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Symptomatic primary Epstein-Barr virus infection is a usually self-limiting illness in adolescents. We present a case of an adolescent who had been receiving azathioprine for inflammatory bowel disease for four years and developed a life-threatening primary Epstein-Barr virus infection successfully treated with rituximab.
An 11-year-old girl presented with chronic, bloody diarrhea. Endoscopic biopsies confirmed a diagnosis of chronic ulcerative colitis with features of Crohn’s disease. Azathioprine was initiated after one year due to active colitis. She responded well and remission was achieved. At the age of 16 years she developed a life-threatening Epstein-Barr virus infection including severe multiple organ failure and was critically ill for 4 weeks in the intensive care unit. Natural killer cells were virtually absent in the lymphocyte subset analysis. Azathioprine was stopped on admission. She was initially treated with corticosteroids, acyclovir and intravenous immunoglobulin. Approximately 30 days after admission, she developed signs of severe hepatitis and pneumonitis and received weekly rituximab infusions for 8 weeks. Primary immunodeficiency was excluded by whole exome sequencing in two independent laboratories. Persistent viremia stopped when the natural killer cell count started to rise, approximately 90 days after the cessation of azathioprine.
We found 17 comparable cases in the literature. None of the previous cases reported in the literature, who had been treated with azathioprine and developed either a severe or a fatal Epstein-Barr virus infection, underwent full genetic and prospective immunological workup to rule out known primary immunodeficiencies. Recently, azathioprine has been shown to cause rather specific immunosuppression, resulting in natural killer cell depletion. Our case demonstrates that slow recovery from azathioprine-induced natural killer cell depletion, 3 months after the stopping of azathioprine, coincided with the clearance of viremia and clinical recovery. Finally, our choice of treating the patient with rituximab, as previously used for patients with a severe immunosuppression and Epstein-Barr virus viremia, appeared to be successful in this case. We suggest testing for Epstein-Barr virus serology before starting azathioprine and measuring natural killer cell counts during the treatment to identify patients at risk of developing an unusually severe primary Epstein-Barr virus infection.
Leah S. Hohman, Nathan C. Peters
The generation of an efficacious vaccine that elicits protective CD4+ T cell-mediated immunity has been elusive. The lack of a vaccine against the Leishmania parasite is particularly perplexing as infected individuals acquire life-long immunity to reinfection. Experimental observations suggest that the relationship between immunological memory and protection against Leishmania is not straightforward and that a new paradigm is required to inform vaccine design. These observations include: (i) induction of Th1 memory is a component of protective immunity, but is not sufficient; (ii) memory T cells may be protective only if they generate circulating effector cells prior to, not after, challenge; and (iii) the low-dose/high-inflammation conditions of physiological vector transmission compromises vaccine efficacy.
The Committee on Climate Change (CCC), an independent body that advises the UK Government, published a report on May 2, Net zero—the UK's contribution to stopping global warming. Stating that net zero is “necessary, feasible, and cost-effective”, the CCC set a target year of 2050 for complete elimination of greenhouse gas (GHG) emissions in the UK. The report provides a comprehensive framework for multiple sectors that the government could feasibly adopt to adhere to the 2015 Paris Agreement and Intergovernmental Panel on Climate Change (IPCC) limits of 1·5–2·0 degrees global warming from pre-industrial levels by 2050.
At the Annual Scientific Meeting of the Australia and New Zealand College of Anaesthetists in Kuala Lumpur (Malaysia) last week, Dr Mary Suma Cardosa, pain specialist at Hospital Selayang and President of the Malaysian Association for the Study of Pain, presented over a decade of work in Malaysia addressing pain. Cardosa described how adoption of “pain as the fifth vital sign” in 2008 improved awareness of pain in hospitals but did not lead to significant practice change. The Pain Free Hospital campaign was subsequently initiated in Malaysia's public health system in 2011, and extended to include primary care and dental services in 2017.
What will the world of research look like in 2029? How will research be funded? What are the pathways to open science? How will researchers work, and what will be the role of technology? How will the research information system change, and what will education look like? On May 2, at a conference organised by the European Health Forum Gastein, and hosted by Wellcome in London (UK), possible drivers shaping the future of research were outlined.
