Effectiveness of nirsevimab against RSV-bronchiolitis in paediatric ambulatory care: a test-negative case-control study.

Background: Respiratory syncytial virus (RSV) is the leading cause of lower-respiratory-tract infection in children. Nirsevimab, a monoclonal antibody against RSV, was implemented in a few countries in September 2023. However, its post-license effectiveness in ambulatory care settings is unknown. We aimed to assess the effectiveness of nirsevimab against RSV-bronchiolitis in outpatients aged <12 months. Methods: We conducted a test-negative case-control study based on a national ambulatory surveillance system. We included all infants aged <12 months who had bronchiolitis and results of an RSV rapid antigen test performed, visiting a network of 107 ambulatory paediatricians from September 15, 2023, to February 1, 2024. Case patients were infants with bronchiolitis and a rapid antigen test positive for RSV. Control patients were infants with bronchiolitis and a rapid antigen test negative for RSV. Effectiveness was assessed by a logistic regression model adjusted for potential confounders. A range of sensitivity analyses were conducted to assess the robustness of the findings. Findings: We included 883 outpatients who had bronchiolitis and results of an RSV rapid antigen test (453 were case patients, and 430 were control patients). Overall, 62/453 (13.7%) case patients and 177/430 (41.2%) control patients had been previously immunised for nirsevimab. The adjusted effectiveness of nirsevimab against RSV-bronchiolitis was 79.7% (95% CI 67.7-87.3). Sensitivity analyses gave similar results. Interpretation: This post-license study indicates that nirsevimab was effective in preventing RSV-bronchiolitis in ambulatory care settings. Funding: The study was supported by Association Clinique et Thérapeutique Infantile du Val de Marne (ACTIV), French Pediatrician Ambulatory Association (AFPA) and unrestricted grants from GSK, MSD, Pfizer and Sanofi.

Nirsevimab and Hospitalization for RSV Bronchiolitis.

BACKGROUND: Respiratory syncytial virus (RSV) is the leading cause of bronchiolitis, resulting in 3 million hospitalizations each year worldwide. Nirsevimab is a monoclonal antibody against RSV that has an extended half-life. Its postlicensure real-world effectiveness against RSV-associated bronchiolitis is unclear. METHODS: We conducted a prospective, multicenter, matched case-control study to analyze the effectiveness of nirsevimab therapy against hospitalization for RSV-associated bronchiolitis in infants younger than 12 months of age. Case patients were infants younger than 12 months of age who were hospitalized for RSV-associated bronchiolitis between October 15 and December 10, 2023. Control patients were infants with clinical visits to the same hospitals for conditions unrelated to RSV infection. Case patients were matched to control patients in a 2:1 ratio on the basis of age, date of hospital visit, and study center. We calculated the effectiveness of nirsevimab therapy against hospitalization for RSV-associated bronchiolitis (primary outcome) by means of a multivariate conditional logistic-regression model with adjustment for confounders. Several sensitivity analyses were performed. RESULTS: The study included 1035 infants, of whom 690 were case patients (median age, 3.1 months; interquartile range, 1.8 to 5.3) and 345 were matched control patients (median age, 3.4 months; interquartile range, 1.6 to 5.6). Overall, 60 case patients (8.7%) and 97 control patients (28.1%) had received nirsevimab previously. The estimated adjusted effectiveness of nirsevimab therapy against hospitalization for RSV-associated bronchiolitis was 83.0% (95% confidence interval [CI], 73.4 to 89.2). Sensitivity analyses gave results similar to those of the primary analysis. The effectiveness of nirsevimab therapy against RSV-associated bronchiolitis resulting in critical care was 69.6% (95% CI, 42.9 to 83.8) (27 of 193 case patients [14.0%] vs. 47 of 146 matched control patients [32.2%]) and against RSV-associated bronchiolitis resulting in ventilatory support was 67.2% (95% CI, 38.6 to 82.5) (27 of 189 case patients [14.3%] vs. 46 of 151 matched control patients [30.5%]). CONCLUSIONS: In a real-world setting, nirsevimab therapy was effective in reducing the risk of hospitalized RSV-associated bronchiolitis. (Funded by the National Agency for AIDS Research-Emerging Infectious Disease and others; ENVIE ClinicalTrials.gov number, NCT06030505.).

