In addition, differentiated hNS-1 cells showed an extensive cytopathic effect whereas the effect was scarce in undifferentiated cells. We describe some of the effects of CMV in neural stem cells, and our observations suggest that the degree of differentiation is important in the acquisition of susceptibility.
Hamprecht, Klaus; Maschmann, Jens; Müller, Denise; Dietz, Klaus; Besenthal, Ingo; Goelz, Rangmar; Middeldorp, Jaap M; Speer, Christian P; Jahn, Gerhard
Breast-feeding mothers frequently transmit cytomegalovirus (CMV) to preterm infants of very low birth weight. Current recommendations for prevention of virus transmission are based on data published 20 y ago in the context of human milk banking. Two recent clinical trials examined storage of breast milk at -20 degrees Celsius to reduce virus transmission. However, in both studies, CMV transmission occurred. Using sensitive tools like quantitative PCR, CMV pp67 late mRNA assay, and a high-speed, centrifugation-based microculture assay for quantification of CMV infectivity, we reassessed the virological and biochemical characteristics of freeze-storing breast milk at -20 degrees Celsius, compared it with traditional Holder pasteurization (30 min at 62.5 degrees Celsius), and a new short-term pasteurization (5 s at 72 degrees Celsius) based on the generation of a milk film. Both heat treatment procedures were able to destroy viral infectivity and pp67 RNA completely. Preliminary results showed short-term heat inactivation below 72 degrees Celsius was less harmful in reducing the activity of marker enzymes than Holder pasteurization. Freezing breast milk preserved the biochemical and immunologic quality of the milk; however, late viral RNA and viral infectivity was also preserved. Compared with viral DNA, CMV-RNA more directly reflects infectious CMV in human milk samples. Further studies are necessary to evaluate short-term heat treatment below 72 degrees Celsius as an effective tool for prevention of CMV transmission.
Goerig, Nicole L; Frey, Benjamin; Korn, Klaus; Fleckenstein, Bernhard; Überla, Klaus; Schmidt, Manuel A; Dörfler, Arnd; Engelhorn, Tobias; Eyüpoglu, Ilker; Rühle, Paul F; Putz, Florian; Semrau, Sabine; Gaipl, Udo S; Fietkau, Rainer
Neurological decline during radio(chemo)therapy of the brain is often attributed to disease progression or side effects of radiotherapy. Diagnosis of opportunistic neurotropic infections such as cytomegalovirus (CMV) infections is uncommon, even though high-grade gliomas and some brain metastases are known to contain CMV particles. We prospectively examined the frequency of CMV encephalopathy during radiotherapy of the brain. Fifty patients requiring whole-brain radiotherapy for brain metastases (n = 27) or local radio(chemo)therapy of the brain for high-grade gliomas (n = 23) were observed in the prospective observational GLIO-CMV-01 study. MRIs and blood samples were obtained before, halfway through, and at the end of radiotherapy. MRIs were screened for disease progression or increased intracranial pressure. Blood was tested for anti-CMV immunoglobulin (Ig)M, anti-CMV IgG, and CMV DNA. Thirty-two of 50 (64%) patients were positive for anti-CMV IgG before radio(chemo)therapy. Fifteen of those 32 (48%) developed viremia during or up to 28 days after treatment. Thirteen of those 15 (87%) required treatment for CMV-associated encephalopathy. MRIs were negative for disease progression, edema, or bleeding. None of the patients negative for anti-CMV IgG developed viremia, suggesting a reactivation rather than a primary infection.In the group at risk consisting of anti-CMV IgG+ patients, age >65 (P = .004) and the amount of dexamethasone taken during radio(chemo)therapy (P = .004) were associated with an increased risk for CMV-associated encephalopathy. One hundred and fifty days after the start of radio(chemo)therapy, survival was 74% (14/19) (no encephalopathy) versus 54% (7/13) (encephalopathy) (odds ratio, 0.42; 95% CI, 0.03-1.86; P = .25). CMV reactivation frequently causes encephalopathy during radio(chemo)therapy of the brain. The unexpected high incidence of this infection makes it highly clinically relevant for every treating physician. © The Author(s) 2016
Eichhorn, Sarah K.
Research on cytomegalovirus (CMV), a herpes virus causing neurological damage (hearing problems and/or mental retardation) in 10 percent of infants born with the condition, is reviewed. Incidence of hearing and retardation in CMV cases is reported and current treatment described. (CL)
Eichhorn, Sarah K.
Research on cytomegalovirus (CMV), a herpes virus causing neurological damage (hearing problems and/or mental retardation) in 10 percent of infants born with the condition, is reviewed. Incidence of hearing and retardation in CMV cases is reported and current treatment described. (CL)
Rico-Torres, C P; Vargas-Villavicencio, J A; Correa, D
In human congenital toxoplasmosis the effects of parasite burden and pregnancy time at infection on clinical outcome are well known, but there is controversy regarding the role of Toxoplasma gondii type. Through a systematic review of the literature, we aimed to discern if T. gondii type has a role on clinical outcome in human congenital toxoplasmosis. We built up a database of congenital toxoplasmosis from reports of cases, case series and screening-based cohorts, which had information about parasite type, gestation time at maternal infection and/or clinical outcome in the product. Then, we obtained frequencies for loci used to genotype geographical origin of cases and types found. Also, odds ratios were calculated for association between time of maternal infection or parasite type on outcome. Type II parasites were the most common in Europe, Asia and Africa, while in America there were mainly atypical strains. More newborns with clinical problems were born from mothers infected during the first half of gestation than from those acquiring the parasite after week 24, regardless of parasite genotype (92.9 vs. 16.1 %, OR = 67.9, CI95 25.4-181.6). Type I and atypical parasites were associated with clinical problems as opposed to types II and III, regardless of pregnancy period at infection (86.9 vs. 72.9 %, OR = 2.47, CI95 1.1-5.4). A significant and remarkable tendency of type I parasites to be present during early pregnancy was also observed (94.4 vs. 5.6 %, P < 0.009). In addition to parasite burden and period of gestation, T. gondii genotype seems involved in CT clinical outcome.
Leal, Mariana C; Muniz, Lilian F; Ferreira, Tamires S A; Santos, Cristiane M; Almeida, Luciana C; Van Der Linden, Vanessa; Ramos, Regina C F; Rodrigues, Laura C; Neto, Silvio S Caldas
Congenital infection with Zika virus causes microcephaly and other brain abnormalities (1). Hearing loss associated with other congenital viral infections is well described; however, little is known about hearing loss in infants with congenital Zika virus infection. A retrospective assessment of a series of 70 infants aged 0-10 months with microcephaly and laboratory evidence of Zika virus infection was conducted by the Hospital Agamenon Magalhães in Brazil and partners. The infants were enrolled during November 2015-May 2016 and had screening and diagnostic hearing tests. Five (7%) infants had sensorineural hearing loss, all of whom had severe microcephaly; however, one child was tested after receiving treatment with an ototoxic antibiotic. If this child is excluded, the prevalence of sensorineural hearing loss was 5.8% (four of 69), which is similar to that seen in association with other congenital viral infections. Additional information is needed to understand the prevalence and spectrum of hearing loss in children with congenital Zika virus infection; all infants born to women with evidence of Zika virus infection during pregnancy should have their hearing tested, including infants who appear normal at birth.
Russell, Kate; Oliver, Sara E; Lewis, Lillianne; Barfield, Wanda D; Cragan, Janet; Meaney-Delman, Dana; Staples, J Erin; Fischer, Marc; Peacock, Georgina; Oduyebo, Titilope; Petersen, Emily E; Zaki, Sherif; Moore, Cynthia A; Rasmussen, Sonja A
CDC has updated its interim guidance for U.S. health care providers caring for infants born to mothers with possible Zika virus infection during pregnancy (1). Laboratory testing is recommended for 1) infants born to mothers with laboratory evidence of Zika virus infection during pregnancy and 2) infants who have abnormal clinical or neuroimaging findings suggestive of congenital Zika syndrome and a maternal epidemiologic link suggesting possible transmission, regardless of maternal Zika virus test results. Congenital Zika syndrome is a recently recognized pattern of congenital anomalies associated with Zika virus infection during pregnancy that includes microcephaly, intracranial calcifications or other brain anomalies, or eye anomalies, among others (2). Recommended infant laboratory evaluation includes both molecular (real-time reverse transcription-polymerase chain reaction [rRT-PCR]) and serologic (immunoglobulin M [IgM]) testing. Initial samples should be collected directly from the infant in the first 2 days of life, if possible; testing of cord blood is not recommended. A positive infant serum or urine rRT-PCR test result confirms congenital Zika virus infection. Positive Zika virus IgM testing, with a negative rRT-PCR result, indicates probable congenital Zika virus infection. In addition to infant Zika virus testing, initial evaluation of all infants born to mothers with laboratory evidence of Zika virus infection during pregnancy should include a comprehensive physical examination, including a neurologic examination, postnatal head ultrasound, and standard newborn hearing screen. Infants with laboratory evidence of congenital Zika virus infection should have a comprehensive ophthalmologic exam and hearing assessment by auditory brainstem response (ABR) testing before 1 month of age. Recommendations for follow-up of infants with laboratory evidence of congenital Zika virus infection depend on whether abnormalities consistent with congenital Zika syndrome
Lago, E G; Conrado, G S; Piccoli, C S; Carvalho, R L; Bender, A L
The purpose of this study was to investigate the antibodies to Toxoplasma gondii in human immunodeficiency virus (HIV)-infected pregnant women and to determine the association between serological profile and the risk of congenital toxoplasmosis. The study, conducted in a public maternity ward from May 2002 to April 2005, included all HIV-infected women who delivered live infants during the 36 months, and, as a control group, all HIV-negative women that delivered live infants in the first 12 months of the study. Antibodies to T. gondii were detected in 1,624 of 2,421 HIV-negative women (67%; 95% confidence interval [CI] 65-69%) and in 121 of 168 HIV-infected patients (72%; 95% CI 65-79%). A total of 547 HIV-negative and 103 HIV-infected patients were tested at delivery and had positive T. gondii-specific IgG. In HIV-negative women, the median of the specific IgG concentration was 79 (interquartile range 38-160), and in HIV-infected patients, it was 283 (interquartile range 94-704) (P < 0.001). In the group of co-infected women, the only infant with congenital toxoplasmosis was born to a mother with acute toxoplasmosis infection acquired during pregnancy who did not have a high specific IgG concentration or a positive result for specific IgM. We concluded that high T. gondii-specific IgG values were much more frequent among HIV-infected pregnant women, but it did not translate into an increased risk of maternal-fetal transmission of toxoplasmosis.
van der Linden, Vanessa; Bezerra, Thiago P.; de Valois, Luciana; Borges, Adriana C.G.; Antunes, Margarida M.C.; Brandt, Kátia G.; Moura, Catharina X.; Rodrigues, Laura C.; Ximenes, Coeli R.
We summarize the characteristics of dysphagia in 9 infants in Brazil with microcephaly caused by congenital Zika virus infection. The Schedule for Oral Motor Assessment, fiberoptic endoscopic evaluation of swallowing, and the videofluoroscopic swallowing study were used as noninstrumental and instrumental assessments. All infants had a degree of neurologic damage and showed abnormalities in the oral phase. Of the 9 infants, 8 lacked oral and upper respiratory tract sensitivity, leading to delays in initiation of the pharyngeal phase of swallowing. Those delays, combined with marked oral dysfunction, increased the risk for aspiration of food, particularly liquid foods. Dysphagia resulting from congenital Zika virus syndrome microcephaly can develop in infants >3 months of age and is severe. PMID:28604336
Leal, Mariana C; van der Linden, Vanessa; Bezerra, Thiago P; de Valois, Luciana; Borges, Adriana C G; Antunes, Margarida M C; Brandt, Kátia G; Moura, Catharina X; Rodrigues, Laura C; Ximenes, Coeli R
We summarize the characteristics of dysphagia in 9 infants in Brazil with microcephaly caused by congenital Zika virus infection. The Schedule for Oral Motor Assessment, fiberoptic endoscopic evaluation of swallowing, and the videofluoroscopic swallowing study were used as noninstrumental and instrumental assessments. All infants had a degree of neurologic damage and showed abnormalities in the oral phase. Of the 9 infants, 8 lacked oral and upper respiratory tract sensitivity, leading to delays in initiation of the pharyngeal phase of swallowing. Those delays, combined with marked oral dysfunction, increased the risk for aspiration of food, particularly liquid foods. Dysphagia resulting from congenital Zika virus syndrome microcephaly can develop in infants >3 months of age and is severe.
Iorio, Matthew L; Barbour, John R
Congenital insensitivity to pain is a rare sensory neuropathy that manifests with multiple and recurrent injuries secondary to a lack of negative pain stimuli. When present with compulsive onychophagia, prompt recognition and behavioral management to prevent chronic digital infection or amputation is imperative. We present the case of two 7 year-old monozygotic twins that presented with congenital insensitivity to pain and compulsive onychophagia without directed parental counseling or behavioral modification strategies. The presenting child was noted to have an acute digital felon and osteomyelitis of several distal phalanges, and the sister had a similar history with distal phalangeal amputations. The occurrence of these overlapping disorders in monozygotic twins has not been previously reported, however, patient and parental education with behavioral modifications of injurious and compulsive behavior is the cornerstone of management. In addition, we have provided a review of the diagnosis for clinical differentiation. © The Author(s) 2013.
Syed-Hussain, S S; Howe, L; Pomroy, W E; West, D M; Hardcastle, M; Williamson, N B
To determine if toltrazuril was effective in eliminating Neospora caninum infection from congenitally infected lambs. Twenty-eight ewes were allocated to 3 groups where animals in Groups A and B were inoculated with 1 × 10(7)N. caninum tachyzoites on Day 120 of gestation and Group C was maintained as a negative control group. Lambs born from ewes in Group A were treated with toltrazuril (20mg/kg) on Days 0, 7, 14 and 21 after birth. Lambs in Groups B and C were untreated. All lambs in Groups A and B were seropositive at 12 weeks of age. At 12 weeks of age, no differences between lambs in Group A and Group B were observed in serological results (ELISA and western blot), presence of N. caninum-related brain histopathological lesions or the number of organisms detected by qPCR. Group C remained negative for serology, detection of N. caninum DNA as well as histopathology throughout the study. Results indicate that N. caninum congenitally-infected lambs had a continuing infection with N. caninum despite being treated with toltrazuril. Copyright © 2015 Elsevier B.V. All rights reserved.
Sund, Fredrik; Lidehäll, Anna-Karin; Claesson, Kerstin; Foss, Aksel; Tötterman, Thomas H; Korsgren, Olle; Eriksson, Britt-Marie
Cytomegalovirus (CMV) infection is still the leading opportunistic infection following solid organ transplantation. The aim of this prospective study of renal transplant recipients was to evaluate the dynamics of CMV-specific T-cells, viral load, and clinical symptoms of CMV infection. Levels of tetramer-selected CD8(+) T-cells (TetraCD8), CMV-specific interferon-gamma producing CD8(+) T-cells (IFNgammaCD8), and CD4(+) T-cells (IFNgammaCD4), measured using major histocompatibility complex-tetramer and cytokine flow cytometry techniques, and CMV DNA were monitored monthly in 17 CMV-seropositive patients up to one yr (median 12 months, range 3-12) after transplantation and correlated to clinical outcome. CMV DNAemia was detected in 94% of the patients, but only one patient developed CMV disease. CMV DNAemia >1 million copies/mL was seen in asymptomatic patients. CMV-specific T-cells decreased rapidly after transplantation. TetraCD8 and IFNgammaCD8 regenerated within three months, whereas IFNgammaCD4 recovery was impaired up to one yr after transplantation. The proportion of IFNgammaCD4 at two months post-transplantation as compared with baseline, correlated strongly with the magnitude of the CMV DNAemia. Monitoring the reduction of IFNgammaCD4 compared with baseline during the first months after transplantation could be considered in predicting risk for high-grade CMV DNAemia and in deciding strategic approaches for pre-emptive and prophylactic therapy.
