A less than one-month-old infant with symptoms of rhinitis died unexpectedly in his sleep. He was not born prematurely and had no known underlying disease. Cerebrospinal fluid, nasopharyngeal and lung samples, and rectal swab were found to be positive for subgroup A rhinovirus, while the blood was negative. This case highlights the important finding that the rhinovirus, a common pathogen associated with upper respiratory tract infections, can sometimes, as the only pathogen, lead to complications such as a cerebrospinal infection and be involved in the sudden infant death syndrome (SIDS). Vigilance is necessary in case of viral infections in the infant’s environment, and measures of hygiene and protection must be encouraged in order to reduce the risk of the SIDS.

The aim of this study was to evaluate whether community-level monitoring of respiratory and enteric viruses in wastewater can provide a comprehensive picture of local virus circulation. Wastewater samples were collected weekly at the wastewater treatment plant (WWTP) inlet and at the outlet of a nearby nursing home (NH) in Burgundy, France, during the winter period of 2022/2023. We searched for the pepper mild mottle virus as an indicator of fecal content as well as for the main respiratory viruses [severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), influenza, and respiratory syncytial virus] and enteric viruses (rotavirus, sapovirus, norovirus, astrovirus, and adenovirus). Samples were analyzed using real-time reverse transcription PCR-based methods. SARS-CoV-2 was the most frequently detected respiratory virus, with 66.7% of positive samples from the WWTP and 28.6% from the NH. Peaks of SARS-CoV-2 were consistent with the chronological incidence of infections recorded in the sentinel surveillance and the nearby hospital databases. The number of positive samples was lower in the NH than in WWTP for the three respiratory viruses. Enteric viruses were frequently detected, most often sapovirus and norovirus genogroup II, accounting both for 77.8% of positive samples in the WWTP and 57.1% and 37%, respectively, in the NH. The large circulation of sapovirus was unexpected in particular in the NH. Combined wastewater surveillance using simple optimized methods can be a valuable tool for monitoring viral circulation and may serve as a suitable early warning system for identifying both local outbreaks and the onset of epidemics. These results encourage the application of wastewater-based surveillance (WBS) to SARS-CoV2, norovirus, and sapovirus.IMPORTANCEWBS provides valuable information on the spread of epidemic viruses in the environment using appropriate and sensitive detection methods. By monitoring the circulation of viruses using reverse transcription PCR methods in wastewater from the inlet of a wastewater treatment plant and the outlet of a nearby retirement home (connected to the same collective sewer network), we aimed to demonstrate that implementing combined WBS at key community sites allows effective detection of the occurrence of respiratory (influenza, respiratory syncytial virus, and SARS-CoV-2) and enteric (norovirus, rotavirus, and sapovirus) virus infections within a given population. This analysis on a localized scale provided new information on the viral circulation in the two different sites. Implementing WBS to monitor the circulation or the emergence of infectious diseases is an important means of alerting the authorities and improving public health management. WBS could participate actively to the health of humans, animals, and the environment.

Human papillomavirus is a predominant sexually transmitted viral pathogen. Our objective was to analyze the relative distribution of genotypes over time and to determine the genotypes associated with adverse clinical lesions. The study was based on data from adult women with cytological abnormalities from whom histological samples were obtained from 2005 to 2021. HPV genotyping was performed using PCR and INNO-LiPA assay (Fujirebio). Among the 1,017 HPV-positive biopsies, 732 (72%) were infected with a single HPV genotype and 285 (28%) were infected with several HPV genotypes. Most of the infections involved the high-risk genotypes 16, 31, and 52. Throughout the study period, HPV 16 was the most encountered genotype (541, 53.2%), while HPV 18 was rather under-represented (46, 4.5%), especially in invasive cervical carcinoma. HVP52 (165, 16.2%) was detected mainly from 2008 to 2014, and its distribution reached 19.7% in 2011. Such epidemiological data underlines the possibility of an emergence of a high-risk genotype. The most detected low-risk HPV in combination with high-risk HPV was HPV 54 in 6.5% of samples. Monoinfection by HPV 16 led statistically more often to severe lesions than multi-infection involving HPV 16 (p < 0.001), while for HPV 52, 31 or 33, multi-infections were significantly associated with severe lesions (p < 0.001 for each of these three genotypes). HPV 16 was involved in 55.2% of high-grade lesions and in situ carcinoma and 76.3% of invasive carcinomas. In severe lesions, HPV 16 participation was predominant, whereas diverse genotypes were seen in low-grade lesions. Importantly, we observed that high-risk genotypes, for example HPV 52, can emerge for a few years then decrease even without vaccine pressure.