Simon Marie Peko, Francine Ntoumi, Christevy Vouvoungui, David Nderu, Simon Charles Kobawila, Velavan P. Thirumalaisamy, Félix Koukouikila−Koussounda
Gonzalo Bearman, Richard P. Wenzel
Warne, T., Edwards, P. C., Dore, A. S., Leslie, A. G. W., Tate, C. G.
G protein-coupled receptors (GPCRs) in the G protein-coupled active state have higher affinity for agonists compared to when they are in the inactive state, but the molecular basis for this is unclear. We have determined four active-state structures of the β1-adrenoceptor (β1AR) bound to conformation-specific nanobodies in the presence of agonists of varying efficacy. Comparison with inactive-state structures of β1AR bound to the identical ligands showed a 24-42% reduction in the volume of the orthosteric binding site. Potential hydrogen bonds were also shorter, and there was up to a 30% increase in the number of atomic contacts between the receptor and ligand. This explains the increase in agonist affinity of GPCRs in the active state for a wide range of structurally distinct agonists.
Brechje de Gier, Merel N. van Kassel, Elisabeth A. M. Sanders, Diederik van de Beek, Susan J. M. Hahné, Arie van der Ende, Merijn W. Bijlsma
by Brechje de Gier, Merel N. van Kassel, Elisabeth A. M. Sanders, Diederik van de Beek, Susan J. M. Hahné, Arie van der Ende, Merijn W. Bijlsma
Background Group B Streptococcus (GBS) is the leading cause of neonatal sepsis and meningitis worldwide. We aimed to estimate the current burden of neonatal invasive GBS disease in the Netherlands, as a first step in providing an evidence base for policy makers on the potential benefits of a future maternal GBS vaccine. Methods Surveillance of neonatal invasive GBS occurs at the National Reference Laboratory for Bacterial Meningitis, where culture isolates from cerebrospinal fluid and blood are sent by diagnostic laboratories. From the number of cultures we estimated the incidence of neonatal (age 0–90 days) GBS meningitis and sepsis. We constructed a disease progression model informed by literature and expert consultation to estimate the disease burden of neonatal invasive GBS infection. As many neonates with a probable GBS sepsis are never confirmed by blood culture, we further estimated the disease burden of unconfirmed cases of probable GBS sepsis in sensitivity analyses. Results An estimated 97 cases and 6.5 deaths occurred in the Netherlands in 2017 due to culture positive neonatal invasive GBS infection. This incidence comprised 15 cases of meningitis and 42 cases of sepsis per 100.000 births, with an estimated mortality of 3.8 per 100.000 live births. A disease burden of 780 disability-adjusted life years (DALY) (95% CI 650–910) or 460 DALY per 100.000 live births was attributed to neonatal invasive GBS infection. In the sensitivity analysis including probable neonatal GBS sepsis the disease burden increased to 71 cases and 550 DALY (95% CI 460–650) per 100.000 live births. Conclusion In conclusion, neonatal invasive GBS infection currently causes a substantial disease burden in the Netherlands. However, important evidence gaps are yet to be filled. Furthermore, cases of GBS sepsis lacking a positive blood culture may contribute considerably to this burden potentially preventable by a future GBS vaccine.