Chistyakov, I S; Medvedev, A P; Pichugin, V V
The purpose of this study was to evaluate the effectiveness of combined surgical and medical treatment of infective endocarditis in patients with congenital valvular heart disease when included in a regimen of the drug Reamberin. In this regard, the analysis of the effectiveness of a combination regimen of 74 patients with valvular congenital heart diseases complicated with infective endocarditis. Given the indications for surgical correction operative technique features and possible technical difficulties in carrying out such operations, due to the inflammatory changes and tissue destruction, and ways to overcome them. For the correction of metabolic disorders in the postoperative period, 47 patients (main group) was appointed Reamberin: once, intravenous drip 400 ml/day during the first 5 days after surgery. 27 patients (control group) was conducted infusion therapy depending on the severity of the condition according to the classical scheme. In addition to standard clinical and laboratory examination, to assess the effectiveness of Reamberin was investigated catalase activity of CPK in blood serum in the dynamics of observation (1, 3 and 5 days after surgery). It is revealed that surgical approach, used in complex treatment of patients with valvular congenital heart diseases, including reorganization of the cavities of the heart, increasing the frequency of joints and the use of reinforcing strips of synthetic material that prevents the cutting of sutures through the inflamed tissue has achieved good short-and long-term results. Infective endocarditis and destruction of the valvular annulus fibrosus the use of a frame of strips of polytetrafluoroethylene allows you to restore its integrity and to implant a mechanical prosthesis. The inclusion in the regimen of patients with infective endocarditis complicated by cardiac insufficiency in the early postoperative period the drug Reamberin improves the efficiency of treatment by a more rapid restoration of the normal
Scanga, Lori; Chaing, Shu; Powell, Cynthia; Aylsworth, Arthur S.; Harrell, Lizzie J.; Henshaw, Nancy G.; Civalier, Chris J.; Thorne, Leigh B.; Weck, Karen; Booker, Jessica; Gulley, Margaret L.
Congenital human cytomegalovirus (HCMV) infection affects 1% of children and is the most common infectious cause of sensorineural hearing loss. Due to the difficulty of diagnosing deafness and other neurological disorders in infants, affected individuals may not be recognized until much later when active infection has resolved and culture is no longer informative. To overcome this problem, congenital HCMV infection was diagnosed retrospectively by testing residual blood samples collected from newborns and dried on perinatal cards as part of the North Carolina Newborn Screening Program. We modified the Qiagen method for purifying DNA from dried blood spots to increase the sample size and recovery of the lysate. A multiplex, real-time TaqMan polymerase chain reaction assay on an ABI 7900 instrument measured a highly conserved segment of the HCMV polymerase gene and the APOB human control gene. HCMV DNA was detected in blood dried on perinatal cards from all seven infants with culture-proven congenital infection, and all 24 negative control cases lacked detectable HCMV DNA. Our findings suggest that it is possible to diagnose congenital HCMV infection using dried blood collected up to 20 months earlier. Further studies are warranted on patients with hearing loss or other neurological deficits to determine the percentage that is attributable to congenital HCMV infection. PMID:16645211
San-Juan, R; Navarro, D; García-Reyne, A; Montejo, M; Muñoz, P; Carratala, J; Len, O; Fortun, J; Muñoz-Cobo, B; Gimenez, E; Eworo, A; Sabe, N; Meije, Y; Martin-Davila, P; Andres, A; Delgado, J; Jimenez, C; Amat, P; Fernández-Ruiz, M; López-Medrano, F; Lumbreras, C; Aguado, J M
Evaluate the protective effect against late CMV disease of delaying antiviral prophylaxis initiation in D+/R- patients receiving solid organ transplant (SOT). Prospective multicenter study in D+/R- SOT recipients in Spain (Sept/09-Sept/12). Whole blood specimens were prospectively collected after Tx for CMV-specific cell-mediated immunity (CMI) determination. Two prophylaxis strategies were compared: early prophylaxis (EP; starting within the first 3 days after Tx) and delayed prophylaxis (DP; starting 14 days after Tx). Risk factors for the occurrence of CMV disease were determined by survival analysis and proportional risk Cox regression models. We included 95 patients (50 EP V 45 DP). Twenty six patients (27.4%) developed CMV disease: 32.7% EP vs. 20% DP; (p = 0.2). No cases of CMV disease were reported previously to beginning delayed prophylaxis. The percentage of individuals with detectable CMI response was higher in patients with DP although differences did not reach statistic significance (42% vs 29.6% at day 200 after Tx; p = 0.4). There was a clear trend towards less end-organ CMV disease in patients receiving DP (18.2% EP vs 5% DP; p = 0.09) and DP was the only protective factor in the multivariate analysis (HR: 0.26; CI: 0.05-1.2; p = 0.09). A 14-day delay in CMV prophylaxis in D+/R- SOT recipients is safe and may reduce the incidence of late CMV end-organ disease although correlation of this effect with CMI responses was not complete. Copyright © 2015 The British Infection Association. Published by Elsevier Ltd. All rights reserved.
Shah, Kairav; Cherabuddi, Kartikeya; Beal, Stacy G; Kalyatanda, Gautam
Opportunistic infections with Pneumocystis jiroveci pneumonia (PCP) are common in patients with HIV (human immunodeficiency virus) and are encountered once the CD4 count decreases below 200 cells/mm3. Cytomegalovirus (CMV) tends to cause disease once the CD4 count drops below 50 cells/mm3. CMV pneumonitis is not common in this population. However, detecting its presence in broncho-alveolar lavage (BAL) fluid has been associated with increased morbidity and mortality. The role of antiviral therapy against CMV remains unclear. We report a newly diagnosed HIV patient with a CD4 count of 44 cells/mm3 presenting with acute respiratory failure secondary to PCP that failed to respond to 3 weeks of standard therapy with trimethoprim-sulfamethoxazole and corticosteroids. He was later diagnosed to have a CMV co-infection causing pneumonitis with BAL cytology findings showing CMV cytopathic effects and PCP. Plasma CMV DNA PCR was 17,424 copies/mL. He responded well after introduction of intravenous ganciclovir. The presence of histopathologic changes demonstrating viral cytopathic effects on BAL cytology along with a high plasma CMV DNA PCR should raise the specificity for diagnosing CMV pneumonitis. True PCP and CMV pneumonitis can occur, and the addition of antiviral therapy with ganciclovir may benefit such patients in the right clinical scenario.
Schoondermark-Van de Ven, E; Melchers, W; Camps, W; Eskes, T; Meuwissen, J; Galama, J
The effectiveness of spiramycin for the treatment of rhesus monkey fetuses congenitally infected with Toxoplasma gondii was studied. Eight monkeys were infected at day 90 of pregnancy. This is comparable to the second trimester of organogenetic development in humans. Transmission of infection was found prenatally in five of the eight monkeys by detection of the parasite in the amniotic fluid. Treatment with spiramycin (20 mg/kg/day in two intermittent doses given intravenously) was started as soon as fetal infection was proven and was continued until birth. Nine to 14 days after initiation of treatment, the parasite was still detectable in amniotic fluid samples from four of these five cases. However, the parasite was detected only by PCR and not by mouse inoculation. T. gondii was also detected only by PCR in the placenta of one monkey that delivered prematurely. This monkey received spiramycin treatment for only 2 weeks. In the four monkeys that received treatment for about 7 weeks, the parasite was not present at birth in the placenta nor in amniotic fluid or neonatal organs. Spiramycin accumulates mainly in maternal tissues. Although concentrations in neonatal tissue were found to be 5 to 28 times higher than the corresponding concentrations in neonatal serum, the concentrations in neonatal tissue were still 11 to 16 times lower than those found in the mothers. However, no spiramycin was found in the fetal brains. Early treatment with spiramycin may prevent transmission of infection to the fetus but most probably cannot interrupt an existing brain infection, which is the most severe outcome of congenital toxoplasmosis in humans. Images PMID:7811000
Strohbusch, M; Müller, N; Hemphill, A; Krebber, R; Greif, G; Gottstein, B
C57BL/6 mice were infected with Neospora caninum tachyzoites during pregnancy, yielding a transplacental infection of developing fetuses. Subsequently, congenitally infected newborn mice were treated either once or three times with toltrazuril (or placebo) at a concentration of 31.25 mg compound per kg body weight. Both toltrazuril and placebo treatment had no negative effect on newborns, as noninfected treated pups developed normally without differences in mortality and morbidity to matching nontreated control animals. Already one application of toltrazuril was significantly (p < 0.01) able to delay the outbreak of neosporosis in newborn mice, when compared to placebo-treated infected controls. We found significantly higher proportion of surviving newborns in one-time-toltrazuril-treated and three-time-toltrazuril-treated groups (34% and 54%, respectively) when compared to one-time-placebo-treated and three-time-placebo-treated groups (14% and 30%, respectively). There was no significant difference (p = 0.2) in the proportion of surviving pups between one-time-toltrazuril and three-time-toltrazuril treatment. However, the number of diseased and Neospora-positive pups (46% and 47%, respectively) was markedly reduced after three-time-toltrazuril treatment compared to all other groups. Three-time-treatment also resulted in the highest antibody (IgG, IgG2a) response. Pharmacokinetic analyses using individual serum samples revealed that, although toltrazuril was absorbed and metabolized to toltrazuril sulfone by newborn mice, medicated animals exhibited an unexpected rapid turn-over (half-life time) of the compound. Toltrazuril and the metabolite were also found in brain tissues, indicating that passage of the blood-brain barrier occurred. In conclusion, we could show that three times treatment with toltrazuril had a high impact on the course of infection in congenitally N. caninum-infected newborn mice.
Parsonson, I M; Della-Porta, A J; Snowdon, W A
Akabane virus (a Bunyavirus) has been associated with epizootics of congenital deformities in cattle, sheep, and goats. Experimental studies using mouse-adapted virus inoculated intravenously into pregnant sheep gave an inapparent infection. Neutralizing antibodies were detected on day 5, and peaks in the titer were seen at days 10 and 48. Ewes infected at day 30 to 36 of pregnancy produced five (31% incidence) deformed lambs. Sera from four of these possessed neutralizing antibodies to Akabane virus before ingesting colostrum. Two lambs had arthrogryposis, hydranencephaly, kyphosis, scoliosis, and brachygnathia; one had micrencephaly; and the other two had porencephaly. The two lambs with arthrogryposis and hydranencephaly also had extensive lesions in other tissues. In the spinal cord there was a marked decrease in the number of ventral horn neurones and a depletion of myelin. Skeletal muscles showed marked atrophy. The medulla of the thymus possessed large Hassall's corpuscles and a reduced number of thymocytes in the cortex. It would appear that the pathogenic effects of Akabane virus are related to the gestational age (30 to 36 days) at which the fetus is infected. Akabane virus can now be included in the growing list of teratogenic viruses and provides an interesting system for studying such congenital diseases.
Yoser, S L; Forster, D J; Rao, N A
Viruses are one of the most common causes of infections involving the posterior segment of the eye. Such infections can occur either on a congenital or an acquired basis, and may affect primarily the retina or the choroid. Congenital cytomegalovirus (CMV) and rubella infections may result in retinitis. CMV retinitis is also the most common cause of acquired viral retinitis, primarily because of the acquired immunodeficiency syndrome (AIDS). Other types of viral retinitis, such as those caused by herpes simplex or herpes zoster, can occur in immunocompromised or immunocompetent individuals. Retinitis or choroiditis caused by viruses such as measles, influenza, Epstein-Barr virus, and Rift Valley fever virus, typically occurs subsequent to an acute viral systemic illness. The systemic and ocular manifestations, as well as the histopathology, laboratory tests, differential diagnoses, and treatment regimens for each of the individual viruses are discussed in detail.
Cytomegalovirus (CMV) is a virus found around the world. It is related to the viruses that cause chickenpox and infectious mononucleosis (mono). Between 50 percent ... in the United States have had a CMV infection by age 40. Once CMV is in a ...
Depatie, C.; Muise, E.; Gros, P.
The mouse chromosome 6 locus Cmv1 controls replication of mouse Cytomegalovirus (MCMV) in the spleen of the infected host. In our effort to clone Cmv1, we have constructed a high-resolution genetic linkage map in the proximity of the gene. For this, a total of 45 DNA markers corresponding to either cloned genes or microsatellites were mapped within a 7.9-cM interval overlapping the Cmv1 region. We have followed the cosegregation of these markers with respect to Cmv1 in a total of 2248 backcross mice from a preexisting interspecific backcross panel of 281 (Mus spretus X C57BL/6J)F1 X C57BL/6J and 2 novel panels of 989 (A/J X C57BL6)F1 X A/J and 978 (BALB/c X C57BL/6J)F1 X BALB/c segregating Cmv1. Combined pedigree analysis allowed us to determine the following gene order and intergene distances (in cM) on the distal region of mouse chromosome 6: D6Mit216-(1.9)-D6Mit336-(2.2)-D6Mit218-(1.0)-D6Mit52-(0.5)-D6Mit194-(0.2)-Nkrp1/D6Mit61/135/257/289/338-(0.4)-Cmv1/Ly49A/D6Mit370-(0.3)-Prp/Kap/D6Mit13/111/219-(0.3)-Tel/D6Mit374/290/220/196/195/110-(1.1)-D6Mit25. Therefore, the minimal genetic interval for Cmv1 of 0.7 cM is defined by 13 tightly linked markers including 2 markers, Ly49A and D6Mit370, that did not show recombination with Cmv1 in 1967 meioses analyzed; the proximal limit of the Cmv1 domain was defined by 8 crossovers between Nkrp1/D6Mit61/135/257/289/338 and Cmv1/Ly49A/D6Mit370, and the distal limit was defined by 5 crossovers between Cmv1/Ly49A/D6Mit370 and Prp/Kap/D6Mit13/111/219. This work demonstrates tight linkage between Cmv1 and genes from the natural killer complex (NKC), such as Nkrp1 and Ly49A suggesting that Cmv1 may represent an NK cell recognition structure encoded in the NKC region. 54 refs., 4 figs., 2 tabs.
Guiu-Aragonés, Cèlia; Sánchez-Pina, María Amelia; Díaz-Pendón, Juan Antonio; Peña, Eduardo J; Heinlein, Manfred; Martín-Hernández, Ana Montserrat
Cucumber mosaic virus (CMV) has the broadest host range among plant viruses, causing enormous losses in agriculture. In melon, strains of subgroup II are unable to establish a systemic infection in the near-isogenic line SC12-1-99, which carries the recessive resistance gene cmv1 from the accession PI 161375, cultivar 'Songwhan Charmi'. Strains of subgroup I overcome cmv1 resistance in a manner dependent on the movement protein. We characterized the resistance conferred by cmv1 and established that CMV-LS (subgroup II) can move from cell to cell up to the veins in the inoculated leaf, but cannot enter the phloem. Immunogold labelling at transmission electron microscopy level showed that CMV-LS remains restricted to the bundle sheath (BS) cells in the resistant line, and does not invade vascular parenchyma or intermediary cells, whereas, in the susceptible line 'Piel de Sapo' (PS), the virus invades all vein cell types. These observations indicate that the resistant allele of cmv1 restricts systemic infection in a virus strain- and cell type-specific manner by acting as an important gatekeeper for virus progression from BS cells to phloem cells. Graft inoculation experiments showed that CMV-LS cannot move from the infected PS stock into the resistant cmv1 scion, thus suggesting an additional role for cmv1 related to CMV transport within or exit from the phloem. The characterization of this new form of recessive resistance, based on a restriction of virus systemic movement, opens up the possibility to design alternative approaches for breeding strategies in melon. © 2015 The Authors. Molecular Plant Pathology published by British Society for Plant Pathology and John Wiley & Sons Ltd.