IntroductionWhile QuantiFERON-TB gold (QFT) is frequently used, little attention is paid to the mitogen response. How it could be impacted and associated with outcomes is poorly known.MethodsRetrospective, case-control study in hospitalized patients who underwent QFT testing in two hospitals between 2016 and 2019. We defined two groups of cases with either negative [interferon (IFN)-γ ≤ 0.5 IU/ml, official threshold] or weak (0.5–2 IU/ml) mitogen response, and one group of controls with normal (>2 IU/ml) mitogen response.ResultsA total of 872 patients were included. An ongoing infection was independently associated with both a negative (RR = 4.34; 95% CI = 2.94–6.41) and a weak mitogen response (RR = 2.44; 95% CI = 1.66–3.58). Among tuberculosis patients, a weak mitogen response was associated with a false-negative QFT result (75%) compared to a normal response (20%). Decreasing mitogen response (normal, weak and negative, respectively) was associated with increasing length of hospital stay [median (interquartile range) 5 (3–13), 11 (5–21) and 15 (10–30) days; p < 0.001] and increasing hospital mortality (3, 7, and 15%; p < 0.001).ConclusionClinicians should take notice of the mitogen response since IFN-γ concentrations lower than <2 IU/ml were associated with false-negative QFT results in tuberculosis patients, independently associated with ongoing infections, and could be associated with worse prognosis.

In the autumn of 2020, a short-lived epidemic of a spike del69-70 deletion variant of SARS-CoV-2 was identified, with most cases (n = 95) found in Montceau-les-Mines, France. This spike gene target failure (SGTF) variant spread quickly in nursing homes. The Alpha variant, which also harbors this deletion, appeared in Burgundy in January 2021 after the disappearance of the Montceau-les-Mines del69-70 variant. Our findings illustrate the risk of the fast spread of geographically isolated variants and reinforce the need for the continuous tracking of outbreaks. In some cases, these studies may reveal emerging variants that affect public health or vaccine development.

IntroductionHeart transplant (HT) recipients have a high risk of developing severe COVID-19. Immunoglobulin G antibodies are considered to provide protective immunity and T-cell activity is thought to confer protection from severe disease. However, data on T-cell response to mRNA vaccination in a context of HT remains limited.MethodsIn 96 HT patients, a IFN-γ release assay and an anti-Spike antibody test were used to evaluate the ability of SARS-CoV-2 mRNA vaccines to generate cellular and humoral immune response. Blood samples were collected few weeks to 7 months after vaccination. Multiple fractional polynomial and LASSO regression models were used to define predictors of T-cell response.ResultsThree to five months after vaccination, three doses of vaccine induced a positive SARS-CoV-2 T-cell response in 47% of recipients and a positive humoral response in 83% of recipients, 11.1% of patients remained negative for both T and B cell responses. Three doses were necessary to reach high IgG response levels (>590 BAU/mL), which were obtained in a third of patients. Immunity was greatly amplified in the group who had three vaccine doses plus COVID-19 infection.ConclusionOur study revealed that T and B immunity decreases over time, leading us to suggest the interest of a booster vaccination at 5 months after the third dose. Moreover, a close follow-up of immune response following vaccination is needed to ensure ongoing immune protection. We also found that significant predictors of higher cellular response were infection and active smoking, regardless of immunosuppressive treatment with mycophenolate mofetil (MMF).