Impact of C-reactive protein point-of-care testing on antibiotic prescriptions for children and adults with suspected respiratory tract infections in primary care: a French patient-level randomized controlled superiority trial.

OBJECTIVES: The value of C-reactive protein point-of-care testing (CRP POCT) to guide antibiotic prescriptions in adults has previously been emphasized. The aim of this study was to assess the impact of CRP POCT on antibiotic prescriptions by general practitioners (GPs) for suspected lower respiratory tract infections in children ≥3 years old and in adults. METHODS: This was an open-label randomized trial (NCT03540706) conducted in 26 GPs in France between October 2019 and March 2023. Of the 404 participating patients, 207 (51.2%) were randomized to the CRP POCT group and 197 (48.8%) to the control group (i.e. no CRP POCT). During consultations, GPs measured CRP levels in patients randomized to the CRP POCT group. The primary endpoint was the proportion of patients in each group who were prescribed antibiotics by their GP during the consultation. Z-tests were used for comparisons. RESULTS: The overall proportion of patients treated with antibiotics was similar in the CRP POCT (n = 89/207, 43% CI: 36.2, 50.0) and in the control group (n = 94/197, 47.7% CI: 40.6, 54.9), difference: -4.7 CI: -14.4, 5.0; p 0.3. Overall, 75% of the GPs followed CRP-based antibiotic prescription recommendations in the CRP POCT group. DISCUSSION: CRP POCT did not reduce antibiotic prescriptions in this trial.

Assessing the Burden of Respiratory Syncytial Virus-related Bronchiolitis in Primary Care and at 15-Day and 6-Month Follow-up Before Prophylaxis in France: A Test-negative Study.

OBJECTIVE: To assess the burden of respiratory syncytial virus (RSV)-related bronchiolitis in primary care and at 15 days and 6 months after a primary care visit. STUDY DESIGN: In this test-negative study, children <2 years old with a first episode of bronchiolitis were prospectively enrolled by 45 ambulatory pediatricians in France from February 2021 to April 2023. RSV was assessed with a rapid antigen detection test. The burden of the disease was assessed with a questionnaire, including quality of life (PedsQL 1.0 Infant Scales), at 15-day and 6-month follow-up. Children with a positive RSV test result (RSV+) were compared to those with a negative test result (RSV-). RESULTS: Among the 1591 children enrolled, 750 (47.1%) were RSV+. At 15 days follow-up (data availability: 69%), as compared with RSV- children, RSV+ children more frequently had fever (20.5% vs. 13.7%, P = 0.004) and decreased food intake (27.0% vs. 17.4%, P < 0.001) during the last 3 days. They had higher rates of hospitalization (11.8% vs. 5.8%, P < 0.001), childcare absenteeism (83.5% vs. 66.1%, P < 0.001) and parents who had to stop working to care for them (59.1% vs. 41.0%, P < 0.001) as well as lower quality of life (median PedsQL score 76.2 vs. 78.4, P = 0.03). At 6 months (data availability: 48.5%), the 2 groups did not differ in proportion of medical attendance, hospitalization, antibiotic treatment or quality of life. CONCLUSION: RSV+ children experienced much more severe disease and follow-up family and societal burden than RSV- children. These data may be used as baseline data as RSV prophylaxis is about to be implemented.

The latest news in France before distribution of third-generation pneumococcal conjugate vaccines.

INTRODUCTION: In 2023 in France, 15 valent- pneumococcal conjugate vaccines (PCV15) have been recommended as alternatives to PCV13 for children < 2 years. PCV20 has been recommended for at-risk adults but not yet for infants, while PCV21 targets older adults. We endeavored to estimate the potential benefit of new pneumococcal vaccines in preventing invasive pneumococcal infections by comparing serotype extension to PCV13. PATIENTS AND METHODS: The National Reference Centre for Pneumococci distributed S. pneumoniae IPD serotypes from children and adults. RESULTS: In 2022, for children under 24 months, PCV15 and PCV20 ensured 10 % and 36 % more coverage against IPD than PCV13. For adults, PCV15, PCV20, and PCV21 covered up to 3 %, 26 %, and 50 % more IPD cases than PCV13. CONCLUSION: The new generation of pneumococcal vaccines could reduce the burden of invasive pneumococcal infections through serotype extension. Additional studies are needed in parallel to optimize their utilization and improve vaccine coverage in France.