Çelikel, Elif; Tezer, Hasan; Kanik-Yuksek, Saliha; Gülhan, Belgin; Ozkaya-Parlakay, Aslinur; Yaralı, Neşe
This study aims to analyze and evaluate the clinic and demographic features of immunocompetent children that have been diagnosed with cytomegalovirus (CMV) infection. The data of children diagnosed with CMV infection between January 2005 and December 2010 and their follow-ups for 2 years were retrospectively evaluated. Ninety-eight patients were included, and the median age at admission was 5.6 months (5 days-36 months). 54.1% was male. The diagnosis of CMV infection was performed by measurement of serum anti-CMV specific Ig M and IgG titers and PCR method in blood and/or urine. In 3.06% of the patients, congenital infection was detected, whereas possible congenital infection was observed in 36.7% of the patients. Furthermore, 44 patients (44.8%) were detected to have perinatal infection while postnatal infection was spotted in 15.3% of the patients. The common presenting manifestations were prolonged jaundice, diarrhea, vomiting, abdominal distension, skin eruption, and seizure. And the most common physical examination findings were hepatosplenomegaly, microcephaly, jaundice, and petechia. The mainstream laboratory results were elevated transaminases (50%), anemia (30.6%), leukocytosis (27.5%), and thrombocytopenia (18.3%). There were intracranial calcification in 5.1% and eye findings in 5.1%. On follow-up of patients, complete improvement (59.1%), neuromotor developmental delay (11.2%), epilepsy (10.2%), hearing loss (3.06 %), hemolytic anemia (2.04%), and growth retardation (1.02%) were detected. CMV infection is a significant disease both in congenital and perinatal period. It must be considered that diagnosed patients need to be monitored for a long time with special attention to their neurodevelopmental follow-ups.
Congenital lues; Fetal syphilis ... which is passed from mother to child during fetal development or at birth. Nearly half of all ... Saunders; 2014:chap 143. Duff P. Maternal and fetal infections. In: Creasy RK, Resnik R, Iams JD, ...
Koedood, M; Fichtel, A; Meier, P; Mitchell, P J
Congenital human cytomegalovirus (HCMV) infection is a common cause of deafness and neurological disabilities. Many aspects of this prenatal infection, including which cell types are infected and how infection proceeds, are poorly understood. Transcription of HCMV immediate-early (IE) genes is required for expression of all other HCMV genes and is dependent on host cell transcription factors. Cell type-specific differences in levels of IE transcription are believed to underlie differences in infection permissivity. However, DNA transfection experiments have paradoxically suggested that the HCMV major IE enhancer/promoter is a broadly active transcriptional element with little cell type specificity. In contrast, we show here that expression of a lacZ gene driven by the HCMV major IE enhancer/promoter -524 to +13 segment is restricted in transgenic mouse embryos to sites that correlate with known sites of congenital HCMV infection in human fetuses. This finding suggests that the IE enhancer/promoter is a major determinant of HCMV infection sites in humans and that transcription factors responsible for its regulation are cell type-specifically conserved between humans and mice. The lacZ expression patterns of these transgenic embryos yield insight into congenital HCMV pathogenesis by providing a spatiotemporal map of the sets of vascular, neural, and epithelial cells that are likely targets of infection. These transgenic mice may constitute a useful model system for investigating IE enhancer/promoter regulation in vivo and for identifying factors that modulate active and latent HCMV infections in humans. PMID:7884867
Nigro, Giovanni; Adler, Stuart P; Parruti, Giustino; Anceschi, Maurizio M; Coclite, Eleonora; Pezone, Ilaria; Di Renzo, Gian Carlo
Primary cytomegalovirus (CMV) infection early in gestation causes severe disease. Case patients were 32 congenitally infected children aged 1-5 years who had either hearing deficit and/or psychomotor retardation and whose mothers had a confirmed or probable primary CMV infection at ≤ 20 weeks' gestation. Control subjects were 32 congenitally infected normal children whose mothers had a confirmed primary infection at ≤ 20 weeks' gestation. Case patients and control subjects were matched by the weeks of maternal gestation (± 1 week) at the mother's infection and by the child's age (± 1 year) at evaluation. For the case patients and control subjects, the mean age was 3.0 years. The mean number of weeks of gestation at maternal infection was 11 weeks. The only risk factor for an affected child was the mother not receiving immunoglobulin (P = .001). Of the 32 case patients, only 4 mothers received CMV immunoglobulin, compared with 27 of the 32 mothers of control infants (adjusted odds ratio, 14 [95% confidence interval, 1.7-110]). The rate of both psychomotor retardation and hearing deficit decreased with immunoglobulin. These results support the efficacy of immunoglobulins for decreasing the severity of disabilities caused by fetal CMV infection after a primary maternal infection during pregnancy.
Faria, Paula Foresti; Nicolau, Juliana Augusta Zeglin; Melek, Marina Zaponi; de Oliveira, Nanci de Santa Palmieri; Bermudez, Beatriz Elizabeth Bagatin Veleda; Nisihara, Renato Mitsunori
There is a high prevalence of congenital heart disease (CHD) in Down syndrome (DS) patients. Children with DS and CHD also present greater susceptibility to pulmonary infections than those without CHD. To investigate the prevalence and types of CHD and their association with severe infections in children with DS in southern Brazil seen in a reference outpatient clinic. Children aged between six and 48 months with a diagnosis of DS were included consecutively in the period May 2001 to May 2012, and the presence of CHD and severe infections (pneumonia and sepsis) was investigated, classified and analyzed. A total of 127 patients were included, of whom 89 (70.1%) had some type of CHD, 33 (37.7%) of them requiring surgical correction. Severe infections (pneumonia and sepsis) were seen in 23.6% and 5.5%, respectively. Of the cases of pneumonia, 70% had associated CHD (p=0.001) and of those with sepsis, 85% presented CHD (p=0.001). Our study showed a high prevalence of CHD and its association with severe infections in children with DS seen in southern Brazil. Copyright © 2013 Sociedade Portuguesa de Cardiologia. Published by Elsevier España. All rights reserved.
Aronoff, David M; Correa, Hernan; Rogers, Lisa M; Arav-Boger, Ravit; Alcendor, Donald J
Placental pericytes are essential for placental microvascular function, stability, and integrity. Mechanisms of human cytomegalovirus (HCMV) pathogenesis incorporating placental pericytes are unknown. HCMV-infected placental tissue was stained by dual-labeled immunohistochemistry. Primary placental pericytes, cytotrophoblasts, and villous fibroblasts were exposed to HCMV; and infectivity was analyzed by microscopy and immunofluorescence. Cytokine expression was examined by Luminex assay. A HCMV-GFP recombinant virus was used to examine replication kinetics. Immunohistochemistry showed HCMV in trophoblast and the villous core with T-cell and macrophage infiltration. Primary HCMV isolate from a patient (SBCMV)- infected pericytes showed dysregulation of proinflammatory and angiogenic cytokines when compared to control cells. A tri-cell model of the villous floor showed a unique expression profile. Finally, we show pericytes infected in vivo with HCMV in placental tissue from a congenitally infected child. Placental pericytes support HCMV replication, inducing proinflammatory and angiogenic cytokines that likely contribute to viral dissemination, placenta inflammation, and dysregulation of placental angiogenesis. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.
Ostermann, Eleonore; Macquin, Cécile; Krezel, Wojciech; Bahram, Seiamak; Georgel, Philippe
Among Herpesviruses, Human Cytomegalovirus (HCMV or HHV-5) represents a major threat during congenital or neonatal infections, which may lead to encephalitis with serious neurological consequences. However, as opposed to other less prevalent pathogens, the mechanisms and genetic susceptibility factors for CMV encephalitis are poorly understood. This lack of information considerably reduces the prognostic and/or therapeutic possibilities. To easily monitor the effects of genetic defects on brain dissemination following CMV infection we used a recently developed in vivo mouse model based on the neonatal inoculation of a MCMV genetically engineered to express Luciferase. Here, we further validate this protocol for live imaging, and demonstrate increased lethality associated with viral infection and encephalitis in mutant mice lacking Dicer activity. Our data indicate that miRNAs are important players in the control of MCMV pathogenesis and suggest that miRNA-based endothelial functions and integrity are crucial for CMV encephalitis. PMID:25955106
Martínez-Contreras, Angélica; Lira, Rosalía; Soria-Rodríguez, Carmen; Hori-Oshima, Sawako; Maldonado-Rodríguez, Angélica; Rojas-Montes, Othón; Ayala-Figueroa, Rafael; Estrada-Guzmán, Julia; Álvarez-Muñoz, Ma Teresa
Introducción: el síndrome de dificultad respiratoria (SDR) es una enfermedad común multifactorial que varía del 15 al 50 % en el recién nacido (RN), y la mortalidad es de 50 %. Puede estar asociado a infecciones bacterianas y virales, una de las más frecuentes: el citomegalovirus (CMV). En el periodo neonatal la incidencia de infección por CMV es de 0.4 a 2.5 % y la seroprevalencia de 50 a 75 %; se desconoce la incidencia de infección en los RN. El objetivo fue determinar la frecuencia de infección por CMV en recién nacidos con SDR e identificar factores de riesgo asociados a infección. Métodos: el DNA-CMV fue identificado en plasma por reacción en cadena de la polimerasa (PCR) cuantitativa, y las variables maternas y neonatales que definieron el cuadro clínico fueron analizadas por regresión logística. Resultados: la frecuencia de infección por CMV en 197 RN con SDR fue de 8.6 % (IC 95 % 4.7-12.5). Las variables significativas en los RN fueron: neutropenia (p = 0.012), trombocitopenia (p = 0.021), piel marmórea (p = 0.03) y la variable materna significativa fue cervicovaginitis (p = 0.05). Conclusiones: se reporta por primera vez la frecuencia más alta de infección por CMV en RN con SDR y la asociación de varios factores de riesgo con la infección por CMV.
Fontaine, Magali J; Jurado, Christine; Miller, Evelyn; Viele, Maurene; Goodnough, Lawrence T
Our goal is to minimize unnecessary cytomegalovirus (CMV)-seronegative blood transfusion to preserve the CMV-seronegative blood inventory for patients who are identified as CMV seronegative. We implemented a CMV antibody reflex testing protocol for patients who require CMV-compatible blood but in whom a CMV serostatus is unknown (coded as CMVT in our computer system). A solid-phase red blood cell (RBC) adherence antibody detection system was validated to detect CMV antibodies in plasma samples (received for ABO/Rh type and RBC antibody screen) with acceptable sensitivity and specificity. We evaluated the impact of this CMV antibody reflex testing on the management of RBC and platelet (PLT) inventory for patients requiring CMV-compatible blood. Over a 16-month period, implementation of CMV antibody reflex testing identified 361 (34%) of 1063 previously CMV-untested patients who required CMV-compatible blood and who were CMV seronegative. We observed a 75% decrease in the number of CMVT patients in our data base from 190 per month before implementation to 57 at 16 months postimplementation. Consequently we reevaluated the percentage in our blood inventory of CMV-seronegative units required while potentially saving 1234 CMV-seronegative blood products (835 RBCs and 399 PLTs) each month. A strategy of performing CMV antibody reflex testing in the transfusion service allows more effective blood inventory management and control in maintaining a CMV-seronegative blood inventory dedicated for patients who truly require it. © 2010 American Association of Blood Banks.
Davalos, Fidencio; Chaucer, Benjamin; Zafar, Wahib; Salman, Shamim; Nfonoyim, Jay
Dasatinib is a common anticancer drug used in the treatment of leukemia. Several side effects have been reported, the most common being myelosuppression, diarrhea, edema, and nausea. Three papers have been published reporting hepatic side effects of dasatinib treatment. A rare side effect of dasatinib treatment is reactivation of latent cytomegalovirus (CMV) infection. Never before has dasatinib therapy shown to be the cause of CMV hepatitis in an immunocompetent patient. We present a case of an immunocompetent patient who was treated with the standard dose of dasatinib therapy and subsequently developed CMV hepatitis. Well-known side effects of dasatinib therapy are understood and documented; unknown adverse drug reactions can occur and should be monitored for. This is a significant finding given the high rate of CMV seropositivity in the general population.
Maine, Gregory T; Stricker, René; Stricker, Reto
Retrospective evaluation of the kinetics of cytomegalovirus (CMV) seroconversion with CMV IgM, IgG, and IgG avidity assays, in a Swiss pregnant women population, has shown that the current published CMV serologic diagnostic algorithms were valid and fit for use. In 19% of the cases analyzed, CMV-specific IgM was detected before IgG.
Abana, Chike O; Pilkinton, Mark A; Gaudieri, Silvana; Chopra, Abha; McDonnell, Wyatt J; Wanjalla, Celestine; Barnett, Louise; Gangula, Rama; Hager, Cindy; Jung, Dae K; Engelhardt, Brian G; Jagasia, Madan H; Klenerman, Paul; Phillips, Elizabeth J; Koelle, David M; Kalams, Spyros A; Mallal, Simon A
Select CMV epitopes drive life-long CD8(+) T cell memory inflation, but the extent of CD4 memory inflation is poorly studied. CD4(+) T cells specific for human CMV (HCMV) are elevated in HIV(+) HCMV(+) subjects. To determine whether HCMV epitope-specific CD4(+) T cell memory inflation occurs during HIV infection, we used HLA-DR7 (DRB1*07:01) tetramers loaded with the glycoprotein B DYSNTHSTRYV (DYS) epitope to characterize circulating CD4(+) T cells in coinfected HLA-DR7(+) long-term nonprogressor HIV subjects with undetectable HCMV plasma viremia. DYS-specific CD4(+) T cells were inflated among these HIV(+) subjects compared with those from an HIV(-) HCMV(+) HLA-DR7(+) cohort or with HLA-DR7-restricted CD4(+) T cells from the HIV-coinfected cohort that were specific for epitopes of HCMV phosphoprotein-65, tetanus toxoid precursor, EBV nuclear Ag 2, or HIV gag protein. Inflated DYS-specific CD4(+) T cells consisted of effector memory or effector memory-RA(+) subsets with restricted TCRβ usage and nearly monoclonal CDR3 containing novel conserved amino acids. Expression of this near-monoclonal TCR in a Jurkat cell-transfection system validated fine DYS specificity. Inflated cells were polyfunctional, not senescent, and displayed high ex vivo levels of granzyme B, CX3CR1, CD38, or HLA-DR but less often coexpressed CD38(+) and HLA-DR(+) The inflation mechanism did not involve apoptosis suppression, increased proliferation, or HIV gag cross-reactivity. Instead, the findings suggest that intermittent or chronic expression of epitopes, such as DYS, drive inflation of activated CD4(+) T cells that home to endothelial cells and have the potential to mediate cytotoxicity and vascular disease. Copyright © 2017 by The American Association of Immunologists, Inc.
Woodward, Cathy S; Son, Minnette; Calhoon, John; Michalek, Joel; Husain, S Adil
Guidelines exist for prevention of sternal wound infections (SWI) in adults. There are no guidelines for pediatric patients and limited reports on SWI incidence. The purpose of this study was to determine the incidence of, and preventative practice regarding pediatric SWIs with a long-term aim to develop best practice guidelines. Eighty-nine congenital heart programs were sent a 31 question on-line survey regarding pediatric SWI. Thirty eight (43%) of the 89 programs responded. They reported 8,774 pediatric congenital procedures with a mean SWI rate of 1.53% (range, 0 to 9.09). Mean yearly volume was 237 operations (range, 50 to 720). Neither program size nor delayed sternal closure was associated with increased incidence of SWI. Variations in preoperative measures, antibiotic regimens, and wound care did not statistically impact incidence of SWI. Programs with protocols to monitor and control blood glucose levels postoperatively had statistically lower infection rates (1.04 vs 2.35, p = 0.03), and those that sent mediastinal cultures at time of delayed sternal closure reported lower infection rates (1.34 vs 1.74, p = 0.051). This report provides a multiinstitutional SWI incidence from pediatric programs of 1.53%. Despite variations in clinical practice between programs, this survey revealed two strategies resulting in reduced SWIs; protocol-based management of glucose levels and mediastinal wound cultures sent at time of closure. Pediatric programs do not consistently follow adult preventative guidelines. Multicenter randomized research is needed to formulate preventative guidelines to reduce the incidence of pediatric SWI. Copyright © 2011 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.
