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.).

Epidemiology of childhood interstitial lung disease in France: the RespiRare cohort.

INTRODUCTION: Interstitial lung disease in children (chILD) are rare and mostly severe lung diseases. Very few epidemiological data are available in limited series of patients. The aim of this study was to assess the prevalence and incidence of chILD in France. METHODS: We performed within the RespiRare network a multicentre retrospective observational study in patients with chILD from 2000 to 2022 and a prospective evaluation of chILD's incidence between February 2022 and 2023. RESULTS: chILD was reported in 790 patients in 42 centres. The estimated 2022 prevalence in France was 44 /million children (95% CI 40.76 to 47.46) and the computed incidence was 4.4 /million children (95% CI 3.44 to 5.56). The median age at diagnosis was 3 months with 16.9% of familial forms. Lung biopsy and genetic analyses were performed in 23.4% and 76.9%, respectively. The most frequent chILD aetiologies in the <2 years group were surfactant metabolism disorders (16.3%) and neuroendocrine cell hyperplasia of infancy (11.8%), and in the 2-18 years group diffuse alveolar haemorrhage (12.2%), connective tissue diseases (11.4%), hypersensitivity pneumonitis (8.8%) and sarcoidosis (8.8%). The management included mainly oxygen therapy (52%), corticosteroid pulses (56%), oral corticosteroids (44%), azithromycin (27.2%), enteral nutrition (26.9%), immunosuppressants (20.3%) and hydroxychloroquine (15.9%). The 5-year survival rate was 57.3% for the patients diagnosed before 2 years and 86% between 2 and 18 years. CONCLUSION: This large and systematic epidemiological study confirms a higher incidence and prevalence of chILD than previously described. In order to develop international studies, efforts are still needed to optimise the case collection and to harmonise diagnostic and management practices.

Genome-Wide Association Study of Susceptibility to Pseudomonas aeruginosa Infection in Cystic Fibrosis.

QUESTION: Pseudomonas aeruginosa (Pa) is a common pathogen that contributes to progressive lung disease in Cystic Fibrosis (CF). Genetic factors other than CF-causing CFTR variations contribute approximately 85% of the variation in chronic Pa infection age in CF according to twin studies, but the susceptibility loci remain unknown. Our objective is to advance understanding of the genetic basis of host susceptibility to Pa infection. MATERIALS AND METHODS: We conducted a genome-wide association study (GWAS) of chronic Pa infection age in 1037 Canadians with CF. We subsequently assessed the genetic correlation between chronic Pa infection age and lung function through polygenic risk score (PRS) analysis and inferred their causal relationship through bi-directional Mendelian Randomization analysis. RESULTS: Two novel genome-wide significant loci with lead SNPs rs62369766 (chr5p12; p-value= 1.98 ×10-8) and rs927553 (chr13q12.12; p-value= 1.91 × 10-8) were associated with chronic Pa infection age. The rs62369766 locus was validated using an independent French cohort (N=501). Furthermore, PRS constructed from CF lung function-associated SNPs was significantly associated with chronic Pa infection age (p-value=0.002). Finally, our analysis presented evidence for a causal effect of lung function on the chronic Pa infection age (Beta=0.782 years, p-value= 4.24 × 10-4). In the reverse direction, we observed a moderate effect (Beta=0.002, p-value=0.012). CONCLUSIONS: We identified two novel loci that are associated with chronic Pa infection age in individuals with CF. Additionally, we provided evidence of common genetic contributors and a potential causal relationship between Pa infection susceptibility and lung function in CF. Therapeutics targeting these genetic factors may delay the onset of chronic infections which accounts for significant remaining morbidity in CF.

Disseminated tuberculosis in a migrant child.

Tuberculosis (TB) poses a major global health threat, substantially affecting children, who contribute notably to new cases and deaths. Diagnosing TB in kids is challenging due to collection issues and the paucibacillary nature of the disease. Disseminated TB, uncommon in children in low TB incidence countries, remains a significant cause of morbidity in migrant populations. We illustrate a rare case of disseminated TB in a middle-childhood boy who migrated from Angola to France, displaying chronic cough, fatigue, weight loss and persistent fever. Investigations revealed widespread TB affecting several organs (lungs, heart, bones and lymph nodes). Prompt diagnosis led to a treatment regimen of four antibiotics (isoniazid, rifampin, pyrazinamide, ethambutol) and corticosteroids, resulting in substantial improvement after 2 months. Subsequent treatment involved two antibiotics (isoniazid and rifampin) for 10 more months. This case underscores the criticality of early identification and comprehensive treatment for disseminated TB, ensuring improved outcomes and reduced risks.