Exploring factors shaping antibiotic resistance patterns in Streptococcus pneumoniae during the 2020 COVID-19 pandemic.

Non-pharmaceutical interventions implemented to block SARS-CoV-2 transmission in early 2020 led to global reductions in the incidence of invasive pneumococcal disease (IPD). By contrast, most European countries reported an increase in antibiotic resistance among invasive Streptococcus pneumoniae isolates from 2019 to 2020, while an increasing number of studies reported stable pneumococcal carriage prevalence over the same period. To disentangle the impacts of the COVID-19 pandemic on pneumococcal epidemiology in the community setting, we propose a mathematical model formalizing simultaneous transmission of SARS-CoV-2 and antibiotic-sensitive and -resistant strains of S. pneumoniae. To test hypotheses underlying these trends five mechanisms were built into the model and examined: (1) a population-wide reduction of antibiotic prescriptions in the community, (2) lockdown effect on pneumococcal transmission, (3) a reduced risk of developing an IPD due to the absence of common respiratory viruses, (4) community azithromycin use in COVID-19 infected individuals, (5) and a longer carriage duration of antibiotic-resistant pneumococcal strains. Among 31 possible pandemic scenarios involving mechanisms individually or in combination, model simulations surprisingly identified only two scenarios that reproduced the reported trends in the general population. They included factors (1), (3), and (4). These scenarios replicated a nearly 50% reduction in annual IPD, and an increase in antibiotic resistance from 20% to 22%, all while maintaining a relatively stable pneumococcal carriage. Exploring further, higher SARS-CoV-2 R0 values and synergistic within-host virus-bacteria interaction mechanisms could have additionally contributed to the observed antibiotic resistance increase. Our work demonstrates the utility of the mathematical modeling approach in unraveling the complex effects of the COVID-19 pandemic responses on AMR dynamics.

Use of Rapid Antigen Triple Test Nasal Swabs (COVID-VIRO ALL-IN TRIPLEX: Severe Acute Respiratory Syndrome Coronavirus 2, Respiratory Syncytial Virus, and Influenza) in Children With Respiratory Symptoms: A Real-life Prospective Study.

Background: In autumn 2022, the epidemics due to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), respiratory syncytial virus (RSV), and influenza overlapped, and these diseases can present with the same symptomatology. The use of a triple antigen test (SARS-CoV-2 + influenza A/B + RSV) seems crucial for accurate viral diagnosis in the context of implementing long-acting monoclonal antibody vaccination against RSV in the upcoming RSV season. Methods: We assessed the usefulness of the triple test in real life in this prospective study performed from October 2022 to May 2023 and involving 116 pediatricians (2 emergency department pediatricians and 114 ambulatory pediatricians). Children <15 years old with flu-like illness (with fever), bronchiolitis (dyspnea ± wheezing), otitis, and croup were enrolled and sampled with a nasal triple test. Results: For 8329 children with flu-like illness (65.3%), bronchiolitis (17.9%), otitis (8.8%), and croup (6.3%), the use of the triple test led to a viral diagnosis in 47.9% of cases. The highest RSV positivity occurred in children with bronchiolitis (32.9%). The highest influenza A and B positivity (24.6% and 19.6%) occurred in children with flu-like illness. A succession of 3 epidemics (RSV and influenza A and B) occurred over time with several overlap periods. Conclusions: The triple test allowed for a viral diagnosis in half of our cases. The upcoming introduction of RSV prevention will emphasize the need for active surveillance with viral results both in ambulatory settings and hospitals. Clinical Trials Registration. NCT0441231.

Unique Changes in the Incidence of Acute Chest Syndrome in Children With Sickle Cell Disease Unravel the Role of Respiratory Pathogens: A Time Series Analysis.