Streja, Elani; Miller, Jessica E.; Bech, Bodil H.; Greene, Naomi; Pedersen, Lars Henning; Yeargin-Allsopp, Marshalyn; Van Naarden Braun, Kim; Schendel, Diana E.; Christensen, Deborah; Uldall, Peter; Olsen, Jørn
OBJECTIVE The objective of the study was to investigate the association between maternal self-reported infections, fever, and smoking in the prenatal period and the subsequent risk for congenital cerebral palsy (CP). STUDY DESIGN We included the 81,066 mothers of singletons born between 1996 and 2003 who participated in the Danish National Birth Cohort. Children were followed up through December 2008. Information on maternal infections, fever, smoking, and other demographic and lifestyle factors during pregnancy were reported by mothers in computer-assisted telephone interviews in early and midgestation. We identified 139 CP cases including 121 cases of spastic CP (sCP) as confirmed by the Danish National Cerebral Palsy Register. Cox proportional hazards regression models were used to estimate adjusted hazard ratios (aHRs) and 95% confidence intervals (CIs). RESULTS Self-reported vaginal infections were associated with an increased risk of CP and sCP (aHR, 1.52; 95% CI, 1.04–2.24; and aHR, 1.73; 95% CI, 1.16–2.60, respectively) and particularly untreated vaginal infections were associated with an increased risk of sCP (aHR, 1.95; 95% CI, 1.16–3.26). Fever was associated with the risk of CP (aHR, 1.53; 95% CI, 1.06–2.21). Smoking 10 or more cigarettes per day during pregnancy was also associated with sCP (aHR, 1.80; 95% CI, 1.10–2.94). There was a modest excess in risk for children exposed to both heavy smoking and vaginal infections. No other self-reported infections were significantly associated with CP. CONCLUSION Self-reported vaginal infections, fever, and smoking 10 or more cigarettes per day during pregnancy were associated with a higher risk of overall CP and/or sCP. PMID:23791566
Pokalyuk, Cornelia; Renzette, Nicholas; Irwin, Kristen K; Pfeifer, Susanne P; Gibson, Laura; Britt, William J; Yamamoto, Aparecida Y; Mussi-Pinhata, Marisa M; Kowalik, Timothy F; Jensen, Jeffrey D
Given the strong selective pressures often faced by populations when colonizing a novel habitat, the level of variation present on which selection may act is an important indicator of adaptive potential. While often discussed in an ecological context, this notion is also highly relevant in our clinical understanding of viral infection, in which the novel habitat is a new host. Thus, quantifying the factors determining levels of variation is of considerable importance for the design of improved treatment strategies. Here, we focus on such a quantification of human cytomegalovirus (HCMV) - a virus which can be transmitted across the placenta, resulting in foetal infection that can potentially cause severe disease in multiple organs. Recent studies using genomewide sequencing data have demonstrated that viral populations in some congenitally infected infants diverge rapidly over time and between tissue compartments within individuals, while in other infants, the populations remain highly stable. Here, we investigate the underlying causes of these extreme differences in observed intrahost levels of variation by estimating the underlying demographic histories of infection. Importantly, reinfection (i.e. population admixture) appears to be an important, and previously unappreciated, player. We highlight illustrative examples likely to represent a single-population transmission from a mother during pregnancy and multiple-population transmissions during pregnancy and after birth.
Lee, Brian; Jeelani, Yasser; McComb, J Gordon
Congenital dermal sinuses (CDS) are epithelium-lined tracts that result from incomplete separation of cutaneous ectoderm from the underlying neuroectoderm. CDS may be associated with dermoid cysts and can cause complications by mass effect and by functioning as a pathway for infection. Cervical and thoracic tracts are rare, making up 1 and 10% of all CDS, respectively. We present an unusual case of a cervico-thoracic CDS with concomitant infected dermoid leading to neurological dysfunction. A 1-year-old male with a normal developmental history presented with a several-week history of progressive weakness. Previous visits to two outside emergency departments diagnosed the patient with acute otitis media. After another episode of fever and worsening of neurological symptoms, the patient was correctly diagnosed as having CDS with an infected dermoid cyst. Antibiotics were initiated, the lesion was resected, and the patient improved neurologically. Although cervical and thoracic CDS with infected dermoids are rare, one should have a high index of suspicion when cutaneous stigmata of spinal dysraphism are identified. Due to the risk of neurological deterioration, the recommended treatment of CDS with or without a concomitant intraspinal dermoid is prompt administration of antibiotics and definitive surgical intervention.
Morton, S; Peniket, A; Malladi, R; Murphy, M F
To identify current UK practice with regards to provision of blood components for cytomegalovirus (CMV)-seronegative, potential, allogeneic stem cell recipients of seronegative grafts. Infection with CMV remains a major cause of morbidity and mortality after allogeneic stem cell transplantation (aSCT). CMV transmission has been a risk associated with the transfusion of blood components from previously exposed donors, but leucocyte reduction has been demonstrated to minimise this risk. In 2012, the UK Advisory Committee for the Safety of Tissues and Organs (SaBTO) recommended that CMV-unselected components could be safely transfused without increased risk of CMV transmission. We surveyed UK aSCT centres to establish current practice. Fifteen adult and seven paediatric centres (75%) responded; 22·7% continue to provide components from CMV-seronegative donors. Reasons cited include the continued perceived risk of CMV transmission by blood transfusion, its associated morbidity and concerns regarding potential for ambiguous CMV serostatus in seronegative potential transplant recipients due to passive antibody transfer from CMV-seropositive blood donors, leading to erroneous donor/recipient CMV matching at transplant. The survey demonstrated a surprisingly high rate (22.7%) of centres continuing to provide blood components from CMV-seronegative donors despite SaBTO guidance. © 2017 British Blood Transfusion Society.
Lomtadze, M; Chkhaidze, M; Mgeladze, E; Metreveli, I; Tsintsadze, A
Nosocomial infections still remain a serious problem in patients undergoing open heart surgery. The aim of the study was to determine the incidence, etiology and main risk factors of nosocomial infections (NI) following cardiac surgery in congenital heart diseases population. Retrospective case study was conducted. 387 patients with congenital heart disease (CHD), who underwent cardiac surgery from January 2007 to December 2008 were studied. The age of the most patients varied between 1 day to 15 years, 73 patients (18,8%) were older than 15 years. All 387 patients underwent cardiac surgery. The rate of NI was 16%. The most common infections were bloodstream infections (BSI) (7,75%) and respiratory tract infections (7%) respectively. The rate of NI was higher in patients under 1 year of age, after urgent surgery and urgent reoperation, long cardiopulmonary bypass (CPB) and aortic cross-clamp time, also in patients with prolonged mechanical ventilation, massive haemotransfusion, with open heart bone after surgery, reintubation, hospitalization in another hospital during last three month. It was concluded that the most common nosocomial infection after cardiac surgery congenital heart diseases in Georgian population was blood stream infection. The main risk factors of NI in the same setting were age under 1 year, urgent surgery, urgent reoperation, long CPB and aortic cross-clamp time, long duration of mechanical ventilation, massive haemotransfusion, open heart bone after surgery, reintubation, hospitalization in another hospital during last three month.
Ito, A; Kamiyama, T
The innate resistance of the unnatural rat host to the mouse tapeworm Hymenolepis nana is cortisone sensitive but thymus independent. When congenitally athymic nude rats were orally given eggs, cysticercoids, or adult worms of H. nana, no lumenal adults were established except when they were treated with cortisone acetate during the expected lumenal development. The effect of cortisone to promote adult maturation in the rats was compared in nude and normal rats given eggs of H. nana. The fecundity of the worms (assessed by the fresh worm biomass and the number of infective eggs produced) was much higher in cortisone-treated nude rats than in cortisone-treated normal rats. When the nude rats reconstituted with thymocytes were given eggs and treated with cortisone, the fecundity of H. nana dropped to the same level as in cortisone-treated normal rats. It is strongly suggested that the unnatural rat host has thymus-independent cortisone sensitive resistance to an initial infection (which is the main component of the innate resistance and blocks the lumenal establishment of this parasite) and thymus-dependent resistance (which suppresses the established worms' fecundity and may be ascribed to acquired resistance to the ongoing infection).
Girard, Céline; Guillot, Bernard; Biron, Christine; Lavabre-Bertrand, Thierry; Navarro, Robert; Bessis, Didier
Congenital afibrinogenaemia is a rare genetic disorder transmitted as an autosomal recessive trait and characterized by the complete absence of fibrinogen in the plasma. We report a 41-year-old woman who suffered from congenital afibrinogenaemia and hepatitis C viral infection and presented with ischaemic necrosis and livedo of the toes. Laboratory investigations showed the presence of mixed cryoglobulinaemia and anticardiolipin antibodies. Resolution occurred with plasmapheresis. We discuss the pathophysiology of this unusual condition and review the literature for skin manifestations associated with this rare haemostasis disorder.
Chimelli, Leila; Melo, Adriana S O; Avvad-Portari, Elyzabeth; Wiley, Clayton A; Camacho, Aline H S; Lopes, Vania S; Machado, Heloisa N; Andrade, Cecilia V; Dock, Dione C A; Moreira, Maria Elisabeth; Tovar-Moll, Fernanda; Oliveira-Szejnfeld, Patricia S; Carvalho, Angela C G; Ugarte, Odile N; Batista, Alba G M; Amorim, Melania M R; Melo, Fabiana O; Ferreira, Thales A; Marinho, Jacqueline R L; Azevedo, Girlene S; Leal, Jeime I B F; da Costa, Rodrigo F Madeiro; Rehen, Stevens; Arruda, Monica B; Brindeiro, Rodrigo M; Delvechio, Rodrigo; Aguiar, Renato S; Tanuri, Amilcar
A major concern associated with ZIKV infection is the increased incidence of microcephaly with frequent calcifications in infants born from infected mothers. To date, postmortem analysis of the central nervous system (CNS) in congenital infection is limited to individual reports or small series. We report a comprehensive neuropathological study in ten newborn babies infected with ZIKV during pregnancy, including the spinal cords and dorsal root ganglia (DRG), and also muscle, pituitaries, eye, systemic organs, and placentas. Using in situ hybridization (ISH) and electron microscopy, we investigated the role of direct viral infection in the pathogenesis of the lesions. Nine women had Zika symptoms between the 4th and 18th and one in the 28th gestational week. Two babies were born at 32, one at 34 and 36 weeks each and six at term. The cephalic perimeter was reduced in four, and normal or enlarged in six patients, although the brain weights were lower than expected. All had arthrogryposis, except the patient infected at 28 weeks gestation. We defined three patterns of CNS lesions, with different patterns of destructive, calcification, hypoplasia, and migration disturbances. Ventriculomegaly was severe in the first pattern due to midbrain damage with aqueduct stenosis/distortion. The second pattern had small brains and mild/moderate (ex-vacuo) ventriculomegaly. The third pattern, a well-formed brain with mild calcification, coincided with late infection. The absence of descending fibres resulted in hypoplastic basis pontis, pyramids, and cortico-spinal tracts. Spinal motor cell loss explained the intrauterine akinesia, arthrogryposis, and neurogenic muscle atrophy. DRG, dorsal nerve roots, and columns were normal. Lympho-histiocytic inflammation was mild. ISH showed meningeal, germinal matrix, and neocortical infection, consistent with neural progenitors death leading to proliferation and migration disorders. A secondary ischemic process may explain the
Naoumov, N V; Alexander, G J; O'Grady, J G; Sutherland, S; Aldis, P; Portmann, B C; Williams, R
Cytomegalovirus (CMV) is a major cause of hepatic dysfunction after liver transplantation, but proof of infection and distinguishing CMV hepatitis from other causes of impaired liver function can be difficult. In-situ hybridisation for CMV-DNA in liver biopsy specimens was assessed in 25 liver graft recipients in whom CMV was suspected on clinical grounds. CMV-DNA was detected in all 10 patients with primary CMV infection, in whom a close correlation was found between the number of CMV-DNA-positive cells and both the number of cells containing viral inclusions identified by light microscopy and the clinical severity of disease. In contrast, CMV-DNA was not detected in patients with secondary CMV infection, or in those without evidence of CMV infection. In-situ hybridisation for CMV-DNA provides an accurate and rapid diagnosis of CMV infection, and allows specific antiviral therapy to be used earlier.
Rendell, Victoria R; Gilman, Robert H; Valencia, Edward; Galdos-Cardenas, Gerson; Verastegui, Manuela; Sanchez, Leny; Acosta, Janet; Sanchez, Gerardo; Ferrufino, Lisbeth; LaFuente, Carlos; Abastoflor, Maria del Carmen; Colanzi, Rony; Bern, Caryn
Congenital transmission is a major source of new Trypanosoma cruzi infections, and as vector and blood bank control continue to improve, the proportion due to congenital infection will grow. A major unanswered question is why reported transmission rates from T. cruzi-infected mothers vary so widely among study populations. Women with high parasite loads during pregnancy are more likely to transmit to their infants, but the factors that govern maternal parasite load are largely unknown. Better understanding of these factors could enable prioritization of screening programs to target women most at risk of transmission to their infants. We screened pregnant women presenting for delivery in a large urban hospital in Bolivia and followed infants of infected women for congenital Chagas disease. Of 596 women screened, 128 (21.5%) had confirmed T. cruzi infection; transmission occurred from 15 (11.7%) infected women to their infants. Parasite loads were significantly higher among women who transmitted compared to those who did not. Congenital transmission occurred from 31.3% (9/29), 15.4% (4/26) and 0% (0/62) of women with high, moderate and low parasite load, respectively (χx2 for trend 18.2; p<0.0001). Twin births were associated with higher transmission risk and higher maternal parasite loads. Infected women without reported vector exposure had significantly higher parasite loads than those who had lived in an infested house (median 26.4 vs 0 parasites/mL; p<0.001) with an inverse relationship between years of living in an infested house and parasite load. We hypothesize that sustained vector-borne parasite exposure and repeated superinfection by T. cruzi may act as an immune booster, allowing women to maintain effective control of the parasite despite the down-regulation of late pregnancy.
