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Table 1 Study goals and features intended to address specific knowledge gaps

From: Influenza and respiratory syncytial virus in infants study (IRIS) of hospitalized and non-ill infants aged <1 year in four countries: study design and methods

A. Assess the frequency of influenza- and RSV-associated hospitalizations among infants ages <1 year old
Knowledge Gap Study Feature
Few studies have examined influenza and RSV hospitalizations outside of high-income countries. Enroll patients in study sites located in four diverse middle-income countries (Albania, Jordan, Nicaragua, and The Philippines).
Studies often enroll only during peak periods of virus circulation. Enroll patients during an extended period to take into account prolonged and overlapping periods of influenza and RSV circulation.
Typical severe acute respiratory illness (SARI) surveillance strategies use highly specific case definitions that overlook non-respiratory and non-febrile manifestations of disease. Enroll admissions due to any acute (respiratory and non-respiratory) illnesses; describe the clinical diagnoses associated with influenza and RSV infections.
Secondary complications, like pneumonia and bronchiolitis, often occur after acute viral infections, and thus viral shedding may be missed by the time of hospitalization. In addition to molecular diagnostics, serologic assays will be used to identify recent influenza and RSV infections.
More information is needed on the virus-specific attributable fraction for influenza and RSV disease. Assess the prevalence of influenza and RSV infections among healthy infants who have not been ill for at least 7 days at specimen collection (all study years) and confirm absence of symptoms up to 4–10 days after collection (starting in year 2 and continuing afterwards).
B. Describe the clinical features of influenza- and RSV-associated hospitalizations among infants and the predictors of very severe disease
Knowledge Gap Study Feature
Information is limited on the non-respiratory disease manifestations of influenza and RSV infections among infants. Assess the frequency of influenza and RSV infections among infants hospitalized with non-respiratory illness (including febrile seizures, otitis media, diarrhea, and sepsis-like syndromes).
The range of clinical severity for influenza and RSV infections among infants is poorly characterized outside of high-income countries. Examine symptoms and signs (including temperature, oxygen saturation, and respiration), oxygen support, and treatments at admission and then daily during hospitalization for influenza and RSV infected infants.
Extent to which antibiotics may be over-utilized and influenza antivirals may be under-utilized among infants is unclear, especially outside of high-income countries. Describe the use of and timing of administration of antibacterial and antiviral agents during infants’ hospitalization.
Further research is needed to identify risk factors for very severe disease (i.e., requiring intensive care), especially outside of high-income countries. Assess the characteristics of infants (e.g., age, sex, prematurity, co-morbid conditions), viruses, and environmental characteristics (e.g., socio-economic status, household composition, distance from hospital) associated with more severe illness presentation.
Information on the clinical course of influenza and RSV infections during and following hospitalization is limited, especially outside of high-income countries. Describe the length of stay in the general ward or ICU and the frequency of death and hospital re-admission within 30 days post-discharge among enrolled infants.
C. Describe the acute antibodies to influenza and RSV by months of age among infants <1 year old and their humoral immune response to infections.
Knowledge Gap Study Feature
Given that infancy is a period of dynamic immune system development, there is limited information on the antibody response of infants. Describe the influenza and RSV antibody response of infants by age sub-strata for all infants at hospital admission.
More information is needed on the prevalence of influenza antibodies among infants of mothers who received influenza vaccination during pregnancy. In study sites where influenza vaccination is available, describe the influenza antibody profiles of infants born to influenza vaccinated vs. unvaccinated mothers.
Implications of pre-infection influenza and RSV antibodies to the manifestation of disease and immune response among infants are unclear (especially those aged <6 months). Compare acute antibodies for influenza and RSV (at hospital admission) and subsequent sero-conversion among infants receiving general vs. intensive care by age sub-strata.
Information on the frequency with which influenza and RSV infections result in robust antibody response is limited, especially by sub-age-strata among infants aged <1 year. Describe the frequency of serologic conversion to influenza and RSV using acute and convalescent sera among infants with infections confirmed by real-time reverse transcriptase polymerase chain reaction (rRT-PCR) assay.