Kan Kledmanee, Tippawan Liabsuetrakul, Somporn Sretrirutchai
by Kan Kledmanee, Tippawan Liabsuetrakul, Somporn Sretrirutchai
Background Brucellosis, coxiellosis, and toxoplasmosis can be transmitted from infected ruminants to pregnant women and may induce adverse pregnancy outcomes; however, there are to date few studies. This study aimed to examine the seropositivities of immunoglobulin G (IgG) against those three pathogens among pregnant women with adverse pregnancy outcomes, and to explore the associated factors. Methods A cross-sectional study was conducted in southern Thailand, where goat production is common. A total of 105 pregnant Thai women who had adverse pregnancy outcomes and serum samples collected at first antenatal care visit before their 28th gestational week from June 2015 to June 2016 were included. The seropositivities of IgG anti-Brucella abortus, Toxoplasma gondii, and Coxiella burnetii antibodies were tested by using commercial enzyme-linked immunosorbent assay (ELISA) kits. Associated factors with seropositivity were analyzed using multiple logistic regression. Results Most women were Muslim aged 20–34 years and 32.4% had a prior history of one or more adverse pregnancy outcomes. One-third of the women had been exposed to goats or raw goat products. Of the 105 serum samples, the seropositivity of anti-T. gondii IgG was highest (33/105, 31.4%), followed by anti-C. burnetii IgG (2/105, 1.9%), and anti-B. abortus IgG (1/105, 1.0%), respectively. None of the pregnant women were found to be co-seropositive for those three pathogens. Conclusions One-third of women with adverse pregnancy outcomes showed positive antibodies for toxoplasmosis, coxiellosis and brucellosis. A dose-response relationship between seropositivity of anti-T. gondii IgG and age was noticed.
Erin McNulty, Amy V. Nalls, Samuel Mellentine, Erin Hughes, Laura Pulscher, Edward A. Hoover, Candace K. Mathiason
by Erin McNulty, Amy V. Nalls, Samuel Mellentine, Erin Hughes, Laura Pulscher, Edward A. Hoover, Candace K. Mathiason
Longitudinal studies of chronic wasting disease (CWD) in the native host have provided considerable understanding of how this prion disease continues to efficiently spread among cervid species. These studies entail great cost in animal, time and financial support. A variety of methods have emerged including transgenic mouse bioassay, western blot, enzyme-linked immunoassay (ELISA), immunohistochemistry (IHC), serial protein misfolding cyclic amplification (sPMCA) and real time quaking-induced conversion (RT-QuIC), that deepen our understanding of this and other protein misfolding disorders. To further characterize an inoculum source used for ongoing CWD studies and to determine how the readouts from each of these assays compare, we assayed a CWD-positive brain pool homogenate (CBP6) and a mouse dilutional bioassay of this homogenate using the above detection methods. We demonstrate that: (i) amplification assays enhanced detection of amyloid seeding activity in the CWD+ cervid brain pool to levels beyond mouse LD50, (ii) conventional detection methods (IHC and western blot) performed well in identifying the presence of PrPSc in terminal brain tissue yet lack sufficient detection sensitivity to identify all CWD-infected mice, and (iii) the incorporation of amplification assays enhanced detection of CWD-infected mice near the LD50. This cross-platform analysis provides a basis to calibrate the relative sensitivities of CWD detection assays.
Christian Mpody, Peyton Thompson, Martine Tabala, Noro Lantoniaina Rosa Ravelomanana, Fathy Malongo, Bienvenu Kawende, Frieda Behets, Emile Okitolonda, Marcel Yotebieng, for the CQI-PMTCT study team
by Christian Mpody, Peyton Thompson, Martine Tabala, Noro Lantoniaina Rosa Ravelomanana, Fathy Malongo, Bienvenu Kawende, Frieda Behets, Emile Okitolonda, Marcel Yotebieng, for the CQI-PMTCT study team