Rendell, Victoria R.; Gilman, Robert H.; Valencia, Edward; Galdos-Cardenas, Gerson; Verastegui, Manuela; Sanchez, Leny; Acosta, Janet; Sanchez, Gerardo; Ferrufino, Lisbeth; LaFuente, Carlos; Abastoflor, Maria del Carmen; Colanzi, Rony; Bern, Caryn
Background Congenital transmission is a major source of new Trypanosoma cruzi infections, and as vector and blood bank control continue to improve, the proportion due to congenital infection will grow. A major unanswered question is why reported transmission rates from T. cruzi-infected mothers vary so widely among study populations. Women with high parasite loads during pregnancy are more likely to transmit to their infants, but the factors that govern maternal parasite load are largely unknown. Better understanding of these factors could enable prioritization of screening programs to target women most at risk of transmission to their infants. Methodology/Principal Findings We screened pregnant women presenting for delivery in a large urban hospital in Bolivia and followed infants of infected women for congenital Chagas disease. Of 596 women screened, 128 (21.5%) had confirmed T. cruzi infection; transmission occurred from 15 (11.7%) infected women to their infants. Parasite loads were significantly higher among women who transmitted compared to those who did not. Congenital transmission occurred from 31.3% (9/29), 15.4% (4/26) and 0% (0/62) of women with high, moderate and low parasite load, respectively (χx2 for trend 18.2; p<0.0001). Twin births were associated with higher transmission risk and higher maternal parasite loads. Infected women without reported vector exposure had significantly higher parasite loads than those who had lived in an infested house (median 26.4 vs 0 parasites/mL; p<0.001) with an inverse relationship between years of living in an infested house and parasite load. Conclusions/Significance We hypothesize that sustained vector-borne parasite exposure and repeated superinfection by T. cruzi may act as an immune booster, allowing women to maintain effective control of the parasite despite the down-regulation of late pregnancy. PMID:25807498
Nguyen, Thong Van; Pham, Van Hung; Abe, Kenji
Development of congenital rubella syndrome associated with rubella virus infection during pregnancy is clinically important, but the pathogenicity of the virus remains unclear. Pathological examination was conducted on 3 aborted fetuses with congenital rubella infection. At autopsy, all 3 aborted fetuses showed congenital cataract confirmed by gross observation. Rubella virus infection occurred via systemic organs including circulating hematopoietic stem cells confirmed by immunohistochemical and molecular investigations, and major histopathogical changes were found in the liver. It is noteworthy that the virus infected the ciliary body of the eye, suggesting a possible cause of cataracts. Our study based on the pathological examination demonstrated that the rubella virus infection occurred via systemic organs of human fetuses. This fact was confirmed by immunohistochemistry and direct detection of viral RNA in multiple organs. To the best of our knowledge, this study is the first report demonstrating that the rubella virus infection occurred via systemic organs of the human body. Importantly, virus infection of the ciliary body could play an important role in cataractogenesis.
Chakravarti, Sujata B; Reformina, Diane A; Lee, Timothy M; Malhotra, Sunil P; Mosca, Ralph S; Bhatla, Puneet
Background: Bacterial infection (BI) after congenital heart surgery (CHS) is associated with increased morbidity and is difficult to differentiate from systemic inflammatory response syndrome caused by cardiopulmonary bypass (CPB). Procalcitonin (PCT) has emerged as a reliable biomarker of BI in various populations. Aim: To determine the optimal PCT threshold to identify BI among children suspected of having infection following CPB. Setting and Design: Single-center retrospective observational study. Materials and Methods: Medical records of all the patients admitted between January 2013 and April 2015 were reviewed. Patients in the age range of 0-21 years of age who underwent CHS requiring CPB in whom PCT was drawn between postoperative days 0-8 due to suspicion of infection were included. Statistical Analysis: The Wilcoxon rank-sum test was used for nonparametric variables. The diagnostic performance of PCT was evaluated using a receiver operating characteristic (ROC) curve. Results: Ninety-eight patients were included. The median age was 2 months (25th and 75th interquartile of 0.1-7.5 months). Eleven patients were included in the BI group. The median PCT for the BI group (3.42 ng/mL, 25th and 75th interquartile of 2.34-5.67) was significantly higher than the median PCT for the noninfected group (0.8 ng/mL, 25th and 75th interquartile 0.38-3.39), P = 0.028. The PCT level that yielded the best compromise between the sensitivity (81.8%) and specificity (66.7%) was 2 ng/mL with an area under the ROC curve of 0.742. Conclusion: A PCT less than 2 ng/mL makes BI unlikely in children suspected of infection after CHS. PMID:27212844
de Paula Freitas, Bruno; de Oliveira Dias, João Rafael; Prazeres, Juliana; Sacramento, Gielson Almeida; Ko, Albert Icksang; Maia, Maurício; Belfort, Rubens
IMPORTANCE The Zika virus (ZIKV) has rapidly reached epidemic proportions, especially in northeastern Brazil, and has rapidly spread to other parts of the Americas. A recent increase in the prevalence of microcephaly in newborn infants and vision-threatening findings in these infants is likely associated with the rapid spread of ZIKV. OBJECTIVE To evaluate the ocular findings in infants with microcephaly associated with presumed intrauterine ZIKV infection in Salvador, Bahia, Brazil. DESIGN, SETTING, AND PARTICIPANTS Case series at a tertiary hospital. Twenty-nine infants with microcephaly (defined by a cephalic circumference of ≤32 cm) with a presumed diagnosis of congenital ZIKV were recruited through an active search and referrals from other hospitals and health unities. The study was conducted between December 1 and December 21, 2015. INTERVENTIONS All infants and mothers underwent systemic and ophthalmic examinations from December 1 through December 21, 2015, in the Roberto Santos General Hospital, Salvador, Brazil. Anterior segment and retinal, choroidal, and optic nerve abnormalities were documented using a wide-field digital imaging system. The differential diagnosis included toxoplasmosis, rubella, cytomegalovirus, herpes simplex virus, syphilis, and human immunodeficiency virus, which were ruled out through serologic and clinical examinations. MAIN OUTCOMES AND MEASURES Ocular abnormalities associated with ZIKV. RESULTS Twenty-three of 29 mothers (79.3%) reported suspected ZIKV infection signs and symptoms during pregnancy, 18 in the first trimester, 4 in the second trimester, and 1 in the third trimester. Of the 29 infants (58 eyes) examined (18 [62.1%] female), ocular abnormalities were present in 17 eyes (29.3%) of 10 children (34.5%). Bilateral findings were found in 7 of 10 patients presenting with ocular lesions, the most common of which were focal pigment mottling of the retina and chorioretinal atrophy in 11 of the 17 eyes with abnormalities (64
Desmonts, G; Couvreur, J; Thulliez, P
Five cases of congenital toxoplasmosis consecutive to a maternal toxoplasma infection that had preceded pregnancy were observed. One woman with normal immune system had developed a well-documented lymph node toxoplasmosis 2 months before conceiving. Four women had chronic toxoplasmosis diagnosed in the course of an immunosuppressive disease: Hodgkin's disease in 1 case, systemic lupus erythematosus in 2 cases and pancytopenia in 1 case. Toxoplasmosis had been recognized 3, 5 and 10 years respectively before conception in 3 women, and at an uncertain date in 1 woman. Three women had received corticosteroids during pregnancy, and 2 had undergone splenectomy. Among the 6 children (2 were twins), 1 presented with severe foetal disease at birth, 1 developed lethal systemic toxoplasmosis after birth, 1 showed hydrocephalus with therapeutically well-controlled chorioretinitis, 1 had isolated eye lesion and 2 had asymptomatic infection. The parasite seems to have been transmitted after the 20th week of pregnancy in all cases. The physiopathology of mother-to child toxoplasma transmission, the role played by maternal immunodeficiency and the practical implications of these exceptional cases are discussed.
Sterkers, Yvon; Pratlong, Francine; Albaba, Sahar; Loubersac, Julie; Picot, Marie-Christine; Pretet, Vanessa; Issert, Eric; Boulot, Pierre
From a prospective cohort of 344 women who seroconverted for toxoplasmosis during pregnancy, 344 amniotic fluid, 264 placenta, and 216 cord blood samples were tested for diagnosis of congenital toxoplasmosis using the same PCR assay. The sensitivity and negative predictive value of the PCR assay using amniotic fluid were 86.3% and 97.2%, respectively, and both specificity and positive predictive value were 100%. Using placenta and cord blood, sensitivities were 79.5% and 21.2%, and specificities were 92% and 100%, respectively. In addition, the calculation of pretest and posttest probabilities and the use of logistic regression allowed us to obtain curves that give a dynamic interpretation of the risk of congenital toxoplasmosis according to gestational age at maternal infection, as represented by the three sample types (amniotic fluid, placenta, and cord blood). Two examples are cited here: for a maternal infection at 25 weeks of amenorrhea, a negative result of prenatal diagnosis allowed estimation of the probability of congenital toxoplasmosis at 5% instead of an a priori (pretest) risk estimate of 33%. For an infection at 10 weeks of amenorrhea associated with a pretest congenital toxoplasmosis risk of 7%, a positive PCR result using placenta at birth yields a risk increase to 43%, while a negative result damps down the risk to 0.02%. Thus, with a molecular diagnosis performing at a high level, and in spite of the persistence of false negatives, posttest risk curves using both negative and positive results prove highly informative, allowing a better assessment of the actual risk of congenital toxoplasmosis and finally an improved decision guide to treatment. PMID:23035201
Mhiri, Leila; Arrouji, Zakia; Slim, Amine; Ben Redjeb, Saida
Human cytomegalovirus (HCMV), a member of the beta-virus herpes family, is a ubiquitous human pathogen. After a primary infection, HCMV establishes life latency. HCMV rarely causes symptomatic disease in an immunocompetent host, however, it is a major cause of infectious morbidity and mortality in immunocompromised individuals and developing fetuses. The HCMV genome consists of 240 kbp of double stranded DNA. Early diagnosis molecular of CMV infection is important. The objective of this study was to develop a molecular methods: Quantitative Hybrid capture for the detection of DNA CMV. We present results for 200 immunocompromised collected from 1999 to 2003 (122 men and 78 women, whom mean age was 35 years). Our results showed that 25% of women and 36% of men were positif for hybrid capture DNA CMV. This simple test (cold probe) provide quantitative and fast results. Also the efficacity of anti-CMV therapy can be followed. More over, in contrary with pp65-antigenemia assay and CMV PCR, this test can be managed on biopsy sample.
Mora, María Celia; Sanchez Negrette, Olga; Marco, Diego; Barrio, Alejandra; Ciaccio, Mirella; Segura, María Asunción; Basombrío, Miguel A
Congenital Trypanosoma cruzi infection is a highly pathogenic and underreported condition. Early recognition is essential for effective treatment. Umbilical chord blood from newborns (n = 302) to infected mothers was analyzed with microhematocrit, hemoculture, and PCR methods. Each subject was then followed serologically. In calibrated suspensions of T. cruzi in blood, the sensitivity of PCR was 27-fold higher than hemoculture. However, this advantage was not reflected during routine testing of samples from maternities, partly because of the uneven distribution of few parasites in small samples. Levels of detection of congenital infection were 2.9% (8/272) for microhematocrit, 6.3% (18/287) for hemoculture, 6.4% (15/235) for PCR, and 8.9% (27/302) for cumulated results. Evaluation against the standard of delayed serology indicates that the regular application of PCR, hemoculture, and microhematocrit to blood samples allows the rapid detection of about 90% of the congenitally infected newborns, in samples that can be obtained before the mother and child leave the maternity ward.
Peperkamp, N H; Luttikholt, S J; Dijkman, R; Vos, J H; Junker, K; Greijdanus, S; Roumen, M P; van Garderen, E; Meertens, N; van Maanen, C; Lievaart, K; van Wuyckhuise, L; Wouda, W
In December 2011, a previously unknown congenital syndrome of arthrogryposis and hydranencephaly in sheep and cattle appeared in the Netherlands as an emerging epizootic due to Schmallenberg virus (SBV). Gross lesions in 102 lambs and 204 calves included porencephaly, hydranencephaly, cerebellar dysplasia and dysplasia of the brainstem and spinal cord, a flattened skull with brachygnathia inferior, arthrogryposis, and vertebral column malformations. Microscopic lesions in the central nervous system showed rarefaction and cavitation in the white matter, as well as degeneration, necrosis, and loss of neurons in the gray matter. Brain and spinal cord lesions were more severe in lambs than in calves. Ovine and bovine cases examined early in the outbreak showed encephalomyelitis. SBV infection was confirmed by real-time quantitative reverse transcription polymerase chain reaction (RT-qPCR) in brain samples in 46 of 102 lambs (45%) and in 32 of 204 calves (16%). Immunohistochemistry, performed on tissue samples from 18 RT-qPCR-positive lambs, confirmed the presence of bunyaviral antigen in neurons of the brain in 16 cases. SBV antibodies were detected by enzyme-linked immunosorbent assay in fetal blood in 56 of 61 sampled ovine cases (92%). In a virus neutralization test, all tested dams of affected newborns, 46 ewes and 190 cows, were seropositive. Compared with other teratogenic viral infections, the pathogenesis and lesions of SBV in sheep and cattle fetuses are similar to those of other ruminant orthobunyaviruses. However, the loss of spinal ventral motor neurons and their tracts, resulting in micromyelia, distinguishes SBV infection from other viral central nervous system lesions in newborn ruminants.
Kanda, Y; Mineishi, S; Saito, T; Seo, S; Saito, A; Suenaga, K; Ohnishi, M; Niiya, H; Nakai, K; Takeuchi, T; Kawahigashi, N; Shoji, N; Ogasawara, T; Tanosaki, R; Kobayashi, Y; Tobinai, K; Kami, M; Mori, S; Suzuki, R; Kunitoh, H; Takaue, Y
From April 1998 to March 2000, a cytomegalovirus (CMV) antigenemia-guided pre-emptive approach for CMV disease was evaluated in 77 adult patients who received allogeneic hematopoietic stem cell transplantation at the National Cancer Center Hospital. A CMV antigenemia assay was performed at least once a week after engraftment. High-level antigenemia was defined as a positive result with 10 or more positive cells per 50 000 cells and low-level antigenemia was defined as less than 10 positive cells. Among the 74 patients with initial engraftment, 51 developed positive antigenemia. Transplantation from alternative donors and the development of grade II-IV GVHD were independent risk factors for positive antigenemia. Ganciclovir was administered as pre-emptive therapy in 39 patients in a risk-adapted manner. None of the nine low-risk patients with low-level antigenemia as their initial positive result developed high-level antigenemia even though ganciclovir was withheld. Only one patient developed early CMV disease (hepatitis) during the study period. CMV antigenemia resolved in all but two cases, in whom ganciclovir was replaced with foscarnet. In eight patients, however, the neutrophil count decreased to 0.5 x 10(9)/l or less after starting ganciclovir, including three with documented infections and two with subsequent secondary graft failure. The total amount of ganciclovir and possibly the duration of high-dose ganciclovir might affect the incidence of neutropenia. We concluded that antigenemia-guided pre-emptive therapy with a decreased dose of ganciclovir and response-oriented dose adjustment might be appropriate to decrease the toxicity of ganciclovir without increasing the risk of CMV disease.
Celik, Hasan Tolga; Sonmez, Kenan; Celik, Melda
A 20-day-old male infant who was born at 39 weeks of gestation was admitted to neonatal intensive care unit due to severe respiratory insufficiency. In retinal examination, peripheric retinal white-black color areas that correspond to necrotizing retinitis, moderate vitritis, macular and optic nerve head involvement, vascular leakage, and sheathing indicating perivasculitis were revealed. Despite the fact that CMV specific IgM was undetectable, CMV DNA with high viral load was found in his blood sample by means of real-time polymerase chain reaction assay. Serologic examination (IgM) for rubella, toxoplasma, herpes simplex type 2, and human immunodeficiency virus (anti-HIV) was negative. During the further evaluation for systemic immune dysfunction, decreased immunoglobulin and lymphocyte levels that confirm the diagnosis of severe combined immunodeficiency have been reached. Although given systemic intravenous ganciclovir and antibiotics treatment, the patient died at the 4th month of life due to respiratory insufficiency. PMID:27999698
Adland, Emily; Klenerman, Paul; Goulder, Philip; Matthews, Philippa C.