Pulmonary mucoepidermoid carcinoma in a 7-year-old child.

A 7-year-old boy presented with exertional dyspnea and cough, initially misdiagnosed as asthma. Imaging revealed a mass obstructing the left main bronchus, later identified as a pulmonary mucoepidermoid carcinoma (MEC). Following surgical sleeve resection, complete tumor removal occurred without malignancy in surrounding lymph nodes, resulting in symptom resolution without additional therapy. Pulmonary MEC, uncommon in pediatric patients, poses diagnostic challenges due to nonspecific symptoms, resulting in delayed diagnosis. Typically managed via complete surgical resection, MEC offers a favorable prognosis, primarily affecting central airways and requiring conservative surgical approaches to preserve lung tissue. This case underscores the diagnostic challenges of primary pulmonary MEC in pediatric patients. It stresses the need to consider unusual causes in pediatric respiratory symptoms and highlights the critical role of precise diagnostic methods and personalized surgical strategies in managing such rare pulmonary malignancies for optimal outcomes.

Bronchiolitis: Increased severity in the post-COVID-19 era.

INTRODUCTION: Acute bronchiolitis is a pressing public health concern, leading to numerous infant hospitalizations worldwide annually. The notable decrease in bronchiolitis hospitalizations during the COVID-19 pandemic sparked concerns about a potential resurgence post-pandemic. Questions also arose about the severity of post-pandemic cases compared to prepandemic ones. This study aimed to compare bronchiolitis severity before and after the COVID-19 pandemic, alongside changes in the epidemiology of bronchiolitis viral agents. MATERIAL AND METHODS: We conducted a retrospective analysis of medical records concerning infants under 12 months hospitalized for acute bronchiolitis in our pediatric pulmonology department over a period of 5 years: 2 pre-COVID years (2018-2020), the COVID year (2020), and 2 post-COVID years (2021-2023). Clinical and laboratory data were collected using standardized forms. RESULTS: Hospital admissions exhibited comparable rates pre- and post-COVID but witnessed a decline during the COVID period. Post-COVID, bronchiolitis severity increased, with longer hospitalization durations (p < 0.001) and increased oxygen therapy (p = 0.04), coinciding with a surge in the prevalence of RSV infections (p = 0.01). Patients testing positive for RSV were significantly younger (p = 0.005) and exhibited more severe symptoms. DISCUSSION AND CONCLUSION: This study reveals a significant increase in bronchiolitis severity and a rise in RSV cases following the COVID pandemic. The implementation of preventive measures such as nirsevimab is crucial to alleviate the burden of respiratory illnesses in vulnerable populations. Continued vigilance and research are needed to address the evolving challenges of bronchiolitis in the post-COVID era.

Septin-dependent defense mechanisms against Pseudomonas aeruginosa are stalled in cystic fibrosis bronchial epithelial cells.

Airway epithelial cells form a physical barrier against inhaled pathogens and coordinate innate immune responses in the lungs. Bronchial cells in people with cystic fibrosis (pwCF) are colonized by Pseudomonas aeruginosa because of the accumulation of mucus in the lower airways and an altered immune response. This leads to chronic inflammation, lung tissue damage, and accelerated decline in lung function. Thus, identifying the molecular factors involved in the host response in the airways is crucial for developing new therapeutic strategies. The septin (SEPT) cytoskeleton is involved in tissue barrier integrity and anti-infective responses. SEPT7 is critical for maintaining SEPT complexes and for sensing pathogenic microbes. In the lungs, SEPT7 may be involved in the epithelial barrier resistance to infection; however, its role in cystic fibrosis (CF) P. aeruginosa infection is unknown. This study aimed to investigate the role of SEPT7 in controlling P. aeruginosa infection in bronchial epithelial cells, particularly in CF. The study findings showed that SEPT7 encages P. aeruginosa in bronchial epithelial cells and its inhibition downregulates the expression of other SEPTs. In addition, P. aeruginosa does not regulate SEPT7 expression. Finally, we found that inhibiting SEPT7 expression in bronchial epithelial cells (BEAS-2B 16HBE14o- and primary cells) resulted in higher levels of internalized P. aeruginosa and decreased IL-6 production during infection, suggesting a crucial role of SEPT7 in the host response against this bacterium. However, these effects were not observed in the CF cells (16HBE14o-/F508del and primary cells) which may explain the persistence of infection in pwCF. The study findings suggest the modification of SEPT7 expression as a potential approach for the anti-infective control of P. aeruginosa, particularly in CF.