Human rhinovirus (hRV) is a predominant respiratory viral pathogen. The determinants that lead to adverse clinical outcomes in hospitalized patients are unclear. Our objective was to analyze the epidemiological and clinical characteristics of hRV infections in a hospitalized population and to compare non-severe and severe infections. The study was based on data from all patients with a respiratory episode admitted to Hospital from October 2015 to September 2016. During the study period, out of 2465 respiratory episodes, 434 were detected positive for hRV. Most of the coinfections involved the respiratory syncytial virus (RSV) and very few influenza viruses. A possible interference between rhinovirus and influenza virus is suggested. Airway involvement was present in a large part of hRV infections with 28.4 % (n = 48/169) of bronchiolitis and 3.6 % (n = 6/169) of bronchitis. One third of patients had at least one of the following severity criteria: need for oxygen therapy, hospitalization >= 5 days, and admission to the ICU. On multivariate analysis, a respiratory co-infection with RSV and the presence of a chronic respiratory disease (including a history of asthma) were shown to be independent risk factors for the onset of a severe infection in patients <= 2 years old. In a case control study based on 70 patients, hRV-A was the predominant lineage, followed closely by hRV-C. High viral load or viral genotypes were not associated with severe infection.

BACKGROUND:Both human metapneumovirus (hMPV) and respiratory syncytial virus (RSV) cause epidemics during the cold season in temperate climates.OBJECTIVES:The purpose of this study was to find out whether climatic factors are associated with RSV and hMPV epidemics.STUDY DESIGN:Our study was based on data from 4300 patients admitted to the Dijon University Hospital for acute respiratory infection (ARI) over three winter seasons chosen for their dissimilar meteorological and virological patterns. Cases of hMPV and RSV were correlated with meteorological parameters recorded in the Dijon area. The relationship between virus data and local meteorological conditions was analyzed by univariate and multivariate negative binomial regression analysis.RESULTS:RSV detection was inversely associated with temperature and positively with relative humidity and air pressure, whereas hMPV was inversely associated with temperature and positively with wind speed.CONCLUSIONS:The association among meteorological variables and weekly ARIs cases due to RSV and hMPV demonstrated the relevance of climate factors as contributors to both hMPV and RSV activities. Meteorological drivers of RSV and hMPV epidemics are different. Low temperatures influence both hMPV and RSV activity. Relative humidity is an important predictor of RSV activity, but it does not influence hMPV activity.

This meta-analysis aimed to estimate the prevalence of human metapneumovirus (hMPV) infections in patients hospitalized for acute respiratory infection (ARI) and to study factors associated with this prevalence. Medline and ScienceDirect databases were searched for prospective observational studies that screened hospitalized patients with ARI for hMPV by RT-PCR, with data available at December 27, 2014. The risk of bias was assessed regarding participation rate, definition of ARI, description of diagnostic technique, method of inclusion identical for all subjects, standardized and identical sampling method for all subjects, analysis performed according to the relevant subgroups, and presentation of data sources. Random-effect meta-analysis with arcsine transformation and meta-regressions was used. In the 75 articles included, the prevalence of hMPV among hospitalized ARI was 6.24% (95% CI 5.25-7.30). An effect of the duration of the inclusion period was observed (p = 0.0114), with a higher prevalence of hMPV in studies conducted during periods of 7-11 months (10.56%, 95% CI 5.97-16.27) or complete years (7.55%, 95% CI 5.90-9.38) than in periods of 6 months or less (5.36%, 95% CI 4.29-6.54). A significant increase in the incidence with increasing distance from the equator was observed (p = 0.0384). hMPV should be taken into account as a possible etiology in hospitalized ARI. (C) 2016 Elsevier B.V. All rights reserved.