Human Cytomegalovirus (CMV) is a well-recognized pathogen in the context of HIV infection, but since the roll out of ART, clinical and scientific interest in the problem of HIV/CMV coinfection has diminished. However, CMV remains a significant cofactor in HIV disease, with an influence on HIV acquisition, disease progression, morbidity, and mortality. Disease manifestations may be a result of direct interplay between the two viruses, or may arise as a secondary consequence of immune dysregulation and systemic inflammation. The problem is most relevant when the rates of coinfection are high, most notably in sub-Saharan Africa, and in children at risk of acquiring both infections early in life. Understanding the interplay between these viruses and developing strategies to diagnose, treat and prevent CMV should be a priority. PMID:26441939
Francis, Stephen Starko; Wallace, Amelia D; Wendt, George A; Li, Linlin; Liu, Fenyong; Riley, Lee W; Kogan, Scott; Walsh, Kyle M; de Smith, Adam J; Dahl, Gary V; Ma, Xiaomei; Delwart, Eric; Metayer, Catherine; Wiemels, Joseph L
It is widely suspected, yet controversial, that infection plays an etiologic role in the development of acute lymphoblastic leukemia (ALL), the most common childhood cancer and a disease with a confirmed prenatal origin in most cases. We investigated infections at diagnosis and then assessed the timing of infection at birth in children with ALL and age, gender, and ethnicity matched controls to identify potential causal initiating infections. Comprehensive untargeted virome and bacterial analyses of pretreatment bone marrow specimens (n = 127 ALL in comparison with 38 acute myeloid leukemia cases in a comparison group) revealed prevalent cytomegalovirus (CMV) infection at diagnosis in childhood ALL, demonstrating active viral transcription in leukemia blasts as well as intact virions in serum. Screening of newborn blood samples revealed a significantly higher prevalence of in utero CMV infection in ALL cases (n = 268) than healthy controls (n = 270) (odds ratio [OR], 3.71, confidence interval [CI], 1.56-7.92, P = .0016). Risk was more pronounced in Hispanics (OR=5.90, CI=1.89-25.96) than in non-Hispanic whites (OR=2.10 CI= 0.69-7.13). This is the first study to suggest that congenital CMV infection is a risk factor for childhood ALL and is more prominent in Hispanic children. Further investigation of CMV as an etiologic agent for ALL is warranted.
Schoondermark-van de Ven, E; Galama, J; Vree, T; Camps, W; Baars, I; Eskes, T; Meuwissen, J; Melchers, W
The efficacy of the combination of pyrimethamine and sulfadiazine for the treatment of congenital Toxoplasma gondii infection in rhesus monkeys was studied. The dosage regimen for pyrimethamine and sulfadiazine was established by pharmacokinetic studies in two monkeys. Those studies showed that the distributions of both drugs followed a one-compartment model. The serum elimination half-lives were found to be 5.2 h for sulfadiazine and 44.4 h for pyrimethamine. Sulfadiazine reached a maximum concentration in serum of 58.7 micrograms/ml, whereas a maximum concentration in serum of 0.22 micrograms/ml was found for pyrimethamine. Ten monkeys were infected intravenously with T. gondii at day 90 of pregnancy, which is comparable to the second trimester of organogenetic development in humans. Treatment was administered to six monkeys, in whose fetuses infection was diagnosed antenatally. From the moment that fetal infection was proven, the monkeys were treated throughout pregnancy with 1 mg of pyrimethamine per kg of body weight per day and 50 mg of sulfadiazine per kg of body weight per day orally. The therapy was supplemented with 3.5 mg of folinic acid once a week. No toxic side effects were found with this drug regimen. The parasite was no longer detectable in the next consecutive amniotic fluid sample, taken 10 to 13 days after treatment was started. Furthermore, T. gondii was also not found in the neonate at birth. The parasite was still present at birth in three of four untreated fetuses that served as controls. Both drugs crossed the placenta very well. Concentrations in fetal serum varied from 0.05 to 0.14 micrograms/ml for pyrimethamine and from 1.0 to 5.4 micrograms/ml for sulfadiazine. In addition, pyrimethamine was found to accumulate in the brain tissue, with concentrations being three to four times higher than the corresponding concentrations in serum. Thirty percent of the sulfadiazine was found to reach the brain tissue when compared with the
Kam, Yiu-Wing; Leite, Juliana Almeida; Lum, Fok-Moon; Tan, Jeslin J L; Lee, Bernett; Judice, Carla C; Teixeira, Daniel Augusto de Toledo; Andreata-Santos, Robert; Vinolo, Marco A; Angerami, Rodrigo; Resende, Mariangela Ribeiro; Freitas, Andre Ricardo Ribas; Amaral, Eliana; Junior, Renato Passini; Costa, Maria Laura; Guida, José Paulo; Arns, Clarice Weis; Ferreira, Luis Carlos S; Rénia, Laurent; Proença-Modena, Jose Luiz; Ng, Lisa F P; Costa, Fabio T M
Zika virus (ZIKV) infections have been linked to different levels of clinical outcomes, ranging from mild rash and fever to severe neurological complications and congenital malformations. We investigated the clinical and immunological response, focusing on the immune mediators profile in 95 acute ZIKV-infected adult patients from Campinas, Brazil. These patients included 6 pregnant women who later delivered during the course of this study. Clinical observations were recorded during hospitalization. Levels of 45 immune mediators were quantified using multiplex microbead-based immunoassays. Whereas 11.6% of patients had neurological complications, 88.4% displayed mild disease of rash and fever. Several immune mediators were specifically higher in ZIKV-infected patients, and levels of interleukin 10, interferon gamma-induced protein 10 (IP-10), and hepatocyte growth factor differentiated between patients with or without neurological complications. Interestingly, higher levels of interleukin 22, monocyte chemoattractant protein 1, TNF-α, and IP-10 were observed in ZIKV-infected pregnant women carrying fetuses with fetal growth-associated malformations. Notably, infants with congenital central nervous system deformities had significantly higher levels of interleukin 18 and IP-10 but lower levels of hepatocyte growth factor than those without such abnormalities born to ZIKV-infected mothers. This study identified several key markers for the control of ZIKV pathogenesis. This will allow a better understanding of the molecular mechanisms of ZIKV infection in patients.
Repair of a Mutation Disrupting the Guinea Pig Cytomegalovirus Pentameric Complex Acquired during Fibroblast Passage Restores Pathogenesis in Immune-Suppressed Guinea Pigs and in the Context of Congenital Infection
McVoy, Michael A.; Wang, Jian Ben; Dittmer, Dirk P.; Swanson, Elizabeth C.; Fernández-Alarcón, Claudia; Hernandez-Alvarado, Nelmary; Zabeli, Jason C.
encoding components of the pentameric complex (PC), in particular homologs of human cytomegalovirus (HCMV) proteins UL128, UL130, and UL131A. These mutations can attenuate the course of infection when the virus is reintroduced into animals for vaccine and pathogenesis studies. This study demonstrates that a deletion that arose during the process of tissue culture passage can be repaired, with subsequent restoration of pathogenicity, using BAC-based mutagenesis. Restoration of pathogenicity by repair of a frameshift mutation in GPCMV gene GP129 using this approach provides a valuable genetic platform for future studies using the guinea pig model of congenital CMV infection. PMID:27307567
Bilavsky, Efraim; Shahar-Nissan, Keren; Pardo, Joseph; Attias, Joseph; Amir, Jacob
Congenital cytomegalovirus (cCMV) is the most common non-genetic cause of childhood sensorineural hearing loss. Antiviral treatment has been shown to prevent hearing deterioration in these infants. However, studies focused on infants with hearing impairment at birth and on the specific degree of impairment and further improvement or deterioration are lacking. To investigate the relationship between hearing status at birth and any change in hearing status at the end of a prolonged follow-up period, after receiving 12 months of antiviral treatment in children born with hearing impairment due to congenital cCMV. Clinical, laboratory, radiological and audiological data of all infants with cCMV infection followed in our centre between 2005 and 2013 were reviewed. Treatment with antiviral medication for hearing impairment found during the neonatal period was12 months of gan/valganciclovir. Hearing studies were performed only on infants who had been followed up for more than 1 year after treatment. Hearing impairment at birth was found in 54 (36.2%) of the 149 infants diagnosed with symptomatic cCMV, and found in 77 affected ears; unilateral in 31 (57.4%) and bilateral in 23 (42.6%). After 1 year of antiviral treatment and a long-term follow-up of the 77 affected ears at baseline, 50 (64.9%) had improved, 22 (28.6%) remained unchanged and 5 (6.5%) had deteriorated. Most improved ears (38/50=76%) returned to normal hearing. Improvement was most likely to occur in infants born with mild or moderate hearing loss and less in those with severe impairment. We found that infants born with cCMV and hearing impairment, receiving 12 months of antiviral treatment, showed significant improvement in hearing status. The probability of hearing improvement seems inversely related to the severity of the impairment at birth. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/
Severino, Mariasavina; Zerem, Ayelet; Biancheri, Roberta; Cristina, Emilio; Rossi, Andrea
Very little is known regarding neuroimaging findings in patients with congenital rubella syndrome. We report a 1.9-year-old boy with congenital rubella syndrome who presented in the neonatal period with severe multisystem involvement and diffuse leukoencephalopathy with subcortical anterior temporal cysts, which showed spontaneous improvement during a period of 3 years.
Vargas-Villavicencio, J A; Cedillo-Peláez, C; Rico-Torres, C P; Besné-Mérida, A; García-Vázquez, F; Saldaña, J I; Correa, D
Congenital transmission of Toxoplasma gondii may occur if the mother gets infected for the first time while pregnant. The risk of mother-to-child transmission depends on the gestation trimester at infection, being lowest in the first and highest in the last. Conversely, fetal damage is frequent and more severe at the beginning of pregnancy. The objective of this study was to evaluate congenital transmission and pathological aspects in the placenta and the fetus using a mouse model of congenital infection of the second gestation third. Forty-five female BALB/c mice were infected intravenously with 2.5-10.0 × 10(6) tachyzoites of the ME49 strain at middle gestation. Samples of maternal spleen and fetal/placental units were taken 72 h later. We determined parasite load and vertical transmission by qPCR, as well as damage macroscopically and by histopathology. With the lowest dose, 18% of the fetuses were infected. Also, 40% of fetuses/litter were altered, while this value was 10% in the control group (P < 0.05). These results are similar to those described in humans in terms of vertical transmission and fetal damage during the second third of gestation. The maternal spleen had 10-1000 times more tachyzoites than the placenta, and the later retained 90-99% of the parasites that could reach the fetus. Nevertheless, we found resorptions, abortions or fetal tissue damage in the presence but also in the absence of parasites. Our data indicate a strong protective effect of maternal organs and the placenta against fetal infection, but extensive damage of the later may led to resorption or abortion without vertical transmission. Copyright © 2016 Elsevier Inc. All rights reserved.
Results of a phase I/II British Society of Bone Marrow Transplantation study on PCR-based pre-emptive therapy with valganciclovir or ganciclovir for active CMV infection following alemtuzumab-based reduced intensity allogeneic stem cell transplantation.
Lim, Z Y; Cook, G; Johnson, P R; Parker, Anne; Zuckerman, M; Marks, D; Wiltshire, H; Mufti, G J; Pagliuca, A
This multi-centre randomized study assessed the bioavailability of ganciclovir in patients undergoing alemtuzumab-based reduced intensity conditioning (RIC) haematopoietic stem cell transplantation (HSCT) after oral administration of valganciclovir. Patients were randomized to 2 groups receiving either oral valganciclovir (900 mg twice daily) or intravenous ganciclovir (5mg/kg twice daily) for 14 days. Twenty-seven patients were recruited and 18 patients (67%) completed allocated treatment resulting in clearance of cytomegolovirus (CMV) DNA load at a median of 14 days. The bioavailability of ganciclovir from valganciclovir was 73% (95% CI: 34-112%). The average exposure in the valganciclovir group (36.9+/-14.9 microg h/ml) was higher than the ganciclovir cohort (27.9+/-7.5 microg h/ml). When compared with intravenous ganciclovir, oral valganciclovir had high bioavailability in patients undergoing alemtuzumab-based RIC HSCT.
Teng, Zhongqiu; Shen, Ye; Li, Jing; Lin, Zhongping; Chen, Min; Wang, Min; Li, Man; Dong, Hongran; Huang, Luqi
Plant viruses, especially tobacco mosaic virus (TMV) and cucumber mosaic virus (CMV) are serious threats to Rehmannia glutinosa which is a "top grade" herb in China. In the present study, TMV- and CMV-resistant Rehmannia glutinosa Libosch. plants were constructed by transforming the protein (CP) genes of TMV and CMV into Rehmannia glutinosa via a modified procedure of Agrobacterium tumefaciens-mediated transformation. Integration and expression of TMV CP and CMV CP transgenes in 2 lines, LBA-1 and LBA-2, were confirmed by PCR, Southern blot and RT-PCR. Both LBA-1 and LBA-2 were resistant to infection of homologous TMV and CMV strains. The quality of transgenic Rehmanniae Radix was evaluated based on fingerprint analysis and components quantitative analysis comparing with control root tubes. These results showed that chemical composition of transgenic Rehmanniae Radix were similar to non-transgenic ones, which demonstrated that the medical quality and biosafety of transgenic Rehmanniae Radix were equivalent to non-transgenic material when consumed as traditional Chinese medicinal (TCM).
Tutarel, Oktay; Alonso-Gonzalez, Rafael; Montanaro, Claudia; Schiff, Renee; Uribarri, Aitor; Kempny, Aleksander; Grübler, Martin R; Uebing, Anselm; Swan, Lorna; Diller, Gerhard-Paul; Dimopoulos, Konstantinos; Gatzoulis, Michael A
Infective endocarditis (IE) is associated with significant morbidity and mortality. Patients with adult congenital heart disease (ACHD) have an increased risk of developing IE. The aim of this study is to describe the incidence, predictors of outcome and mortality associated with IE in ACHD in a contemporary cohort. All episodes of IE in adults with congenital heart disease referred to our tertiary centre between 1999 and 2013 were included in the study. Patients were identified from the hospital database. The diagnosis of endocarditis was established according to the modified Duke criteria. The primary endpoint of the study was endocarditis-associated mortality. There were 164 episodes of IE in 144 patients (male 102, 70.8%). Mean age at presentation was 32.3±22.7 years. Out of these, 43% had a simple, 23% a moderate and 32% a complex lesion. It was at least the second bout of IE in 37 episodes (23%). A predisposing event could be identified in only 26.2% of episodes. Surgical intervention during the same admission was performed in 61 episodes (37.2%). During a median follow-up of 6.7 years (IQR 2.9-11.4), 28 (19.4%) patients died. Out of these, 10 deaths were related to IE (IE mortality 6.9%). On unvariate regression analysis, the development of an abscess (OR: 7.23; 95% CI 1.81 to 28.94, p<0.01) and age (OR: 1.05; 95% CI 1.01 to 1.10, p=0.03) were the only predictors of IE-associated mortality. There was no increase in IE cases at our centre during the period of the study. IE-associated morbidity and mortality in a contemporary cohort of ACHD patients is still high in the current era. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.
Ulrick, Nicole; Goldstein, Amy; Simons, Cas; Taft, Ryan J; Helman, Guy; Pizzino, Amy; Bloom, Miriam; Vogt, Julie; Pysden, Karen; Diodato, Daria; Martinelli, Diego; Monavari, Ahmad; Buhas, Daniela; van Karnebeek, Clara D M; Dorboz, Imen; Boespflug-Tanguy, Odile; Rodriguez, Diana; Tétreault, Martine; Majewski, Jacek; Bernard, Genevieve; Ng, Yi Shiau; McFarland, Robert; Vanderver, Adeline
Leukoencephalopathy with temporal lobe cysts may be associated with monogenetic conditions such as Aicardi-Goutières syndrome or RNASET2 mutations and with congenital infections such as cytomegalovirus. In view of the fact that congenital cytomegalovirus is difficult to confirm outside the neonatal period, excluding a Mendelian disorder is extremely relevant, changing family planning and medical management in affected families. We performed diagnostic testing in individuals with leukoencephalopathy with temporal lobe cysts without a definitive diagnosis of congenital cytomegalovirus infection. We reviewed a large-scale biorepository of patients with unsolved leukodystrophies and identified two individuals with required for meiotic nuclear division 1 (RMND1) mutations and similar magnetic resonance imaging (MRI) features, including temporal lobe cysts. Ten additional subjects with confirmed RMND1 mutations were identified as part of a separate disease specific cohort. Brain MRIs from all 12 individuals were reviewed for common neuroradiological features. MRI features in RMND1 mutations included temporal lobe swelling, with rarefaction and cystic evolution, enlarged tips of the temporal lobes, and multifocal subcortical white matter changes with confluent periatrial T2 signal hyperintensity. A combination of these features was present in ten of the 12 individuals reviewed. Despite the small number of reported individuals with RMND1 mutations, a clinically recognizable phenotype of leukoencephalopathy with temporal lobe swelling, rarefaction, and cystic changes has emerged in a subset of individuals. Careful clinical phenotyping, including for lactic acidosis, deafness, and severe muscle involvement seen in RMND1 mutation positive individuals, and MRI pattern recognition will be important in differentiating these patients from children with congenital infections like cytomegalovirus. Copyright © 2016 Elsevier Inc. All rights reserved.
