Association between nutritional status and severity of RSV-associated lower respiratory tract infection: a retrospective study in hospitalised children under 5 years of age

Respiratory syncytial virus (RSV) is undoubtedly the single most important cause of severe lower respiratory tract infection (LRTI) globally. While new prevention measures in young infants have become available, their use in developing countries is likely many years away. While risk factors for severe or very severe RSV LRTI in impoverished rural areas likely differ to urban areas, there are very few studies, especially those conducted in India, the major country contributing to the global burden of disease. Active surveillance for acute LRTI in enrolled infants and children <2 years of age, was conducted through weekly home visits in 93 villages of Melghat, India, from August 2016 to December 2020. Local hospitals and primary health centres were surveyed for admissions of enrolled subjects. Nasopharyngeal swabs were collected from children with severe, or very severe LRTIs and all who died, with RSV testing using nucleic acid tests at ICMR, National Institute of Virology Pune. Risk factors for both RSV associated and non-RSV associated, severe and very severe LRTI were identified through univariate and multivariate logistic regression. There were 483 severe or very severe RSV LRTI cases and 2807 non-RSV severe or very severe LRTI infections in a cohort of 13,318 children. Weight for age z-score ≤-2, the use of kerosene or wood for cooking, obtaining drinking water from a public tap and low gestational age significantly increased the risk of RSV LRTI. A higher wealth score index and water purification were protective. Comparison with non-RSV LRTI showed male sex as an additional risk factor. The analysis highlighted the risk of kerosene use [OR = 17.8 (3.0-104.4) (p ≤ 0.001)] and [OR = 3.4 (0.8-14.4) (p ≤ 0.05)] for RSV and non-RSV LRTIs, respectively. Nutritional status and environmental air quality are predisposing factors for developing an RSV LRI in young children, factors which are amenable to environmental and behavioural interventions.

BackgroundAlthough respiratory syncytial virus (RSV) is the most important viral cause of lower respiratory tract infection deaths in infants, there are few data on infant community deaths caused by RSV.MethodsThis was an active surveillance of children younger than 2 years of age in 93 villages, 5 primary health centers, and 3 hospitals serving these villages. Village health workers and counselors at the health facilities monitored all lower respiratory tract infections (LRTIs) in consented subjects. Children with severe, or very severe LRTIs and all who died, had nasopharyngeal swabs collected for detection of RSV by molecular methods.ResultsIn the 12 134 subjects, there were 2064 episodes of severe LRTIs and 1732 of very severe LRTIs, of which 271 and 195, respectively, had RSV. Fifteen of 16 (94%) children with RSV died of LRTIs, 14 in the community and 1 in the hospital. The case fatality ratios for severe RSV LRTIs in the first 6 months of life were 3/52 (7.1%) and 1/36 (2.8%) in the community and hospital, respectively. Of those with very severe LRTIs in the community, 17.6% died. There were no very severe RSV LRTI hospital deaths. The adjusted RSV LRTI mortality rates ranged from 1.0 to 3.0/1000 child-years (CY) overall, and 2.0 to 6.1/1000 CY, accounting for 20% of the LRTI deaths and 10% of the postneonatal infant mortality.ConclusionsCommunity deaths from RSV account for the majority of RSV LRTI deaths, and efforts at prevention should be preferentially directed at populations where access to care is limited.