Background Hepatitis B virus (HBV) co-infection in HIV-infected individuals increases the risk of hepatic complications and mortality. Further, the risk of perinatal HBV transmission increases among HBV/HIV co-infected pregnant women. Although HBV is endemic in the Democratic Republic of Congo, there is little data on HBV/HIV co-infection. We aimed to assess the burden and risk factors of HBV surface antigen (HBsAg) positivity among HIV-infected pregnant and post-partum women. Methods This cross-sectional study was conducted as part of an ongoing trial to assess the effect of data-driven continuous quality improvement interventions (CQI) for optimal prevention of mother-to-child transmission (PMTCT) of HIV (CQI-PMTCT study, NCT03048669). In each of the 35 health zones of Kinshasa province, all HIV-infected pregnant or breastfeeding women (≤1 year post-delivery) presenting for care in one of the three busiest maternal and child health clinics of the health zone were tested for HBsAg using Alere Determine, Japan. We used logistic regression with general estimating equation accounting for within-clinic clustering to assess risk factors of HBsAg positivity. Results Between November 2016 and June 2018, a total of 1377 women, all on antiretroviral therapy, were tested for HBsAg. Overall, 4.7% [95% binomial confidence interval (CI): 3.7%-5.7%] tested positive for HBsAg. HBsAg prevalence was 3.3% (95% CI: 2.1%-4.8%) for women tested during pregnancy, 4.5% (2.5%-7.4%) for those tested at delivery, and 8.5% (5.6%-12.2%) for those tested post-partum (Ptrend = 0.001). In multivariate models including socio-economic status (SES), type of care facility, duration of antiretroviral therapy, HIV viral load, and self-reported intimate partner violence (IPV), lowest tertile of SES, ≤ 6 months of ART, and IPV were all consistently and positively associated with higher prevalence of HBsAg across pregnancy, delivery, and postpartum period while been tested in a health centre or having a viral load ≥ 1000 copies/mL were consistently associated with lower prevalence. However, only the association with IPV (OR = 2.74, 95% CI: 1.10–6.84) and viral load between 40–1000 copies/ml (OR = 4.28, 95% CI: 1.22–15.01) achieved statistical significance among pregnant women. Conclusion This study revealed an overall high prevalence of HBsAg among HIV-infected pregnant and post-partum women in Kinshasa with the latter showing the highest HBsAg prevalence. Among pregnant women, intimate partner violence was independently and statistically associated with HBsAg positivity, requiring further investigation.
Mioljub Ristić, Vesna Milošević, Snežana Medić, Jelena Djekić Malbaša, Smiljana Rajčević, Jasmina Boban, Vladimir Petrović
by Mioljub Ristić, Vesna Milošević, Snežana Medić, Jelena Djekić Malbaša, Smiljana Rajčević, Jasmina Boban, Vladimir Petrović
Background Age-stratified serologic surveys provide insight into the gaps of measles-specific immunity as well as estimates of the age-specific seroprevalence. The aim of this study was to describe the measles sero-epidemiology in Vojvodina before the occurrence of outbreak in 2017/18 and to discuss preventive measures for potential future epidemics. Methods A seroprevalence study was conducted from April 2015 to June 2017 on serum bank of 3199 residual samples. Study was performed prior to the last measles outbreak in Vojvodina that occurred between 12th November 2017 and 30th June 2018. Measles-specific IgG antibodies were determined using an indirect chemiluminescent immunoassay (CLIA). Results Median age of enrolled participants was 20 years (IQR 11–37). Overall, 86.9% serum samples were seropositive. The highest proportion of measles seronegativity was observed in children aged 12–23 months of age and in adults aged 20–39 years (56.1% and 18.5%, respectively). Prevalence of measles seronegativity above WHO target levels susceptibility was observed in the following age groups: 2, 7, 13, 15, and among all adults aged between 20 and 49 years. Out of total measles outbreak cases (177), there were 91 (51.4%) participants aged 20–39 years. A significant positive correlation was observed between measles seronegativity and the number of reported measles cases aged ≥ 12 months (r = 0.4675, p = 0.0213). Conclusions In order to prevent new outbreaks and achieve the elimination of measles in Vojvodina, the vaccination coverage of both measles-mumps-rubella (MMR1 and MMR2) vaccines needs to be improved and sustained. Educational campaigns for the improvement of acceptance and timely vaccination with vaccine against measles among doctors and the general population are crucial. Our results indicate possible gap in measles protection in adults born during implementation of one dose of measles vaccine and prioritize supplementary immunization activities targeting adults in Vojvodina, Serbia.