Kozak, Igor; Vaidya, Vijay; Van Natta, Mark L.; Pak, Jeong W.; May, K. Patrick; Thorne, Jennifer E.
Purpose. To determine the prevalence and incidence of epiretinal membranes (ERM) in eyes with inactive extramacular cytomegalovirus (CMV) retinitis in patients with acquired immune deficiency syndrome (AIDS). Methods. A case–control report from a longitudinal multicenter observational study by the Studies of the Ocular Complications of AIDS (SOCA) Research Group. A total of 357 eyes of 270 patients with inactive CMV retinitis and 1084 eyes of 552 patients with no ocular opportunistic infection (OOI) were studied. Stereoscopic views of the posterior pole from fundus photographs were assessed at baseline and year 5 visits for the presence of macular ERM. Generalized estimating equations (GEE) logistic regression was used to compare the prevalence and 5-year incidence of ERM in eyes with and without CMV retinitis at enrollment. Crude and adjusted logistic regression was performed adjusting for possible confounders. Main outcome measures included the prevalence, incidence, estimated prevalence, and incidence odds ratios. Results. The prevalence of ERM at enrollment was 14.8% (53/357) in eyes with CMV retinitis versus 1.8% (19/1084) in eyes with no OOI. The incidence of ERM at 5 years was 18.6% (16/86) in eyes with CMV retinitis versus 2.4% (6/253) in eyes with no OOI. The crude odds ratio (OR) (95% confidence interval, CI) for prevalence was 9.8 (5.5–17.5) (P < 0.01). The crude OR (95% CI) for incidence was 9.4 (3.2–27.9) (P < 0.01). Conclusions. A history of extramacular CMV retinitis is associated with increased prevalence and incidence of ERM formation compared to what is seen in eyes without ocular opportunistic infections in AIDS patients. PMID:24925880
Jackson, Sarah E; Redeker, Anke; Arens, Ramon; van Baarle, Debbie; van den Berg, Sara P H; Benedict, Chris A; Čičin-Šain, Luka; Hill, Ann B; Wills, Mark R
Human cytomegalovirus (HCMV) encodes numerous proteins and microRNAs that function to evade the immune response and allow the virus to replicate and disseminate in the face of a competent innate and acquired immune system. The establishment of a latent infection by CMV, which if completely quiescent at the level of viral gene expression would represent an ultimate in immune evasion strategies, is not sufficient for lifelong persistence and dissemination of the virus. CMV needs to reactivate and replicate in a lytic cycle of infection in order to disseminate further, which occurs in the face of a fully primed secondary immune response. Without reactivation, latency itself would be redundant for the virus. It is also becoming clear that latency is not a totally quiescent state, but is characterized by limited viral gene expression. Therefore, the virus also needs immune evasion strategies during latency. An effective immune response to CMV is required or viral replication will cause morbidity and ultimately mortality in the host. There is clearly a complex balance between virus immune evasion and host immune recognition over a lifetime. This poses the important question of whether long-term evasion or manipulation of the immune response driven by CMV is detrimental to health. In this meeting report, three groups used the murine model of CMV (MCMV) to examine if the contribution of the virus to immune senescence is set by the (i) initial viral inoculum, (ii) inflation of T cell responses, (iii) or the balance between functionally distinct effector CD4+ T cells. The work of other groups studying the CMV response in humans is discussed. Their work asks whether the ability to make immune responses to new antigens is compromised by (i) age and HCMV carriage, (ii) long-term exposure to HCMV giving rise to an overall immunosuppressive environment and increased levels of latent virus, or (iii) adapted virus mutants (used as potential vaccines) that have the capacity to
Kozak, Igor; Vaidya, Vijay; Van Natta, Mark L; Pak, Jeong W; May, K Patrick; Thorne, Jennifer E
To determine the prevalence and incidence of epiretinal membranes (ERM) in eyes with inactive extramacular cytomegalovirus (CMV) retinitis in patients with acquired immune deficiency syndrome (AIDS). A case-control report from a longitudinal multicenter observational study by the Studies of the Ocular Complications of AIDS (SOCA) Research Group. A total of 357 eyes of 270 patients with inactive CMV retinitis and 1084 eyes of 552 patients with no ocular opportunistic infection (OOI) were studied. Stereoscopic views of the posterior pole from fundus photographs were assessed at baseline and year 5 visits for the presence of macular ERM. Generalized estimating equations (GEE) logistic regression was used to compare the prevalence and 5-year incidence of ERM in eyes with and without CMV retinitis at enrollment. Crude and adjusted logistic regression was performed adjusting for possible confounders. Main outcome measures included the prevalence, incidence, estimated prevalence, and incidence odds ratios. The prevalence of ERM at enrollment was 14.8% (53/357) in eyes with CMV retinitis versus 1.8% (19/1084) in eyes with no OOI. The incidence of ERM at 5 years was 18.6% (16/86) in eyes with CMV retinitis versus 2.4% (6/253) in eyes with no OOI. The crude odds ratio (OR) (95% confidence interval, CI) for prevalence was 9.8 (5.5-17.5) (P < 0.01). The crude OR (95% CI) for incidence was 9.4 (3.2-27.9) (P < 0.01). A history of extramacular CMV retinitis is associated with increased prevalence and incidence of ERM formation compared to what is seen in eyes without ocular opportunistic infections in AIDS patients. Copyright 2014 The Association for Research in Vision and Ophthalmology, Inc.
Smith, Corinne J.; Quinn, Michael; Snyder, Christopher M.
Human cytomegalovirus (HCMV) is a ubiquitous virus that causes chronic infection and, thus, is one of the most common infectious complications of immune suppression. Adoptive transfer of HCMV-specific T cells has emerged as an effective method to reduce the risk for HCMV infection and/or reactivation by restoring immunity in transplant recipients. However, the CMV-specific CD8+ T cell response is comprised of a heterogenous mixture of subsets with distinct functions and localization, and it is not clear if current adoptive immunotherapy protocols can reconstitute the full spectrum of CD8+ T cell immunity. The aim of this review is to briefly summarize the role of these T cell subsets in CMV immunity and to describe how current adoptive immunotherapy practices might affect their reconstitution in patients. The bulk of the CMV-specific CD8+ T cell population is made up of terminally differentiated effector T cells with immediate effector function and a short life span. Self-renewing memory T cells within the CMV-specific population retain the capacity to expand and differentiate upon challenge and are important for the long-term persistence of the CD8+ T cell response. Finally, mucosal organs, which are frequent sites of CMV reactivation, are primarily inhabited by tissue-resident memory T cells, which do not recirculate. Future work on adoptive transfer strategies may need to focus on striking a balance between the formation of these subsets to ensure the development of long lasting and protective immune responses that can access the organs affected by CMV disease. PMID:27695453
Smith, Corinne J; Quinn, Michael; Snyder, Christopher M
Human cytomegalovirus (HCMV) is a ubiquitous virus that causes chronic infection and, thus, is one of the most common infectious complications of immune suppression. Adoptive transfer of HCMV-specific T cells has emerged as an effective method to reduce the risk for HCMV infection and/or reactivation by restoring immunity in transplant recipients. However, the CMV-specific CD8(+) T cell response is comprised of a heterogenous mixture of subsets with distinct functions and localization, and it is not clear if current adoptive immunotherapy protocols can reconstitute the full spectrum of CD8(+) T cell immunity. The aim of this review is to briefly summarize the role of these T cell subsets in CMV immunity and to describe how current adoptive immunotherapy practices might affect their reconstitution in patients. The bulk of the CMV-specific CD8(+) T cell population is made up of terminally differentiated effector T cells with immediate effector function and a short life span. Self-renewing memory T cells within the CMV-specific population retain the capacity to expand and differentiate upon challenge and are important for the long-term persistence of the CD8(+) T cell response. Finally, mucosal organs, which are frequent sites of CMV reactivation, are primarily inhabited by tissue-resident memory T cells, which do not recirculate. Future work on adoptive transfer strategies may need to focus on striking a balance between the formation of these subsets to ensure the development of long lasting and protective immune responses that can access the organs affected by CMV disease.
Goldman, Allen S.; And Others
There are two general categories (not necessarily mutually exclusive) of congenital defects: (1) abnormalities that have an hereditary basis, such as single and multiple genes, or chromosomal abberration; and (2) abnormalities that are caused by nonhereditary factors, such as malnutrition, maternal disease, radiation, infections, drugs, or…
Goldman, Allen S.; And Others
There are two general categories (not necessarily mutually exclusive) of congenital defects: (1) abnormalities that have an hereditary basis, such as single and multiple genes, or chromosomal abberration; and (2) abnormalities that are caused by nonhereditary factors, such as malnutrition, maternal disease, radiation, infections, drugs, or…
Tan, Dora S. K.; Stern, H.
Healthy Malaysians from various parts of Peninsular Malaysia were examined for CF antibodies against cytomegalovirus (CMV) and herpes simplex virus (HSV) type 2. CMV antibodies were detected in 1114 out of 1556 persons (71.6%) and HSV antibodies were detected in 954 persons out of 1554 (61.4%). The age distribution patterns were similar for the two infections, with maximum prevalence at 5 - 14 years of age. Prevalence was higher in women than in men. There were no significant differences among the Malay, Chinese, and Indian groups of the population with respect to CMV, 72 - 78% possessing antibodies, but in the case of HSV, 76% of the Chinese had antibodies, compared with 57 - 60% of the Malays and Indians. More than 90% of newborn infants had CMV and HSV CF antibodies, confirming the highly immune status of childbearing women in Malaysia. No CMV-specific IgM was detected in the Malaysian neonates examined but this does not exclude the possibility of congenital infection. PMID:6279323
Leruez-Ville, Marianne; Ramirez-Torres, Adela; Lacroix, Chrystelle; Breuil, Benjamin; Froment, Carine; Bascands, Jean-Loup; Schanstra, Joost P.; Ville, Yves
Cytomegalovirus (CMV) is the most common cause of congenital infection, and is a major cause of sensorineural hearing loss and neurological disabilities. Evaluating the risk for a CMV infected fetus to develop severe clinical symptoms after birth is crucial to provide appropriate guidance to pregnant women who might have to consider termination of pregnancy or experimental prenatal medical therapies. However, establishing the prognosis before birth remains a challenge. This evaluation is currently based upon fetal imaging and fetal biological parameters, but the positive and negative predictive values of these parameters are not optimal, leaving room for the development of new prognostic factors. Here, we compared the amniotic fluid peptidome between asymptomatic fetuses who were born as asymptomatic neonates and symptomatic fetuses who were either terminated in view of severe cerebral lesions or born as severely symptomatic neonates. This comparison allowed us to identify a 34-peptide classifier in a discovery cohort of 13 symptomatic and 13 asymptomatic neonates. This classifier further yielded 89% sensitivity, 75% specificity and an area under the curve of 0.90 to segregate 9 severely symptomatic from 12 asymptomatic neonates in a validation cohort, showing an overall better performance than that of classical fetal laboratory parameters. Pathway analysis of the 34 peptides underlined the role of viral entry in fetuses with severe brain disease as well as the potential importance of both beta-2-microglobulin and adiponectin to protect the injured fetal brain infected with CMV. The results also suggested the mechanistic implication of the T calcium channel alpha-1G (CACNA1G) protein in the development of seizures in severely CMV infected children. These results open a new field for potential therapeutic options. In conclusion, this study demonstrates that amniotic fluid peptidome analysis can effectively predict the severity of congenital CMV infection. This
Schwartz, David A
Attention is increasingly focused on the potential mechanism(s) for Zika virus infection to be transmitted from an infected mother to her fetus. This communication addresses current evidence for the role of the placenta in vertical transmission of the Zika virus. Placentas from second and third trimester fetuses with confirmed intrauterine Zika virus infection were examined with routine staining to determine the spectrum of pathologic changes. In addition, immunohistochemical staining for macrophages and nuclear proliferation antigens was performed. Viral localization was identified using RNA hybridization. These observations were combined with the recent published results of placental pathology to increase the strength of the pathology data. Results were correlated with published data from experimental studies of Zika virus infection in placental cells and chorionic villous explants. Placentas from fetuses with congenital Zika virus infection are concordant in not having viral-induced placental inflammation. Special stains reveal proliferation and prominent hyperplasia of placental stromal macrophages, termed Hofbauer cells, in the chorionic villi of infected placentas. Zika virus infection is present in Hofbauer cells from second and third trimester placentas. Experimental studies and placentae from infected fetuses reveal that the spectrum of placental cell types infected with the Zika virus is broader during the first trimester than later in gestation. Inflammatory abnormalities of the placenta are not a component of vertical transmission of the Zika virus. The major placental response in second and third trimester transplacental Zika virus infection is proliferation and hyperplasia of Hofbauer cells, which also demonstrate viral infection.
Kapoor, A K; Buckmaster, A; Nash, A A; Field, H J; Wildy, P
Congenitally athymic nude mice were infected with 10(4) p.f.u. herpes simplex type 1 (strain SC16). Following the passive transfer of neutralizing monoclonal antibodies (AP7, AP8 and AP12) it was observed that AP7 alone reduced the virus infectivity in the nervous system; AP8 and AP12 failed to protect mice probably due to poor in vivo binding to the neutralization site on the virus. Latent ganglionic infection could be established in nude mice following adoptive transfer of optimum number (2 x 10(7) cells/mouse) of immune lymph node cells from day 7 herpes virus-infected hairy immunocompetent donor mice. Moreover, in some of the immune lymph node cell protected nudes, latency could be maintained even in complete absence of neutralizing antibodies. Results of ear-ablation experiments revealed that removal of primary source of infection after day 5 of infection reduced the amount of virus in the ganglia and spinal cord. Acute neurological infection was not detected following transfer of protective anti-gp-D neutralizing antibody (LP2) in combination with removal of infected pinna. These data suggest that continuous seeding of virus occurs in related ganglia via the axonal route from infected ear pinna. It appears that local T-cell-mediated immune mechanisms are involved in maintenance of latency.
