Nicolas Dauby

Meropenem/clavulanate and linezolid treatment for extensively drug-resistant tuberculosis.

The combination of meropenem with clavulanate has high antimycobacterial activity in vitro against extensively drug-resistant Mycobacterium tuberculosis strains. We report the successful use of this combination in association with linezolid in the management of an advanced extensively drug-resistant tuberculosis disease with complex second-line drug resistance in a 14-year-old teenager.

Characteristics of non-AIDS-defining malignancies in the HAART era: a clinico-epidemiological study

BackgroundNon-AIDS-defining malignancies (NADM) are becoming a major cause of mortality in the era of highly active antiretroviral therapy. We wished to investigate the incidence, risks factors and outcome of NADM in an urban cohort.MethodsWe carried out an observational cohort of HIV patients with 12,746 patient-years of follow up between January 2002 and March 2009. Socio-demographics and clinical characteristics of patients diagnosed with NADM were retrospectively compared with the rest of the cohort. Causes of death and risk factors associated with NADM were assessed using logistic regression. Survival analyses were performed with Kaplan-Meier estimates. Cancer incidences were compared with those of the general population of the Brussels-Capital Region using the standardized incidence ratio (SIR).ResultsForty-five NADM were diagnosed. At inclusion in the study, patients with NADM were older than patients without NADM (47 years vs. 38 years, p < 0.001), had a longer history of HIV infection (59 months vs. 39 months, p = 0.0174), a lower nadir CD4 count (110 cells/mm3 vs. 224 cells/mm3, p < 0.0001) and a higher rate of previous AIDS events (33% vs. 20%, p = 0.0455) and of hepatitis C virus co-infection (22.2% vs. 10%, p = 0.0149). In multivariate analysis, age over 45 at baseline (OR 3.25; 95% CI 1.70-6.22) and a nadir CD4 count of less than 200 cells/mm3 (OR 3.10; 95% CI 1.40-6.87) were associated with NADM. NADM were independently associated with higher mortality in the cohort (OR 14.79; 95% CI 6.95-31.49). Women with cancer, the majority of whom were of sub-Saharan African origin, had poorer survival compared with men. The SIR for both sexes were higher than expected for Hodgkins lymphoma (17.78; 95% CI 6.49-38.71), liver cancers (8.73; 95% CI 2.35-22.34), anal cancers (22.67; 95% CI 8.28-49.34) and bladder cancers (3.79; 95% CI 1.02-9.70). The SIR for breast cancer was lower in women (SIR 0.29; 95% CI 0.06-0.85).ConclusionsAge over 45 and a nadir CD4 count of less than 200 cells/mm3 were predictive of NADM in our cohort. Mortality was high, especially in sub-Saharan African women. Cancers with increased incidences were Hodgkins lymphoma and anal, bladder and liver cancers in both sexes; women had a lower incidence of breast cancer.

Maternal infection with Trypanosoma cruzi and congenital Chagas disease induce a trend to a type 1 polarization of infant immune responses to vaccines.

Background We previously showed that newborns congenitally infected with Trypanosoma cruzi (M+B+) display a strong type 1 parasite-specific T cell immune response, whereas uninfected newborns from T. cruzi-infected mothers (M+B−) are prone to produce higher levels of proinflammatory cytokines than control neonates (M−B−). The purpose of the present study was to determine if such fetal/neonatal immunological environments could alter the response to standard vaccines administered in early life. Methodology Infants (6–7 months old) living in Bolivia, an area highly endemic for T. cruzi infection, and having received Bacillus Calmette Guerin (BCG), hepatitis B virus (HBV), diphtheria and tetanus vaccines, were enrolled into the M+B+, M+B−, M−B− groups mentioned above. The production of IFN-γ and IL-13, as markers of Th1 and Th2 responses respectively, by peripherical blood mononuclear cells stimulated with tuberculin purified protein derivative of Mycobacterium tuberculosis (PPD) or the vaccinal antigens HBs, diphtheria toxoid (DT) or tetanus toxoid (TT), as well as circulating levels of IgG antibodies against HBsAg, DT and TT were analyzed in infants. Cellular responses to the superantigen SEB were also monitored in M+B+, M+B−, M−B−infants and newborns. Principal Findings M+B+ infants developed a stronger IFN-γ response to hepatitis B, diphtheria and tetanus vaccines than did M+B− and M−B− groups. They also displayed an enhanced antibody production to HBsAg. This was associated with a type 1-biased immune environment at birth, since cells of M+B+ newborns produced higher IFN-γ levels in response to SEB. M+B− infants produced more IFN-γ in response to PPD than the other groups. IL-13 production remained low and similar in all the three groups, whatever the subjects ages or vaccine status. Conclusion These results show that: i) both maternal infection with T. cruzi and congenital Chagas disease do not interfere with responses to BCG, hepatitis B, diphtheria and tetanus vaccines in the neonatal period, and ii) the overcoming of immunological immaturity by T. cruzi infection in early life is not limited to the development of parasite-specific immune responses, but also tends to favour type 1 immune responses to vaccinal antigens.