Panagiota Economopoulou, George Koutsodontis, Margaritis Avgeris, Areti Strati, Christos Kroupis, Ioannis Pateras, Euthymios Kirodimos, Evangelos Giotakis, Ioannis Kotsantis, Pavlos Maragoudakis, Vassilis Gorgoulis, Andreas Scorilas, Evi Lianidou, Amanda Psyrri
by Panagiota Economopoulou, George Koutsodontis, Margaritis Avgeris, Areti Strati, Christos Kroupis, Ioannis Pateras, Euthymios Kirodimos, Evangelos Giotakis, Ioannis Kotsantis, Pavlos Maragoudakis, Vassilis Gorgoulis, Andreas Scorilas, Evi Lianidou, Amanda Psyrri
Objectives Human papillomavirus-related oropharyngeal squamous cell carcinoma (HPV+ OPSCC) is increasing in incidence. Although HPV+ OPSCC has favorable prognosis, 10 to 25% of HPV+ OPSCCs eventually recur. We sought to evaluate the feasibility of detection of HPV16 E6/E7 expression in Circulating Tumor Cells (CTCs) and its utility as a prognostic tool in HPV16-associated OPSCC. Materials and methods We developed a highly sensitive RT-qPCR assay for HPV mRNA expression in EpCAM(+) CTCs. In 22 patients with early stage and locally advanced OPSCC we evaluated HPV16 E6/E7 expression in the EpCAM(+) CTC fraction at baseline and at the end of concurrent chemoradiotherapy. HPV status in pre-therapy formalin-fixed paraffin-embedded (FFPE) tumor biopsies was assessed by p16 immunohistochemistry and polymerase chain reaction (PCR) and double positives were subjected to Real-time qPCR assay for detection of HPV16, 18 and 31 types. Results Fourteen of 22 OPSCC (63.6%) were HPV DNA+/p16+. Among HPV+/p16+ patients, 10 patients (71.4%) were HPV16 DNA+. HPV16 E6/E7(+) CTCs were detected in 3 of 10 patients (30%) at baseline and 4 of 9 patients (44.4%) at the end-of-treatment, all of which were p16+/HPV16 DNA+. Survival analysis showed a significantly higher risk for disease relapse (p = 0.001) and death (p = 0.005) in patients with HPV16 E6/E7(+) baseline CTCs. Conclusion Detection of HPV E6/E7(+) CTCs might be a useful noninvasive test in liquid biopsy samples for determination of a clinically relevant HPV infection in HPV+ OPSCC. Combined interpretation of HPV E6/E7(+) CTCs with UICC staging data may lead to alteration of risk definition of patient subsets, with improved risk discrimination in early-stage disease.
José-Ramón Blanco, Inmaculada Barrio, Enrique Ramalle-Gómara, María Isabel Beltran, Valvanera Ibarra, Luis Metola, Mercedes Sanz, José A. Oteo, Estrella Melús, Lucía Antón
by José-Ramón Blanco, Inmaculada Barrio, Enrique Ramalle-Gómara, María Isabel Beltran, Valvanera Ibarra, Luis Metola, Mercedes Sanz, José A. Oteo, Estrella Melús, Lucía Antón
Background Patients with HIV infection suffer from accelerated aging. In this context, frailty could be a relevant problem that aggravates the quality of life (QoL) and morbi-mortality of these patients. Our objective was to determine the prevalence of frailty and pre-frailty in HIV-infected patients in our cohort as well as their risk factors and QoL. Methods This was a prospective cross-sectional study of HIV-infected people aged ≥18 years on a stable antiretroviral regimen (ART) ≥1 year. Frailty was defined by ≥3 of 5 Fried's criteria: weight loss, low physical activity, exhaustion, weak grip strength and slow walking time. Variables related to sociodemographics, HIV infection, comorbidities, polypharmacy, and QoL were evaluated. Independent predictors of frailty were evaluated using collinearity in a multivariate logistic regression analyses (backward stepwise elimination). Results The 248 people studied has a mean age of 49 years, 63.7% were male, and 81% were Caucasian. The prevalence of pre-frailty and fragility was 39.1% and 4.4%, respectively. The main route of HIV acquisition was heterosexual (47.2%). At the inclusion time 26.6% of the patients had AIDS events, 60.9% were anti-HCV negative, and 91.5% had HIV RNA 2 comorbidities, and 13.3% were receiving >5 non-HIV drugs. Frailty patients had a higher age (p 0.006), more sensitive deficits (visual or auditory) (p 0.002), a greater number of falls during the previous year (p 0.0001), a higher Charlson comorbidity index (p 0.001), and a higher VACS index (p 0.001). All comorbidities, excluding bone and liver, were significantly more frequent in fragile patients. The presence of >2 comorbidities and treatment with >5 drugs not related to HIV they were also more frequent in frail patienst (p 0.0001 and p 0.004, respectively). Independent predictors of pre-frailty/frailty in the multivariable analysis differ in men (VACS index, C-reactive protein [CRP], and falls) and women (CRP, AIDS, and menopause). Patients with pre-frailty/frailty had some indicator of a lower QoL. Conclusion Factors associated with pre-frailty/frailty in HIV-infected patients differ by gender, which should be considered when establishing measures for prevention. The role of menopause in the risk of pre-frailty/frailty warrants further investigations.