To improve the management of lower respiratory tract infections (LRTI) in human immunodeficiency virus type 1 (HIV-1)-infected children, we assessed the burden of disease, clinical outcome and antibiotic susceptibility of bacteria causing severe community-acquired LRTI in children. A prospective, descriptive study was performed in the pediatric wards at a secondary and tertiary care hospital in South Africa. Urban black children aged 2-60 months admitted with severe acute LRTI from March 1997 through February 1998 were enrolled. HIV-1 infection was present in 45.1% of 1215 cases of severe LRTI. Bacteremia occurred in 14.9% of HIV-1-infected and in 6.5% of HIV-1-uninfected children (P<.00001). The estimated relative incidence of bacteremic severe LRTI in children aged from 2 to 24 months were greater in HIV-1-infected than in -uninfected children for Streptococcus pneumoniae (risk ratio [RR], 42.9; 95% confidence interval [CI], 20.7-90.2), Haemophilus influenzae type b (RR, 21.4; 95% CI, 9.4-48.4), Staphylococcus aureus (RR, 97.9; 95% CI, 11.4-838.2) and Escherichia coli (RR, 49.0; 95% CI, 15.4-156). Isolation of Mycobacterium tuberculosis was also more common in HIV-1-infected than in -uninfected children (RR, 22.5; 95% CI, 13.4-37.6). In HIV-1-infected children, 60% of S. aureus and 85.7% of E. coli isolates were resistant to methicillin and trimethoprim-sulfamethoxazole, respectively. The case-fatality rates among HIV-1-infected children was 13.1%, and among HIV-1-uninfected children, 2.1% (adjusted odds ratio [AOR]; 6.52, 95% CI, 3.53-12.05; P<.00001). The changing spectrum of bacteria and antibiotic susceptibility patterns in HIV-1-infected children requires a reevaluation of the empirical treatment of community-acquired severe LRTI in children from developing countries with a high prevalence of childhood HIV-1 infection.

The association between respiratory syncytial virus (RSV) bronchiolitis and asthma has been established for more than 30 yr. However, the question of causality remains unanswered: Does severe RSV lower respiratory tract infection (LRTI) cause long-term pulmonary morbidity or do factors that predispose a child to wheeze later in life also predispose the child to severe RSV LRTI? In several human studies (1–4), obstructive airway disease appears to occur up to 10 yr after an initial RSV infection. The Tucson Children’s Respiratory Study showed an effect at 10 yr (5) but not by 13 yr (6). Hall and coworkers prospectively monitored 29 children who were hospitalized during infancy for RSV LRTI for 8 yr (7). Six children continued to have lower respiratory tract disease and six (21%) had persistently low oxyhemoglobin levels (Sa O2 ) at follow-up. Sigurs and colleagues found that children who had experienced RSV LRTI were more likely to have asthma and recurrent wheeze for 7 yr (4). Weber and colleagues (8) determined in Gambia that RSV LRTI predisposed children to recurrent wheeze, but only for 2 yr; after 3 yr, there was no significant difference between RSV-infected children and control children with respect to wheezing episodes. Many of the patients in the Tucson study had only RSV upper respiratory tract infections and none were hospitalized (5, 6). Patients in the study by Sigurs and coworkers (4), Hall and colleagues (7), and those in the Gambia study (8) had severe RSV disease. The reason for the observed varying degree and length of long-term sequelae may lie in the differing degrees of severity of illness studied (mild versus severe), or differences in location (developed versus developing countries), or ecological differences in sensitizing allergens (desert versus temperate versus tropical), or other undetermined factors. It remains to be determined whether severe RSV LRTI causes the pulmonary sequelae observed in longitudinal studies (i.e., a causeand-effect relationship) or whether inherent genetic or structural abnormalities that predispose a child to wheeze later in life also predispose the child to severe RSV LRTI. If causality exists, reducing severe RSV LRTI would reduce subsequent wheezing; if causality does not exist, reducing severe RSV LRTI would have no effect on subsequent wheezing. This is, therefore, a key clinical issue, which has been addressed in three sets of studies: antiviral therapy for RSV LRTI, antiinflammatory therapy for RSV LRTI, and prevention of RSV LRTI.

Nebulised ALX-0171 for respiratory syncytial virus lower respiratory tract infection in hospitalised children: a double-blind, randomised, placebo-controlled, phase 2b trial

ObjectivePrematurely born infants who develop respiratory syncytial virus (RSV) lower respiratory tract infections (LRTIs) have lung function abnormalities at follow-up. The aim of this study was to determine whether prematurely...