Primary Human Cytomegalovirus Infection Induces the Expansion of Virus-Specific Activated and Atypical Memory B Cells

BACKGROUND Although neutralizing antibodies play a central role in the control of cytomegalovirus (CMV) dissemination, little is known about the response of B lymphocytes to primary human CMV infection. METHODS The proportion, phenotype, specificity, and functionality of B-cell subsets were studied in a cohort of pregnant women with primary CMV infection. CMV-seronegative pregnant women, as well as CMV-seronegative and CMV-seropositive healthy adults, were included as controls. RESULTS Primary CMV infection was associated with a sustained expansion of activated (CD27(+)CD20(+)CD21(low)) and atypical (CD27(-)CD20(+)CD21(low)) memory B cells (MBCs). Both subsets expressed an effector phenotype, and their proportions were correlated with viremia. Activated MBCs expressed high levels of activation markers and included high frequencies of tumor necrosis α (TNF-α)-producing cells, whereas atypical MBCs expressed high levels of inhibitory receptors and had low TNF-α responses. Fluorescent-labeled antigen experiments indicated that activated and atypical MBCs were enriched in CMV-specific cells. CONCLUSIONS Primary CMV infection mobilizes a large pool of memory B cells that includes activated and atypical MBCs. The functional regulation of CMV-specific MBCs may limit the production of antibodies and the control of viral dissemination.

Maternal immunisation: collaborating with mother nature

Maternal immunisation has the potential to substantially reduce morbidity and mortality from infectious diseases after birth. The success of tetanus, influenza, and pertussis immunisation during pregnancy has led to consideration of additional maternal immunisation strategies to prevent group B streptococcus and respiratory syncytial virus infections, among others. However, many gaps in knowledge regarding the immunobiology of maternal immunisation prevent the optimal design and application of this successful public health intervention. Therefore, we did an innovative landscape analysis to identify research priorities. Key topics were delineated through review of the published literature, consultation with vaccine developers and regulatory agencies, and a collaborative workshop that gathered experts across several maternal immunisation initiatives-group B streptococcus, respiratory syncytial virus, pertussis, and influenza. Finally, a global online survey prioritised the identified knowledge gaps on the basis of expert opinion about their importance and relevance. Here we present the results of this worldwide landscape analysis and discuss the identified research gaps.

Immunity to cytomegalovirus in early life

Cytomegalovirus (CMV) is the most common congenital infection and is the leading non-genetic cause of neurological defects. CMV infection in early life is also associated with intense and prolonged viral excretion, indicating limited control of viral replication. This review summarizes our current understanding of the innate and adaptive immune responses to CMV infection during fetal life and infancy. It illustrates the fact that studies of congenital CMV infection have provided a proof of principle that the human fetus can develop anti-viral innate and adaptive immune responses, indicating that such responses should be inducible by vaccination in early life. The review also emphasizes the fact that our understanding of the mechanisms involved in symptomatic congenital CMV infection remains limited.

Limited Effector Memory B-Cell Response to Envelope Glycoprotein B During Primary Human Cytomegalovirus Infection

BACKGROUND Following primary human cytomegalovirus (HCMV) infection, the production of antibodies against envelope glycoprotein B (gB) is delayed, compared with production of antibodies against tegument proteins, and this likely reduces the control of HCMV dissemination. METHODS The frequency and the phenotype of gB-specific and tegument protein-specific B cells were studied in a cohort of pregnant women with primary HCMV infection. Healthy adults who had chronic HCMV infection or were recently immunized with tetanus toxoid (TT) were included as controls. RESULTS Primary HCMV infection was associated with high and similar frequencies of gB-specific and tegument protein-specific B cells following primary HCMV infection. During primary infection, tegument protein-specific B cells expressed an activated (CD21(low)) memory B-cell (MBC) phenotype. Activated MBCs were also induced by TT booster immunization, indicating that the expansion of this subset is part of the physiological B-cell response to protein antigens. In contrast, gB-specific B cells had a predominant classical (CD21(+)) MBC phenotype during both primary and chronic infections. CONCLUSIONS The delayed production of gB-specific immunoglobulin G (IgG) during primary HCMV infection is associated with a limited induction of MBCs with effector potential. This novel mechanism by which HCMV may interfere with the production of neutralizing antibodies could represent a target for therapeutic immunization.