In 2014, the United States (US) experienced a nationwide outbreak of enterovirus D68 (EV-D68) infection with 1,152 cases reported mainly in hospitalised children with severe asthma or bronchiolitis. Following the US alert, 11 laboratories of the French enterovirus (EV) surveillance network participated in an EV-D68 survey. A total of 6,229 respiratory samples, collected from 1 July to 31 December 2014, were screened for EV-D68 resulting in 212 EV-D68-positive samples. These 212 samples corresponded to 200 EV-D68 cases. The overall EV-D68 positivity rates among respiratory samples were of 5% (184/3,645) and 1.1% (28/2,584) in hospitalised children and adults respectively. The maximum weekly EV-D68 positivity rates were of 16.1% for children (n = 24/149; week 43) and 2.6% for adults (n = 3/115; week 42). Of 173 children with EV-D68 infection alone, the main symptoms were asthma (n = 83; 48.0%) and bronchiolitis (n = 37; 21.4%). One child developed acute flaccid paralysis (AFP) following EV-D68-associated pneumonia. Although there was no significant increase in severe respiratory tract infections reported to the French public health authorities, 10.7% (19/177) of the EV-D68 infected children and 14.3% (3/21) of the EV-D68 infected adults were hospitalised in intensive care units. Phylogenetic analysis of the viral protein 1 (VP1) sequences of 179 EV-D68 cases, revealed that 117 sequences (65.4%), including that of the case of AFP, belonged to the B2 variant of clade B viruses. Continuous surveillance of EV-D68 infections is warranted and could benefit from existing influenza-like illness and EV surveillance networks.

BACKGROUND Hepatitis C virus (HCV) is a major cause of chronic liver disease worldwide. A patient was recently found to be HCV seropositive during hemodialysis follow-up. OBJECTIVE To determine whether nosocomial transmission had occurred and which viral populations were transmitted. DESIGN HCV transmission case. SETTING A dialysis unit in a French hospital. METHODS Molecular and epidemiologic investigations were conducted to determine whether 2 cases were related. Risk analysis and auditing procedures were performed to determine the transmission pathway(s). RESULTS Sequence analyses of the NS5b region revealed a 5a genotype in the newly infected patient. Epidemiologic investigations suggested that a highly viremic genotype 5a HCV-infected patient who underwent dialysis in the same unit was the source of the infection. Phylogenetic analysis of NS5b and hypervariable region-1 sequences revealed a genetically related virus (>99.9% nucleotide identity). Deep sequencing of hypervariable region-1 indicated that HCV quasispecies were found in the source whereas a single hypervariable region-1 HCV variant was found in the newly infected patient, and that this was identical to the major variant identified in the source patient. Risk analysis and auditing procedures were performed to determine the transmission pathway(s). Nosocomial patient-to-patient transmission via healthcare workers’ hands was the most likely explanation. In our dialysis unit, this unique incident led to the adjustment of infection control policy. CONCLUSIONS The data support transmission of a unique variant from a source with a high viral load and genetic diversity. This investigation also underlines the need to periodically evaluate prevention and control practices. Infect. Control Hosp. Epidemiol. 2016;37(2):134–139

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The human metapneumovirus has acquired the attention of the scientific community because it has been shown to be one of the most important viral pathogens in respiratory tract infections. Since its discovery in 2001, it has rapidly been shown that the virus infects all age groups, but the major burden is observed in pediatric patients. In this review, we focus on the clinical features of the human metapneumovirus, its epidemiology, antiviral therapy of HMPV infections and future treatment options.

Human metapneumovirus causes respiratory diseases with outcomes that can be severe in children, the immunocompromised, and the elderly. Synthetic small interfering RNAs (siRNAs) that silence targeted genes can be used as therapeutic agents. Currently, there is no specific therapy for hMPV. In this study, we designed Dicer-substrate siRNAs (DsiRNAs) that target metapneumovirus sequences on the mRNAs of the N, P, and L genes. In vitro, six DsiRNAs were shown to inhibit virus replication using cell proliferation tests. Of those, the DsiRNA that targets the most conserved mRNA sequence was then resynthesized in Evader (TM) format with heavy 2'-O-methyl modification of the guide strand. In a murine model, the prophylactic administration of this Evader (TM) DsiRNA was effective at partially inhibiting viral replication of hMPV (13 x 10(3) vs. 29 x 10(3) PFU/g of lung; p < 0.01), which was not the case for the control, a mismatched DsiRNA. Inhibition was achieved without inducing cytokines or off-target effects. Moreover, the specificity of the siRNA mechanism of action was demonstrated in vitro and in vivo using 5'-RACE methodology. This in vivo approach of using a DsiRNA against hMPV is an important step in the development of synthetic siRNA as a therapeutic agent for this virus. (C) 2012 Elsevier B.V. All rights reserved.