BACKGROUND: Acute chest syndrome (ACS) is a life-threatening complication of sickle cell disease (SCD). Although respiratory pathogens are frequently detected in children with ACS, their respective role in triggering the disease is still unclear. We hypothesized that the incidence of ACS followed the unprecedented population-level changes in respiratory pathogen dynamics after COVID-19-related nonpharmaceutical interventions (NPIs). RESEARCH QUESTION: What is the respective role of respiratory pathogens in ACS epidemiology? STUDY DESIGN AND METHODS: This study was an interrupted time series analysis of patient records from a national hospital-based surveillance system. All children aged < 18 years with SCD hospitalized for ACS in France between January 2015 and May 2022 were included. The monthly incidence of ACS per 1,000 children with SCD over time was analyzed by using a quasi-Poisson regression model. The circulation of 12 respiratory pathogens in the general pediatric population over the same period was included in the model to assess the fraction of ACS potentially attributable to each respiratory pathogen. RESULTS: Among the 55,941 hospitalizations of children with SCD, 2,306 episodes of ACS were included (median [interquartile range] age, 9 [5-13] years). A significant decrease was observed in ACS incidence after NPI implementation in March 2020 (-29.5%; 95% CI, -46.8 to -12.2; P = .001) and a significant increase after lifting of the NPIs in April 2021 (24.4%; 95% CI, 7.2 to 41.6; P = .007). Using population-level incidence of several respiratory pathogens, Streptococcus pneumoniae accounted for 30.9% (95% CI, 4.9 to 56.9; P = .02) of ACS incidence over the study period and influenza 6.8% (95% CI, 2.3 to 11.3; P = .004); other respiratory pathogens had only a minor role. INTERPRETATION: NPIs were associated with significant changes in ACS incidence concomitantly with major changes in the circulation of several respiratory pathogens in the general population. This unique epidemiologic situation allowed determination of the contribution of these respiratory pathogens, in particular S pneumoniae and influenza, to the burden of childhood ACS, highlighting the potential benefit of vaccine prevention in this vulnerable population.

Age-Specific Resurgence in Invasive Pneumococcal Disease Incidence in the COVID-19 Pandemic Era and Its Association With Respiratory Virus and Pneumococcal Carriage Dynamics: A Time-Series Analysis.

Using multiple national surveillance systems, we found an increase in the incidence of invasive pneumococcal disease during after the relaxation of non-pharmaceutical interventions against COVID-19, which strongly varied by age. Age groups with higher incidence of respiratory syncytial virus and influenza also experienced higher increase in invasive pneumococcal disease incidence, with no change in pneumococcal carriage.

Vaccine-preventable Pediatric Acute Bacterial Meningitis in France: A Time Series Analysis of a 19-Year Prospective National Surveillance Network.

BACKGROUND: In France, vaccination has been implemented against Hi serotype b (Hib), pneumococcus with pneumococcal conjugate vaccines (PCV), and Neisseria meningitidis serogroup C (MenC). These interventions with different coverage and uptake have disrupted the epidemiology of vaccine-preventable acute bacterial meningitis (ABM). METHODS: We analyzed data from a French prospective surveillance network of ABM in children ≤15 years old enrolled by 259 pediatric wards (estimated national coverage: 61%). From 2001 to 2020, the effect of vaccine implementation was estimated with segmented linear regression. RESULTS: We analyzed 7,186 cases, mainly due to meningococcus (35.0%), pneumococcus (29.8%), and Hi (3.7%). MenC ABM incidence decreased (-0.12%/month, 95% CI: -0.17 to -0.07, P < 0.001) with no change for the overall meningococcal ABM when comparing the pre-MenC vaccination and the post-MenC vaccination trends. Despite a decreasing MenB ABM incidence without a vaccination program (-0.43%/month, 95% CI: -0.53 to -0.34, P < 0.001), 68.3% of meningococcal ABM involved MenB. No change in pneumococcal ABM incidence was observed after the PCV7 recommendation. By contrast, this incidence significantly decreased after the switch to PCV13 (-0.9%/month, 95% CI: -1.6 to -0.2%, P = 0.01). After May 2014, a rebound occurred (0.5%/month, 95% CI: 0.3-0.8%, P < 0.001), with 89.5% of non-PCV13 vaccine serotypes. Hib ABM incidence increased after June 2017. CONCLUSIONS: PCV7 and MenC vaccine introduction in France, with slow vaccine uptake and low coverage, had no to little impact as compared to the switch from PCV7 to PCV13, which occurred when coverage was optimal. Our data suggest that MenB and next-generation PCVs could prevent a large part of the ABM incidence in France.