Multicentric investigations of the role in the disease severity of accelerated phospholipid changes in COVID-19 patient airway.

CONTEXT: The changes in host membrane phospholipids are crucial in airway infection pathogenesis. Phospholipase A2 hydrolyzes host cell membranes, producing lyso-phospholipids and free fatty acids, including arachidonic acid (AA), which contributes significantly to lung inflammation. AIM: Follow these changes and their evolution from day 1, day 3 to day 7 in airway aspirates of 89 patients with COVID-19-associated acute respiratory distress syndrome and examine whether they correlate with the severity of the disease. The patients were recruited in three French intensive care units. The analysis was conducted from admission to the intensive care unit until the end of the first week of mechanical ventilation. RESULTS: In the airway aspirates, we found significant increases in the levels of host cell phospholipids, including phosphatidyl-serine and phosphatidyl-ethanolamine, and their corresponding lyso-phospholipids. This was accompanied by increased levels of AA and its inflammatory metabolite prostaglandin E2 (PGE2). Additionally, enhanced levels of ceramides, sphingomyelin, and free cholesterol were observed in these aspirates. These lipids are known to be involved in cell death and/or apoptosis, whereas free cholesterol plays a role in virus entry and replication in host cells. However, there were no significant changes in the levels of dipalmitoyl-phosphatidylcholine, the major surfactant phospholipid. A correlation analysis revealed an association between mortality risk and levels of AA and PGE2, as well as host cell phospholipids. CONCLUSION: Our findings indicate a correlation between heightened cellular phospholipid modifications and variations in AA and PGE2 with the severity of the disease in patients. Nevertheless, there is no indication of surfactant alteration in the initial phases of the illness.

Lung biopsies in infants and children in critical care situation.

INTRODUCTION: Lung biopsy is considered as the last step investigation for diagnosing lung diseases; however, its indication must be carefully balanced with its invasiveness. The present study aims to evaluate the diagnostic yield of lung biopsy in critically ill patients hospitalized in the pediatric intensive care unit (ICU). MATERIAL AND METHODS: Children who underwent a lung biopsy in the ICU between 1995 and 2022 were included. Biopsies performed in the operating room and post-mortem biopsies were excluded. RESULTS: Thirty-one patients were included, with a median age of 18 days (2 days to 10.8 years); 21 (67.7%) were newborns. All patients required invasive mechanical ventilation, 26 (89.7%) had a pulmonary hypertension, and 22 (70.9%) were placed under extracorporeal membrane oxygenation (ECMO). The lung biopsy led to a diagnosis in 81% of the patients. The diagnostic reliability seemed to decrease with age (95% in newborns, 71% in 1 month to 2 years and 0/3 patients aged over 2 years old). Diffuse developmental disorders of the lung accounted for 15 (49%) patients, primarily alveolar capillary dysplasia, followed by surfactant disorders in 5 (16%) patients. Complications occurred in 9/31 (29%) patients including eight under ECMO, with massive hemorrhages in seven cases. DISCUSSION AND CONCLUSION: In critical situations, lung biopsy should be performed. Lung biopsy is a reliable diagnostic procedure for neonates in critical situation when a diffuse developmental disorder of the lung is suspected. The majority of lung biopsy complication was associated with the use of ECMO. The prospective evaluation of the complications of such procedure under ECMO, and particularly over 10 days of ECMO and in children over 2-year-old remains to be ascertained.