We estimated that in 2005, at least 33·8 (95% CI 19·3–46·2) million episodes of RSV-associated ALRI occurred worldwide in children younger than 5 years, with incidence in developing countries more than twice that of industrialised countries. This estimate represents roughly 22% of all episodes of ALRI in young children. By comparison, 13·8 (10·8–17·2) million episodes of pneumococcal pneumonia and 7·9 (7·2–12·9) million episodes of Haemophilus influenzae
type b pneumonia occurred in the same age group.43,44
However, this comparison should be interpreted with caution since the estimates for pneumococcal pneumonia and Haemophilus influenzae
type b were calculated by extrapolation from data derived from vaccine probe studies. A substantial proportion of RSV-associated morbidity occurs in the first year of life, with incidence in infants that is twice or three times greater than is reported for children younger than 5 years overall. We also estimated that in 2005, 3·4 (2·8–4·3) million young children worldwide developed RSV-associated severe ALRI necessitating hospital admission, and 66 000–199 000 children younger than 5 years died from RSV-associated ALRI, with 99% of these deaths occurring in developing countries.
Estimates of RSV-associated ALRI incidence are highly variable within countries or regions and between regions. We cannot deduce how much of this variation is due to methodological differences and how much is due to variation in RSV epidemiology between study populations. Thus, the true uncertainty is wider than that expressed in a standard 95% CI. Three methodological factors affect estimates: method of case ascertainment; precise case definition for non-severe and severe episodes; and differences in sensitivity and specificity of diagnostic assays to identify RSV infection.
Hospital-based passive case ascertainment is likely to yield falsely low estimates of RSV-associated ALRI incidence, especially in developing countries.45
For example, Nokes and colleagues46
reported that only 20–25% of cases of RSV-associated severe infections that were referred from the community could be identified as hospital admissions, mainly showing low health-service use. Additionally, in some studies a substantial proportion of all children with ALRI were not tested for RSV for various reasons, resulting in falsely low estimates. In hospital-based passive ascertainment studies, distance from hospital is an important factor. Results of a study in the western region of The Gambia29
showed that the rate of hospital admission for RSV-associated severe ALRI was inversely proportional to the cost of getting to the health centre. Similarly, in the Kilifi hospital study,46
though overall incidence for RSV-associated ALRI was 11 per 1000 infants, incidence was 21 per 1000 infants in sublocations closest to hospitals. In one study,47
investigators attempted to keep this effect to a minimum by reimbursing patients for travel costs, but still showed that roughly 25% of children referred with RSV-associated severe ALRI did not attend hospital. This finding supports our decision to base the RSV-associated ALRI incidence estimate in developing countries on data from studies with active case ascertainment.
Case definitions varied from the WHO definition to physician-diagnosed ALRI (with or without chest radiographic confirmation) and unspecified acute respiratory infection that was severe enough to necessitate hospital admission. We noted that investigators using the WHO definition reported the highest incidences. For example, Nokes and colleagues reported in the Kilifi birth cohort study (webappendix p 17
) that 75% of WHO-defined severe ALRI cases did not warrant admission to hospital, according to study clinical officers. The studies we included also differed in method of nasal sampling and in the specific diagnostic assays used, which will also have contributed to some of the variation in reported incidence estimates.
The RSV-associated ALRI incidence estimates are more likely to underestimate than to overestimate true incidence in developing countries. However, this conclusion is uncertain because of various factors affecting the estimate. First, estimation depends on the relative sensitivity and specificity of the WHO case definition for true ALRI—both are reported to be fairly high (median specificity of 86% for infants and 93% for children aged 1–4 years).11
Second, almost all studies identified RSV by ELISA or immunofluorescence assays, which have a 12–50% lower sensitivity than does PCR-based diagnosis.48
However, the overall effect of these factors on estimates depends also on relative test specificities, which are unknown for most studies. Finally, although we based our estimate on data from community-based studies with active case ascertainment and facilitated referral of patients to hospital, they could have still missed an unknown proportion of cases.
Substantial uncertainty surrounds case fatality ratio estimates from developing countries. First, 4–28% of children admitted to hospital with ALRI were not tested for RSV for various reasons (such as the child being critically ill, sampling not done on weekends or for night-time admissions, death before sampling, or refusal to get the test done; webappendix p 6
). The absence of sampling in these children introduces a bias towards falsely low reported estimates because mortality tends to be higher in these groups. Second, we have estimated case fatality ratios separately for broad developing and industrialised country categories and the degree to which included studies are representative of these broad categories is unknown. We omitted three developing country studies reporting data from paediatric intensive care units and reduced bias in combination of incidence and case fatality ratio data by using only data for the incidence and case fatality ratios from cases admitted to hospital. More generally, these studies might be from settings with above-average resources, and thus report an underestimate of the true case fatality ratio in hospital settings in developing countries.
We based our estimate of the lower bound on reported incidence of RSV-associated severe ALRI necessitating hospital admission and on reported case fatality ratios in developing-country hospitals. However, not all cases of severe disease are admitted to hospital. Furthermore, hospital-based case fatality ratios from the studies we included cannot be regarded as representative of whole population groups. In the most resource-poor settings, the case fatality ratio for RSV-associated ALRI could be higher than these reported estimates and closer to that of bacterial pneumonias, especially since RSV-associated ALRI might predispose to bacterial infection. Results of studies from developing countries have shown variable rates of bacterial co-infection in RSV-associated ALRI, ranging from 3·5% in The Gambia49
to 31% in a study from Pakistan.4
In Lombok, Indonesia, peaks in ALRI case fatality ratios occurred after peaks in RSV case fatality ratios, potentially implicating bacterial co-infections (). During strategic planning to reduce childhood pneumonia deaths, co-attribution of mortality in patients with RSV and bacterial co-infection to RSV in addition to bacteria might be worthwhile.
Our estimate of the upper bound was based on only one study and so replication in other settings is needed. Additionally, although we attributed all excess ALRI mortality during the RSV season to RSV, several other viral and bacterial pathogens causing ALRI have seasonal patterns. We have thus not considered the context of multiplicity of other respiratory viruses (eg, human metapneumovirus or influenza A) that co-circulate during the RSV season and in some areas account for as much as 10–20% of ALRI hospital admissions and probably have a similar, if not higher, case fatality ratio to RSV.50–53
The plausibility of our global mortality boundary estimates are supported by the internal consistency of the RSV-associated severe ALRI incidence, case fatality ratios, and RSV-associated ALRI mortality estimates. However, evidence to support valid and precise estimates of global RSV-associated ALRI mortality is of low quality. Research investment to gather further data is clearly needed—eg, by gathering RSV isolation data from ALRI patients in sites where demographic surveillance records community-based pneumonia mortality. Further large-scale unselected case series reporting age-specific case fatality ratios from many well described clinical settings in developing countries and large-scale post-mortem studies of ALRI that include investigation of possible RSV causes would also substantially improve the evidence base for this estimate. Until the widespread delivery of an effective RSV vaccine, measures such as promotion of health-service use, provision of regular oxygen supplies at health centres54
and hospitals, and immunoprophylaxis with monoclonal antibodies (when appropriate and affordable) can be expected to substantially reduce mortality associated with this disease.55,56