Reveiz, Ludovic; Oladapo, Olufemi T.; Martínez-Vega, Ruth; Haefliger, Anina
Background The World Health Organization (WHO) stated in March 2016 that there was scientific consensus that the mosquito-borne Zika virus was a cause of the neurological disorder Guillain–Barré syndrome (GBS) and of microcephaly and other congenital brain abnormalities based on rapid evidence assessments. Decisions about causality require systematic assessment to guide public health actions. The objectives of this study were to update and reassess the evidence for causality through a rapid and systematic review about links between Zika virus infection and (a) congenital brain abnormalities, including microcephaly, in the foetuses and offspring of pregnant women and (b) GBS in any population, and to describe the process and outcomes of an expert assessment of the evidence about causality. Methods and Findings The study had three linked components. First, in February 2016, we developed a causality framework that defined questions about the relationship between Zika virus infection and each of the two clinical outcomes in ten dimensions: temporality, biological plausibility, strength of association, alternative explanations, cessation, dose–response relationship, animal experiments, analogy, specificity, and consistency. Second, we did a systematic review (protocol number CRD42016036693). We searched multiple online sources up to May 30, 2016 to find studies that directly addressed either outcome and any causality dimension, used methods to expedite study selection, data extraction, and quality assessment, and summarised evidence descriptively. Third, WHO convened a multidisciplinary panel of experts who assessed the review findings and reached consensus statements to update the WHO position on causality. We found 1,091 unique items up to May 30, 2016. For congenital brain abnormalities, including microcephaly, we included 72 items; for eight of ten causality dimensions (all except dose–response relationship and specificity), we found that more than half the
Krauer, Fabienne; Riesen, Maurane; Reveiz, Ludovic; Oladapo, Olufemi T; Martínez-Vega, Ruth; Porgo, Teegwendé V; Haefliger, Anina; Broutet, Nathalie J; Low, Nicola
The World Health Organization (WHO) stated in March 2016 that there was scientific consensus that the mosquito-borne Zika virus was a cause of the neurological disorder Guillain-Barré syndrome (GBS) and of microcephaly and other congenital brain abnormalities based on rapid evidence assessments. Decisions about causality require systematic assessment to guide public health actions. The objectives of this study were to update and reassess the evidence for causality through a rapid and systematic review about links between Zika virus infection and (a) congenital brain abnormalities, including microcephaly, in the foetuses and offspring of pregnant women and (b) GBS in any population, and to describe the process and outcomes of an expert assessment of the evidence about causality. The study had three linked components. First, in February 2016, we developed a causality framework that defined questions about the relationship between Zika virus infection and each of the two clinical outcomes in ten dimensions: temporality, biological plausibility, strength of association, alternative explanations, cessation, dose-response relationship, animal experiments, analogy, specificity, and consistency. Second, we did a systematic review (protocol number CRD42016036693). We searched multiple online sources up to May 30, 2016 to find studies that directly addressed either outcome and any causality dimension, used methods to expedite study selection, data extraction, and quality assessment, and summarised evidence descriptively. Third, WHO convened a multidisciplinary panel of experts who assessed the review findings and reached consensus statements to update the WHO position on causality. We found 1,091 unique items up to May 30, 2016. For congenital brain abnormalities, including microcephaly, we included 72 items; for eight of ten causality dimensions (all except dose-response relationship and specificity), we found that more than half the relevant studies supported a causal
Havenith, Simone H C; Yong, Si La; van Donselaar-van der Pant, Karlijn A M I; van Lier, René A W; ten Berge, Ineke J M; Bemelman, Fréderike J
In renal transplant recipients, mammalian target of rapamycin (mTOR) inhibitors have been reported to protect against cytomegalovirus (CMV) disease. Here, we questioned whether mTOR inhibitors specifically influence human CMV-induced T-cell responses. We studied renal transplant recipients treated with prednisolone, cyclosporine A (CsA), and mycophenolate sodium (MPS) for the first 6 months after transplantation followed by double therapy consisting of prednisolone/everolimus, which is an mTOR inhibitor (P/EVL; n=10), prednisolone/CsA (P/CsA; n=7), or prednisolone/MPS (P/MPS; n=9). All patients were CMV-IgG positive before transplantation. CMV reactivation was detectable in the first 6 months after transplantation and not thereafter. None of the patients included in this study suffered from CMV disease. Both CD27CD8 and CD27CD28CD4 effector-type T-cell counts, known to be associated with CMV infection, were measured before transplantation and at 6 and 24 months after transplantation. Additionally, we determined both number and function of CMV-specific CD8 T cells at these time points. The number of total CD8 T cells, CD27CD8 T cells, and CD28CD4 T cells increased significantly after switch to therapy with P/EVL but not after switch to P/CsA or P/MPS. Specifically, CMV-specific CD8 T-cell counts significantly increased after switch to therapy with P/EVL. Furthermore, the mTOR inhibitor sirolimus strongly inhibited alloresponses in vitro, whereas it did not affect CMV-specific responses. We observed a significant increase in (CMV-specific) effector-type CD8 and CD4 T-cell counts in everolimus-treated patients. These findings may at least in part explain the reported low incidence of CMV-related pathology in everolimus-treated patients.
McAuley, James B.
Toxoplasmosis is caused by infection with the parasite Toxoplasma gondii. It is one of the most common parasitic infections in humans and is most typically asymptomatic. However, primary infection in a pregnant woman can cause severe and disabling disease in the developing fetus. Recent developments have included increased understanding of the role of parasite genotype in determining infectivity and disease severity. Risk factors for acquisition of infection have been better defined, and the important role of foodborne transmission has been further delineated. In addition, strategies have emerged to decrease mother-to-child transmission through prompt identification of acutely infected pregnant women followed by appropriate treatment. Refined diagnostic tools, particularly the addition of immunoglobulin G avidity testing, allow for more accurate timing of maternal infection and hence better decision making during pregnancy. Congenitally infected children can be treated, beginning in utero and continuing through the first year of life, to ameliorate the severity of disease. However, despite these many advances in our understanding of congenital toxoplasmosis prevention and treatment, significant areas of study remain: we need better drugs, well defined strategies for screening of pregnant women, improved food safety, and improved diagnostic tests. PMID:25232475
Sifakis, S; Ergazaki, M; Sourvinos, G; Koffa, M; Koumantakis, E; Spandidos, D A
To investigate the role of human parvovirus B19 (Parvo B19), cytomegalovirus (CMV) and human papilloma virus (HPV) viruses in the aetiopathogenesis of spontaneous abortions. Abortion material from 102 cases of women with spontaneous abortions were analysed for the presence of Parvo B19, CMV and HPV DNA using the polymerase chain reaction (PCR) technique. Serological assays were used for the detection of specific IgM and IgG antibodies against Parvo B19 virus and CMV in the maternal sera. Parvo B19 virus genome was detected in two cases of spontaneous abortion, by PCR amplification, while CMV and HPV genomes were not observed. Serological markers were indicative for Parvo B19 virus and CMV infection in ten and four cases, respectively. PCR is a useful method for investigating the viral contribution to the aetiopathogenesis of spontaneous abortions and for detecting the viral genome in the abortion material. This study of 102 cases of spontaneous abortion does not implicate CMV and HPV in the aetiopathogenesis of spontaneous abortion, although it indicates a possible abortional role for Parvo B19 virus.
Bua, Jacqueline; Volta, Bibiana J.; Perrone, Alina E.; Scollo, Karenina; Velázquez, Elsa B.; Ruiz, Andres M.; De Rissio, Ana M.
Background According to the Chagas congenital transmission guides, the diagnosis of infants, born to Trypanosoma cruzi infected mothers, relies on the detection of parasites by INP micromethod, and/or the persistence of T. cruzi specific antibody titers at 10–12 months of age. Methodology and Principal Findings Parasitemia levels were quantified by PCR in T. cruzi-infected children, grouped according to the results of one-year follow-up diagnosis: A) Neonates that were diagnosed in the first month after delivery by microscopic blood examination (INP micromethod) (n = 19) had a median parasitemia of 1,700 Pe/mL (equivalent amounts of parasite DNA per mL); B) Infants that required a second parasitological diagnosis at six months of age (n = 10) showed a median parasitemia of around 20 Pe/mL and 500 Pe/mL at 1 and 6 months old, respectively, and C) babies with undetectable parasitemia by three blood microscopic observations but diagnosed by specific anti - T. cruzi serology at around 1 year old, (n = 22), exhibited a parasitemia of around 5 Pe/mL, 800 Pe/mL and 20 Pe/mL 1, 6 and 12 month after delivery, respectively. T. cruzi parasites were isolated by hemoculture from 19 congenitally infected children, 18 of which were genotypified as DTU TcV, (former lineage TcIId) and only one as TcI. Significance This report is the first to quantify parasitemia levels in more than 50 children congenitally infected with T. cruzi, at three different diagnostic controls during one-year follow-up after delivery. Our results show that the parasite burden in some children (22 out of 51) is below the detection limit of the INP micromethod. As the current trypanocidal treatment proved to be very effective to cure T. cruzi - infected children, more sensitive parasitological methods should be developed to assure an early T. cruzi congenital diagnosis. PMID:24147166
Bodosheva, Aigerim; Kuttubaev, Omurbek; Hehl, Adrian B.; Tanner, Isabelle; Ziadinov, Iskender; Torgerson, Paul R.; Deplazes, Peter
Background HIV-prevalence, as well as incidence of zoonotic parasitic diseases like cystic echinococcosis, has increased in the Kyrgyz Republic due to fundamental socio-economic changes after the breakdown of the Soviet Union. The possible impact on morbidity and mortality caused by Toxoplasma gondii infection in congenital toxoplasmosis or as an opportunistic infection in the emerging AIDS pandemic has not been reported from Kyrgyzstan. Methodology/Principal Findings We screened 1,061 rural and 899 urban people to determine the seroprevalence of T. gondii infection in 2 representative but epidemiologically distinct populations in Kyrgyzstan. The rural population was from a typical agricultural district where sheep husbandry is a major occupation. The urban population was selected in collaboration with several diagnostic laboratories in Bishkek, the largest city in Kyrgyzstan. We designed a questionnaire that was used on all rural subjects so a risk-factor analysis could be undertaken. The samples from the urban population were anonymous and only data with regard to age and gender was available. Estimates of putative cases of congenital and AIDS-related toxoplasmosis in the whole country were made from the results of the serology. Specific antibodies (IgG) against Triton X-100 extracted antigens of T. gondii tachyzoites from in vitro cultures were determined by ELISA. Overall seroprevalence of infection with T. gondii in people living in rural vs. urban areas was 6.2% (95%CI: 4.8–7.8) (adjusted seroprevalence based on census figures 5.1%, 95% CI 3.9–6.5), and 19.0% (95%CI: 16.5–21.7) (adjusted 16.4%, 95% CI 14.1–19.3), respectively, without significant gender-specific differences. The seroprevalence increased with age. Independently low social status increased the risk of Toxoplasma seropositivity while increasing numbers of sheep owned decreased the risk of seropositivity. Water supply, consumption of unpasteurized milk products or undercooked meat, as
Human cytomegalovirus (HCMV) is the most common virus infection in the developing fetus. A fraction of infants infected in utero develop significant life-threatening and organ-threatening disease with over 90% of infected infants exhibiting no clinical evidence of infection in the newborn period. However, about 10% of all infected infants will develop long-term sequelae. Early studies stressed the importance of primary maternal HCMV infection during pregnancy as a critical determinant of intrauterine transmission and outcome. This concept serves as the foundation for the development of prophylactic vaccines and biologics such as HCMV immune globulins. More recently, studies in maternal populations with high HCMV seroprevalence have challenged the concept of protective maternal immunity. Findings from multiple studies suggest that preexisting maternal HCMV immunity provides at best, partial protection from disease in the infected offspring and similarly may have limited impact on intrauterine transmission. This brief review will provide some considerations about the apparent paradox of maternal HCMV immunity and congenital infection.
Early Detection of Autism (ASD) by a Non-invasive Quick Measurement of Markedly Reduced Acetylcholine & DHEA and Increased β-Amyloid (1-42), Asbestos (Chrysotile), Titanium Dioxide, Al, Hg & often Coexisting Virus Infections (CMV, HPV 16 and 18), Bacterial Infections etc. in the Brain and Corresponding Safe Individualized Effective Treatment.
Omura, Yoshiaki; Lu, Dominic; Jones, Marilyn K; Nihrane, Ahdallah; Duvvi, Harsha; Shimotsuura, Yasuhiro; Ohki, Motomu
A brief historical background on Autism & some of the important symptoms associated with Autism are summarized. Using strong Electro Magnetic Field Resonance Phenomenon between 2 identical molecules with identical weight (which received U.S. Patent) non-invasively & rapidly we can detect various molecules including neurotransmitters, bacteria, virus, fungus, metals & abnormal molecules. Simple non- invasive measurement of various molecules through pupils & head of diagnosed or suspected Autism patients indicated that in Autism patients following changes were often found: 1) Acetylcholine is markedly reduced; 2) Alzheimer's disease markers (i.e. β-Amyloid (1-42), Tau Protein, Apolipoprotein (Apo E4)) are markedly increased; 3) Chrysotile Asbestos is increased; 4) Titanium Dioxide (TiO2) is moderately increased; 5) Al is moderately increased; 6) Hg is moderately increased; 7) Dopamine, Serotonin & GABA are significantly reduced (up to about 1/10 of normal); 8) Often viral infections (such as CMV, HHV-6, HPV-16, HPV-18, etc.), and Bacterial infections (such as Chlamydia trachomatis, Mycobacterium TB, Borrelia Burgdorferi, etc.) coexist. Research by others on Autism spectrum disorder (ASD) shows that it is a group of complex neurodevelopmental disorders, with about 70% of ASD patients also suffering from gastro-intestinal problems. While Alzheimer disease (AD) is characterized by formation of 1) Amyloid plaques, 2) Neurofibrillary tangles inside of neurons, and 3) Loss of connections between neurons. More than 90% of AD develops in people over the age of 65. These 3 characteristics often progressively worsen over time. Although Autism Spectrum Disorder and Alzheimer's disease are completely different diseases they have some similar biochemical changes. Eight examples of such measurement & analysis are shown for comparison. Most of Autism patients improved significantly by removing the source or preventing intake of Asbestos, TiO2, Al & Hg or enhancing urinary output
Spagnoli, Carlotta; Iodice, Alessandro; Salerno, Grazia Gabriella; Frattini, Daniele; Bertani, Gianna; Pisani, Francesco; Fusco, Carlo
Guillain-Barré syndrome is the most frequent cause of flaccid paresis in Western countries. Moreover, CMV infection is the most common antecedent viral infection in adult patients and the presence of specific IGM antiganglioside antibodies is often identified. Instead, Guillain-Barré syndrome following CMV infections is rarely reported in childhood and often presents severe symptoms at onset and longer recovery times. One year of clinical, electrophysiological and serological follow-up of a 9-year old child with axonal sensory-motor Guillain-Barré syndrome following CMV infection is reported. Moreover, the literature data on paediatric sensory-motor axonal GBS and GBS secondary to CMV infection and antiganglioside antibodies are reviewed. Our patient presented with paraesthesias and a pattern of weakness showing proximal predominance and affecting the upper limbs more than the lower limbs. At nadir, unilateral facial palsy was also present and he was unable to walk. Electroneurography showed motor-sensory axonal damage. Both anti-CMV and anti-GM2 IgM were positive. After early treatment with IVIG and IV methylprednisolone the patient recovered deambulation. Six months later, his neurological examination was normal and electroneurography showed normal data. The sensory-motor axonal form of Guillain-Barré syndrome following CMV infection may present a good prognosis and a prompt full recovery also in children, if adequate treatment is started in time. Copyright © 2015 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved.
Varga, Zsolt; Parmar, Dipak; Brown, Kevin E.
There is growing evidence for the role of rubella virus in Fuchs' uveitis syndrome (FUS). This report is the first to show persistent intraocular rubella virus in a 28-year-old man with congenital rubella syndrome (CRS), who presented with blurred vision and was diagnosed with FUS. PMID:23426927
Fang, Yuan-Yuan; Zhao, Jian-Hua; Liu, Shang-Wu; Wang, Sheng; Duan, Cheng-Guo; Guo, Hui-Shan
Using a transient plant system, it was previously found that the suppression of Cucumber mosaic virus (CMV) 2b protein relies on its double-strand (ds) RNA binding capacity, but it is independent of its interaction with ARGONAUTE (AGO) proteins. Thus, the biological meaning of the 2b-AGO interaction in the context of virus infection remains elusive. In this study, we created infectious clones of CMV mutants that expressed the 2b functional domains of dsRNA or AGO binding and tested the effect of these CMV mutants on viral pathogenicity. We found that the mutant CMV2b(1–76) expressing the 2b ds