Antibiotic Resistance of Haemophilus influenzae in Nasopharyngeal Carriage of Children with Acute Otitis Media and in Middle Ear Fluid from Otorrhea.

Haemophilus influenzae (Hi) is one of the leading bacteria implicated in childhood acute otitis media (AOM). Recent concerns have been raised about the emergence of Hi-resistant strains. We aimed to analyze the evolution of ß-lactam resistance to Hi among strains isolated from nasopharyngeal carriage in children with AOM and in mild ear fluid (MEF) after the spontaneous perforation of the tympanic membrane (SPTM) in France. In this national ambulatory-based cohort study over 16 years, we analyzed the rate of Hi nasopharyngeal carriage and the proportion of ß-lactam-resistant Hi strains over time using a segmented linear regression model. Among the 13,865 children (median [IQR] age, 12.7 [9.3-17.3] months; 7400 [53.4%] male) with AOM included from November 2006 to July 2022, Hi was isolated in 7311 (52.7%) children by nasopharyngeal sampling. The proportion of ß-lactamase-producing and ß-lactamase-negative, ampicillin-resistant (BLNAR) Hi strains in nasopharyngeal carriage remained stable during the study period. Among the 783 children (median [IQR] age, 20 [12.3-37.8] months; 409 [52.2%] male) with SPTM included from October 2015 to July 2022, Hi was isolated in 177 (22.6%) cases by MEF sampling. The proportions of ß-lactamase-producing and BLNAR Hi strains did not significantly differ between nasopharyngeal (17.6% and 8.8%, respectively) and MEF (12.6% and 7.4%) samples. Accordingly, amoxicillin remains a valid recommendation as the first-line drug for AOM in France.

Respiratory Syncytial Virus in Outpatient Children with Bronchiolitis: Continuous Virus Circulation During the Nonepidemic Period.

We aimed to estimate the respiratory syncytial virus positivity rate among ambulatory children with bronchiolitis according to the bronchiolitis epidemic period as defined by the French Public Health Institute. The positivity rate was 28.9% during the nonepidemic period and 50.6% during the epidemic period, which suggests continuous virus circulation between bronchiolitis annual peaks.

Diagnostic accuracy of a rapid antigen triple test (SARS-CoV-2, respiratory syncytial virus, and influenza) using anterior nasal swabs versus multiplex RT-PCR in children in an emergency department.

BACKGROUND: In children, respiratory infections such as SARS-CoV-2, respiratory syncytial virus (RSV), and influenza share similar clinical signs and symptoms. Here we compared the performance of a rapid antigen diagnostic test using a self-collected anterior nasal swab (COVID-VIRO ALL IN TRIPLEX) and multiplex RT-PCR. METHODS: From October to December 2022, in the emergency pediatrics unit of Orleans Hospital, France, we evaluated the diagnostic accuracy of the triplex test. RESULTS: For the 263 children, sensitivity of the test was 88.9% (95%CI 51.8-99.7), 79.1% (95%CI 64.0-90.0), and 91.6% (95%CI 84.1-96.3), for SARS-CoV-2, RSV, and influenza, respectively. Specificity was 100% for each virus. For RT-PCR with cycle threshold < 32, sensitivity was 100.0% [95%CI 59.0-100.0], 87.2% [95%CI 72.6-95.7] and 92.3% [95%CI 84.896.9] for SARS-CoV-2, RSV, and influenza respectively. CONCLUSIONS: This easy-to-perform triplex test is a considerable advance, allowing clinicians to obtain an accurate diagnosis in most cases of respiratory infection. More data are needed to validate this test in different contexts and across several seasons.

Diagnostic accuracy of a rapid nucleic acid test for group A streptococcal pharyngitis using saliva samples: protocol for a prospective multicenter study in primary care.