It has been suggested that co-infection of human metapneumovirus (hMPV) in severe respiratory syncytial (RSV) virus bronchiolitis is very common. To evaluate the epidemiology of hMPV co-infection in children with severe lower respiratory tract infection caused by RSV virus. This was an observational cohort study in which hMPV and RSV viral load was measured by RT-PCR in tracheal specimens from the target population. hMPV could not be detected in any of the 30 mechanically ventilated children with RSV lower respiratory tract infection. Our study suggests that hMPV co-infection is not very common in severe RSV lower respiratory tract infection.

BackgroundRespiratory syncytial virus (RSV) is the leading viral cause of severe lower respiratory tract infection (LRTI) in infants worldwide, with severe disease occurring in the first months of life. We assessed the efficacy of maternal immunization with an RSV F protein vaccine against RSV LRTI over the first 180 days of life.MethodsWe enrolled 4,636 women with low-risk third trimester singleton pregnancies in 11 countries to receive RSV F vaccine or placebo in a randomized, observer-blind trial. Women were followed for 6 months post-delivery, and infants for ~1 year. Surveillance for RSV LRTI in infants, identified by RT–PCR detection of RSV, physical examination, and pulse oximetry, was carried out for 180 days from delivery.ResultsThe RSV F vaccine induced modest reactogenicity and no excess fever. Live births resulted from 98.7% of pregnancies, with no difference between treatment groups in prematurity (< 37 weeks) or mean interval from treatment to delivery. There were no apparent negative impacts on pregnancy, delivery, or infant well-being. Vaccine immunogenicity resembled that in non-pregnant women. Transplacental transfer of vaccine-induced antibodies was markedly more efficient when the interval from immunization to delivery was ≥30 days. 85 to 95% of primary and secondary endpoint RSV LRTI events in the placebo group occurred in the first 90 days of life (see Figure 1). Overall, through 180 days of infant life, RSV was associated with 11.3% of all acute respiratory illnesses and 16.7% of all LRTI, but 49.1% of LRTI with SpO2 < 95% or tachypnea, and 60.3% of all LRTI with SpO2 < 92% in the placebo group. Vaccine efficacy was greatest in the first 75 days of life but clearly persisted to the primary, per-protocol analysis at 90 days, and was supported by the ITT analysis, per Table 1. Efficacy against all-cause LRTI with severe hypoxemia (46.0%) or hospitalization (27.8%) was observed in the per-protocol population, as well as an apparent impact on the clinical diagnosis of pneumonia through both 180 and 364 days.ConclusionRSV F vaccine in the third trimester was safe and had clinically-meaningful impacts on RSV and all-cause LRTI over the first 6 months of life.DisclosuresAll authors: No reported disclosures.

Respiratory syncytial virus (RSV) causes seasonal epidemics between December and March (April) and remains the main agent that causes severe lower respiratory tract infections in young infants. Children with bronchopulmonary dysplasia up to 24 months of age and preterm infants with a gestational age of 32 weeks and below, who are less than six months of age, are at highest risk for severe RSV infection. RSV-IGIV has been demonstrated to reduce significantly RSV associated hospitalizations, RSV associated hospital days and the incidence of severe RSV lower respiratory tract infections. Monthly infusions during RSV season were safe and well tolerated. Adverse events related to the hyperimmune globulin infusion were generally mild (< 3%) including fluid overload, decreased oxygen saturation and fever. Palivizumab, an intramuscularly administered humanized monoclonal antibody (RSV-glycoprotein-F antibody), will be preferable for the future because of ease of administration and comparable reduction in the risk of hospitalization. RSV-IGIV and palivizumab are both cost expansive and prophylaxis should be limited to high-risk infants.