Uchechukwu M. Chukwuocha, Gregory N. Iwuoha, Geoffrey C. Nwakwuo, Peter K. Egbe, Chidinma D. Ezeihekaibe, Christopher P. Ekiyor, Ikechukwu N. S. Dozie, Sahai Burrowes
by Uchechukwu M. Chukwuocha, Gregory N. Iwuoha, Geoffrey C. Nwakwuo, Peter K. Egbe, Chidinma D. Ezeihekaibe, Christopher P. Ekiyor, Ikechukwu N. S. Dozie, Sahai Burrowes
This study assesses malaria prevention and treatment behaviour among people living with HIV/AIDS (PLWHA) in Owerri, South Eastern Nigeria. Although Nigeria bears one of the world’s largest burdens of both malaria and HIV, there is almost no research studying how co-infected patients manage their care. We systematically sampled 398 PLWHA receiving care at Imo State Specialist Hospital and the Federal Medical Centre in Owerri to complete a structured, pre-tested questionnaire on malaria care-seeking behaviour. Descriptive statistics were reported and chi-square tests and multivariate logistic regressions were also used. The majority of HIV-infected patients (78.9%) reported having had an episode of suspected malaria quarterly or more often. There was a large variation in care-seeking patterns: on suspicion of malaria, 29.1% of participants engaged in self-medication; 39.2% went to drug shops, and only 22.6% visited HIV/AIDS care centres. Almost 40% waited more than 24 hours before initiating treatment. Most (60.3%), reported taking recommended artemisinin-based combination treatments (ACT) but a significant minority took only paracetamol (25.6%) or herbal remedies (3.5%). Most (80%) finished their chosen course of treatment; and completion of treatment was significantly associated with the frequency of suspected malaria occurrence (p = 0.03). Most (62.8%) did not take anti-malaria medication while taking antiretroviral treatment (ART) and almost all (87.6%) reported taking an ACT regimen that could potentially interact with Nigeria’s first-line ART regimen. Our findings suggest the need to pay more attention to malaria prevention and control as a crucial element in HIV/AIDS management in this part of Nigeria and other areas where malaria and HIV/AIDS are co-endemic. Also, more research on ART-ACT interactions, better outreach to community-level drug shops and other private sector stakeholders, and clearer guidelines for clinicians and patients on preventing and managing co-infection may be needed. This will require improved collaboration between programmes for both diseases.
Lee N, Walsh E, Sander I, et al.
AbstractBackgroundDespite the prevalence of respiratory syncytial virus (RSV) in adults hospitalized with acute respiratory infections, guidelines for the diagnosis and management of RSV have not been established. This analysis evaluated the role and timeliness of RSV diagnostic testing and its potential impact on clinical outcomes.MethodsWe analyzed individual patient data from hospitalized adults with confirmed RSV infections during two North American RSV seasons. Participating physicians reported clinical, virologic diagnosis, and outcome variables using a standardized online case form.ResultsOne-hundred-and-thirty-two physicians across thirty-two US states reported 379 RSV cases. PCR-based diagnostics were the most common type of test ordered (94.2%) with
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