SUMMARYIt has been 10 years since human metapneumovirus (HMPV) was identified as a causative agent of respiratory illness in humans. Since then, numerous studies have contributed to a substantial body of knowledge on many aspects of HMPV. This review summarizes our current knowledge on HMPV, HMPV disease pathogenesis, and disease intervention strategies and identifies a number of areas with key questions to be addressed in the future.

Human respiratory syncytial virus (hRSV) is the main viral cause of severe respiratory infections in children and a common cause of morbidity in the elderly. The nucleocapsid (N) and fusion (F) proteins of hRSV were expressed in insect cells and used as antigens in two independent enzyme-linked immunosorbent assays (ELISAs) to measure the serum antibody response in two populations at high risk of hRSV infection, children and the elderly. Fifty-seven serum specimens from children aged from 1 to 10 years old and 91 sera from adults over 60 years old were tested. The ELISA results were compared with those obtained by an immunofluorescence assay (IFA) based on hRSV-infected cells, which was considered as the reference technique. Sensitivity and specificity were 94% and 85% for the N-ELISA and 86% and 81% for the F-ELISA, respectively. When the immune responses of the two groups of individuals were compared, it appeared that almost 100% of the elderly had antibodies against the N or F protein whereas only 50% of the sera from children had antibodies against either of the two viral proteins. In conclusion, the F and N ELISAs can be used successfully for detecting a specific antibody response to hRSV.

Human metapneumovirus is a cause of respiratory tract infections at all ages. Our objectives were to analyze the distribution of the A and B genotypes over 7 years in Dijon and to investigate a possible association between hMPV genotypes and disease severity. During 2002-2009, we genotyped the 100 isolates from children <3 years old with hMPV. Phylogenetic analysis indicated a change in the distribution of hMPV genotype over the years. Severity was then measured by detailed clinical evaluation. The hospitalization rate was greater when genotype B was involved 72.5% versus 53.3% (P = 0.054). Those infected with genotype B tended to have a higher clinical score, as measured by Vicente et al. 2006 (P = 0.07). We showed that, although clinical severity is not clearly associated with hMPV genotype in this study, pathological signs on chest X-ray were observed more often in B subgroup (P < 0.01).

Human metapneumovirus (hMPV) is associated with respiratory tract infections among children and adults. Because hMPV induces significant morbidity and mortality in the elderly, a model of hMPV infection in aged BALB/c mice was established. Young (8 weeks old) and aged (18 months old) mice were intranasally inoculated with hMPV. The infected mice showed respiratory dysfunction, as measured by plethysmography, a marked loss in weight (up to 24%), and severe histopathological abnormalities including bronchiolitis obliterans organizing pneumonia. However, clinical severity was far higher in the aged mice, and none of the young infected mice died. Although virus replication in the lung was greater in the older mice, clearance of virus was not delayed compared to young mice. Production of virus-specific antibody as well as neutralizing antibody was lower. Gamma interferon and monocyte chemotactic protein-1 levels in bronchoalveolar lavage fluid were significantly lower in older mice, whereas interleukin-6 and interleukin-4 levels were significantly higher. We observed by flow cytometry a significant increase in the CD4(+) T lymphocytes (P<0.05) of the aged mice and no difference in CD8(+) T-cell recruitment to the respiratory tract between the two groups. The present study investigated the effects of aging on the immunopathogenesis of hMPV infection and suggests that CD4(+) T lymphocytes, the cytokine response, or a defect in humoral response may be associated with the increased disease severity observed in the aged mice.