Respiratory syncytial virus (RSV) and influenza virus are common causes of infantile lower respiratory tract infection (LRTI). It is widely believed that both viral replication and inappropriately enhanced immune responses contribute to disease severity. In infants, RSV LRTI is known to be more severe than influenza virus LRTI. We compared cytokines and chemokines in secretions of infants surviving various forms of respiratory illness caused by RSV or influenza viruses, to determine which mediators were associated with more severe illness. We analyzed lung tissue from fatal cases of RSV and influenza LRTI to determine the types of inflammatory cells present. Quantities of lymphocyte-derived cytokines were minimal in secretions from infants with RSV infection. Concentrations of most cytokines were greater in influenza, rather than RSV, infection. Lung tissues from fatal RSV and influenza LRTI cases demonstrated extensive presence of viral antigen and a near absence of CD8-positive lymphocytes and natural killer cells, with marked expression of markers of apoptosis. Severe infantile RSV and influenza virus LRTI is characterized by inadequate (rather than excessive) adaptive immune responses, robust viral replication and apoptotic crisis.

BackgroundThe safety of the monoclonal antibody nirsevimab and the effect of nirsevimab on hospitalizations for respiratory syncytial virus (RSV)–associated lower respiratory tract infection when administered in healthy infants are unclear.MethodsIn a pragmatic trial, we randomly assigned, in a 1:1 ratio, infants who were 12 months of age or younger, had been born at a gestational age of at least 29 weeks, and were entering their first RSV season in France, Germany, or the United Kingdom to receive either a single intramuscular injection of nirsevimab or standard care (no intervention) before or during the RSV season. The primary end point was hospitalization for RSV-associated lower respiratory tract infection, defined as hospital admission and an RSV-positive test result. A key secondary end point was very severe RSV-associated lower respiratory tract infection, defined as hospitalization for RSV-associated lower respiratory tract infection with an oxygen saturation of less than 90% and the need for supplemental oxygen.ResultsA total of 8058 infants were randomly assigned to receive nirsevimab (4037 infants) or standard care (4021 infants). Eleven infants (0.3%) in the nirsevimab group and 60 (1.5%) in the standard-care group were hospitalized for RSV-associated lower respiratory tract infection, which corresponded to a nirsevimab efficacy of 83.2% (95% confidence interval [CI], 67.8 to 92.0; P<0.001). Very severe RSV-associated lower respiratory tract infection occurred in 5 infants (0.1%) in the nirsevimab group and in 19 (0.5%) in the standard-care group, which represented a nirsevimab efficacy of 75.7% (95% CI, 32.8 to 92.9; P=0.004). The efficacy of nirsevimab against hospitalization for RSV-associated lower respiratory tract infection was 89.6% (adjusted 95% CI, 58.8 to 98.7; multiplicity-adjusted P<0.001) in France, 74.2% (adjusted 95% CI, 27.9 to 92.5; multiplicity-adjusted P=0.006) in Germany, and 83.4% (adjusted 95% CI, 34.3 to 97.6; multiplicity-adjusted P=0.003) in the United Kingdom. Treatment-related adverse events occurred in 86 infants (2.1%) in the nirsevimab group.ConclusionsNirsevimab protected infants against hospitalization for RSV-associated lower respiratory tract infection and against very severe RSV-associated lower respiratory tract infection in conditions that approximated real-world settings. (Funded by Sanofi and AstraZeneca; HARMONIE ClinicalTrials.gov number, NCT05437510).

BackgroundThe incidence trends and disease burden of pediatric respiratory syncytial virus (RSV) infection in Japan have yet to be fully elucidated.MethodsWith the cooperation of all 16 pediatric inpatient facilities in Fukushima Prefecture, we prospectively investigated the numbers of hospitalizations due to lower respiratory tract infections (LRTIs) caused by RSV and severe LRTIs requiring respiratory support caused by RSV and other pathogens during a 6‐year period between 2014 and 19. In addition, the number of RSV infection cases at sentinel sites was obtained.ResultsDuring the study period, there were 1117–1520 (average 1306) severe LRTI cases per year in Fukushima Prefecture, of which 23.7%–33.6% (average 30.6%) were due to RSV. The number of pediatric hospitalized patients with RSV infection ranged from 998 to 1426 per year (average 1177), and the number of RSV infection cases reported from sentinel sites in Fukushima Prefecture ranged from 2523 to 3477 per year (average 3005). A strong correlation was observed between the number of hospitalized patients and that reported from the sentinel sites. The annual incidence of RSV‐related LRTIs during the same period was estimated to be 174 cases per 10,000 children aged under 5 years, with 59 severe cases.ConclusionThe present study demonstrated that RSV infection was the leading cause of severe LRTIs in children in Fukushima Prefecture, accounting for approximately 30% of all cases. Furthermore, 1.7% of children under the age of 5 required hospitalization, highlighting the significant disease burden of RSV infection in this population.