Increased Risk of Group B Streptococcus Invasive Infection in HIV-Exposed but Uninfected Infants: A Review of the Evidence and Possible Mechanisms

Group B Streptococcus (GBS) is a major cause of neonatal sepsis and mortality worldwide. Studies from both developed and developing countries have shown that HIV-exposed but uninfected (HEU) infants are at increased risk of infectious morbidity, as compared to HIV-unexposed uninfected infants (HUU). A higher susceptibility to GBS infections has been reported in HEU infants, particularly late-onset diseases and more severe manifestations of GBS diseases. We review here the possible explanations for increased susceptibility to GBS infection. Maternal GBS colonization during pregnancy is a major risk factor for early-onset GBS invasive disease, but colonization rates are not higher in HIV-infected compared to HIV-uninfected pregnant women, while selective colonization with more virulent strains in HIV-infected women is suggested in some studies. Lower serotype-specific GBS maternal antibody transfer and quantitative and qualitative defects of innate immune responses in HEU infants may play a role in the increased risk of GBS invasive disease. The impact of maternal antiretroviral treatment and its consequences on immune activation in HEU newborns are important to study. Maternal immunization presents a promising intervention to reduce GBS burden in the growing HEU population.

Prevalence and risk factors of measles seronegativity in a cohort of HIV-positive subjects: a retrospective study

OBJECTIVES Measles infection is a vaccine-preventable disease currently resurging in Europe. HIV-infected subjects are at higher risk of complications following measles infection. We investigated the risk factors associated with being seronegative in a cohort of HIV-infected subjects. METHODS All HIV-infected subjects in our cohort who had a measles serological test performed between December 2005 and May 2017 were retrospectively identified. A measles immunoglobulin G (IgG) titre > 275 mIU/mL was considered protective. Risk factors were analysed using logistic regression. RESULTS Measles serology was available in 273 of 3124 subjects in active follow-up (8.7%). The prevalence of measles seronegativity was 21.6% (59 of 273). In the univariate analysis, being born after 1970 and HIV infection by vertical transmission were both associated with a higher risk of measles seronegativity, while a nadir CD4 T-cell count < 200 cells/μL was associated with a lower risk of measles seronegativity. In the multivariate analysis, only being born after 1970 [odds ratio (OR) 4.9; 95% confidence interval (CI) 1.3-18.7] and vertical transmission (OR 7.7; 95% CI 3.3-18.3) were significantly associated with seronegativity. Among the vertically infected subjects with measles-mumps-rubella (MMR) immunization documentation, the median number of doses of vaccine received before testing was 2 (range 1-3). CONCLUSIONS HIV-infected subjects born after 1970 and vertically infected subjects should be screened for measles seropositivity.

Case Report: Delayed or Recurrent Plasmodium falciparum Malaria in Migrants: A Report of Three Cases with a Literature Review

Emerging evidence indicates that migrants from Plasmodium falciparum endemic regions are at risk of delayed presentation of P. falciparum malaria. We report three cases of P. falciparum malaria occurring years after arrival in Europe. All patients were originally from Sub-Saharan Africa. Two subjects had controlled human immunodeficiency virus infection and one was a pregnant woman. We performed a literature review of all published cases of delayed presentation of P. falciparum in migrants and identified 32 additional cases. All cases but one originate from sub-Saharan Africa. There was a median time of 36 months between the last visit to a malaria-endemic country and clinical malaria (range: 3 months to 10 years). Pregnancy was the most frequently reported risk factor (11/35 or 31.4%). Parasitemia was ≤ 0.1% in 38% of cases (11/29 reported), and no death was reported. The underlying possible mechanisms for this delayed presentation in migrants from an endemic area probably include the persistence of submicroscopic parasitemia combined with decaying P. falciparum-specific immunity. Suspicion of P. falciparum delayed malaria should remain high in migrants, mainly from sub-Saharan Africa, even without a recent travel history, especially in those presenting risk factors for impaired parasite clearance or distinct immune responses such as pregnancy and HIV infection. In these patients, new prevention and screening strategies should be studied and blood safety policies adapted.