Underdetection of laboratory-confirmed influenza-associated hospital admissions among infants: a multicentre, prospective study

Abstract

Background-Since influenza often presents non-specifically in infancy, we aimed to assess the extent to which existing respiratory surveillance platforms might underestimate the frequency of severe influenza disease among infants.Methods-The Influenza and Respiratory Syncytial Virus in Infants (IRIS) study was a prospective observational study done at four hospitals in Albania, Jordan, Nicaragua, and the Philippines. We included acutely ill infants aged younger than 1 year admitted to hospital within 10 days or less of illness onset during two influenza seasons (2015-16 and 2016-17) in Albania, Jordan, and Nicaragua, and over a continuous 34 week period in the Philippines. We assessed the frequency of influenza virus infections by real-time RT-PCR (rRT-PCR) and serology. The main study outcome was seroconversion, defined as convalescent antibody titres more than or equal to four-fold higher than acute sera antibody titres, and convalescent antibody titres of 40 or higher. Seroconverison was confirmed by haemagglutination inhibition assay for influenza A viruses, and by hemagglutination inhibition assay and microneutralisation for influenza B viruses.Findings-Between June 27, 2015, and April 21, 2017, 3634 acutely ill infants were enrolled, of whom 1943 were enrolled during influenza seasons and had complete acute-convalescent pairs and thus were included in the final analytical sample. Of the 1943 infants, 94 (5%) were influenzapositive by both rRT-PCR and serology, 58 (3%) were positive by rRT-PCR-only, and 102 (5%) were positive by serology only. Seroconversion to at least one of the influenza A or B viruses was observed among 196 (77%) of 254 influenza-positive infants. Of the 254 infants with influenza virus, 84 (33%) only had non-respiratory clinical discharge diagnoses (eg, sepsis, febrile seizures, dehydration, or other non-respiratory viral illness). A focus on respiratory diagnoses and rRT-PCR-confirmed influenza underdetects influenza-associated hospital admissions among infants by a factor of 2•6 (95% CI 2•0-3•6). Findings were unchanged when syndromic severe acute respiratory infection criteria were applied instead of clinical diagnosis. Interpretation-If the true incidence of laboratory-confirmed influenza-associated hospital admissions among infants is at least twice that of previous estimates, this substantially increases the global burden of severe influenza and expands our estimates of the preventive value of maternal and infant influenza vaccination programmes.

Antibody Responsiveness to Influenza: What Drives It?

“…In the latter study, seroconversion was more frequently observed in hospitalized patients, consistent with data from human challenge and COVID-19 studies [102] that suggest that severity of infection may correlate with the induction of antibody responses [95]. A recent multicenter study on the burden of respiratory infections in infants showed that 23% of influenza-positive infants did not seroconvert to the tested strains by HAI or microneutralization assays [103]. Overall, the correlation between the initial infection dose, disease severity, and antibody development is a challenge to address in any naturally-acquired infection studies due to difficulties in determining the time of infection.…”

Global burden of upper respiratory infections in 204 countries and territories, from 1990 to 2019

“…In this study based on GBD 2019, we reported that the estimated incident cases of URIs reached more than 17 billion in 2019, accounting for about 43% cases of all the GBD diseases and injuries. As an important and common presentation for the reproduction and circulation of more than 200 known virus strains [ 23 , 24 ], the massive incidence of URIs may possess an unexpected threat to human health and should never be overlooked. The current pandemic of SARS-CoV-2, which presents mild URI syndromes in most of the patients, has led to severe diseases in some cases and caused more than three million deaths to date [25] .…”

Influenza in Children

“…Delayed presentation to healthcare facilities combined with a reliance on molecular testing can also lead to underestimations of burden. Indeed, a recent study that combined molecular and serological testing with wide testing criteria indicated that the burden of severe influenza in infants may be twice that of current global estimates (Thompson et al 2019). In addition, maternal influenza infection is associated with increased maternal morbidity and mortality, as well as increased occurrence of premature and small-for-gestational-age births.…”