Viral etiology of severe lower respiratory tract infections in SARS-CoV-2 negative hospitalized patients during the COVID-19 pandemic in Kuwait

Respiratory syncytial virus (RSV) is associated with severe lower respiratory tract infection (LRTI), especially in preterm infants. Other viruses, co-detected with RSV, may play a role in the severity of respiratory outcomes. This prospective epidemiologic study of severe LRTI incidence among children born ≤35 weeks gestational age at 3 sites in Brazil (2008-2010) followed a birth cohort for 1 year post-enrollment. Nasal washes from subjects with LRTI were tested for respiratory viruses using polymerase chain reaction. The primary outcome was the incidence of severe LRTI requiring hospitalization associated with RSV infection. Secondary outcomes included identification of viruses associated with LRTI, alone or coinfections, and risk factors associated with severe LRTI. Among 303 subjects, 176 (58.1%) experienced LRTI. Among these subjects, 162 had samples tested using polymerase chain reaction; 27.8% (45/162) experienced severe LRTI. More subjects with severe LRTI were infected with RSV (30/45, 66.7%) than with other viruses. RSV was present in 33.1% (143/432) of LRTI events tested, 57.3% (82/143) were coinfections. RSV was the virus most frequently associated with severe LRTIs (34/56 events, 60.7%); 50% (17/34 events) single and 50% coinfections. Significantly longer hospital stays were associated with LRTI events involving RSV coinfections compared with RSV single infections (P = 0.012). Infants with severe LRTIs had significantly lower mean RSV-IgG levels at study entry compared with those with nonsevere or no LRTIs (P < 0.05). This study confirms the association of RSV alone or as a coinfection with severe LRTI and reinforces the importance of providing adequate prophylaxis for susceptible infants.

Viral lower respiratory tract infections (LRTIs) are a leading cause of mortality among children. Bacterial coinfections in viral LRTI are associated with severe clinical outcomes. Identifying lower airway bacterial involvement in viral LRTI is challenging. Our objective was to define the concordance of bacterial detection between paired upper nasopharyngeal (NP) swabs and lower endotracheal airway samples (ETAs) in children with severe viral LRTI. Convenience sample of children <5 years intubated with LRTI. Children were enrolled within 48 hours of ICU admission, and NP/ETAs were obtained for the detection of Moraxella catarrhalis, Streptococcus pneumoniae, Haemophilus influenzae and Staphylococcus aureus. Concordance was assessed via intraclass correlation coefficient (ICC), according to the respiratory virus and age. Clinical outcomes were also assessed. From 2017 to 2021, we enrolled 76 children [median age: 2.1 (1.2-4.3) months]. The most common respiratory virus was respiratory syncytial virus (RSV) (73.7%). Overall concordance for bacterial detection was high for M. catarrhalis, H. influenzae, and S. pneumoniae (ICC ≥0.75) but low for S. aureus (ICC 0.36). Detection rates varied by viral pathogen, with M. catarrhalis and S. pneumoniae showing the highest agreement in children with RSV. Agreement was higher in infants <6 months. Prolonged intubation was observed in children with RSV and NP codetection of S. pneumoniae or H. influenzae. Concordance was high for M. catarrhalis, H. influenzae, and S. pneumoniae, but not for S. aureus, and was influenced by the viral etiology and age. These findings suggest the applicability of NP swabs as surrogates for lower airway cultures for specific bacterial-virus combinations in children with severe LRTI.