BACKGROUND: Group A streptococcus is found in 20-40% of cases of childhood pharyngitis; the remaining cases are viral. Streptococcal pharyngitis ("strep throat") is usually treated with antibiotics, while these are not indicated in viral cases. Most guidelines recommend relying on a diagnostic test confirming the presence of group A streptococcus before prescribing antibiotics. Conventional first-line tests are rapid antigen detection tests based on throat swabs. Recently, rapid nucleic acid tests were developed; they allow the detection of elements of the genome of group A streptococcus. We hypothesize that these rapid nucleic acid tests are sensitive enough to be performed on saliva samples instead of throat swabs, which could be more convenient in practice. METHODS: This is a multicenter, prospective diagnostic accuracy study evaluating the performance of a rapid nucleic acid test for group A streptococcus (Abbott ID NOW STREP A2) in saliva, compared with a conventional pharyngeal rapid antigen detection test (EXACTO PRO STREPTATEST, lateral flow assay, comparator test), with a composite reference standard of throat culture and group A streptococcus PCR in children with pharyngitis in primary care (i.e., 27 primary care pediatricians or general practitioners). To ensure group A streptococcus is not missed, the salivary rapid nucleic acid test requires a minimally acceptable value of sensitivity (primary outcome) set at 80%. Assuming 35% of participants will have group A streptococcus, we will recruit 800 consecutive children with pharyngitis. Secondary outcomes will include difference in sensitivity between the pharyngeal rapid antigen detection test and the salivary rapid nucleic acid test; variability in sensitivity and specificity of the salivary rapid nucleic acid test with the level of McIsaac score; time to obtain the result of the salivary rapid nucleic acid test; patient, physician, and parents satisfaction; and barriers and facilitators to using rapid tests for group A streptococcus in primary care. ETHICS AND DISSEMINATION: Approved by the Institutional Review Board "Comité de protection des personnes Ile de France I" (no. 2022-A00085-38). Results will be presented at international meetings and disseminated in peer-reviewed journals. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov: NCT05521568.

Diagnostic Accuracy of Group A Streptococcus Rapid Antigen Detection Test on Middle Ear Fluid in Children With Acute Otitis Media With Spontaneous Perforation: A Prospective Multicenter Evaluation.

Group A Streptococcus is one of the leading causes of otorrhea. The performance of rapid antigen tests in 256 children with otorrhea showed excellent sensitivity, 97.3% (95% confidence interval: 90.7%-99.7%), and specificity, 100% (95% confidence interval: 98.0%-100%). In a period of increasing invasive and noninvasive group A Streptococcus infections, an early diagnosis could be useful.

Dynamics of Antibiotic Resistance of Streptococcus pneumoniae in France: A Pediatric Prospective Nasopharyngeal Carriage Study from 2001 to 2022.

Epidemiological surveillance of nasopharyngeal pneumococcal carriage is important for monitoring serotype distribution and antibiotic resistance, particularly before and after the implementation of pneumococcal conjugate vaccines (PCVs). With a prospective surveillance study in France, we aimed to analyze the dynamics of pneumococcal carriage, antibiotic susceptibility and serotype distribution in children aged 6 to 24 months who had acute otitis media between 2001 and 2022 with a focus on the late PCV13 period from May 2014 to July 2022. Trends were analyzed with segmented linear regression with autoregressive error. For the 17,136 children enrolled, overall pneumococcal carriage was stable during the study. During the late PCV13 period, the five most frequent serotypes were all non-PCV13 serotypes: 15B/C (14.3%), 23B (11.0%), 11A (9.6%), 15A (7.4%) and 35B (6.5%). During the same period, we observed a rebound of penicillin non-susceptibility (+0.15% per month, 95% confidence interval, +0.08 to 0.22, p < 0.001). Five serotypes accounted for 64.4% of the penicillin non-susceptible strains: 11A (17.5%), 35B (14.9%), 15A (13.9%), 15B/C (9.9%) and 19F (8.2%); non-PCV13/PCV15 accounted for <1%, and non-PCV15/PCV20 accounted for 28%. The next generation PCVs, particularly PCV20, may disrupt nasopharyngeal carriage and contribute to decreasing the rate of antibiotic resistance among pneumococci.