The study took place in the pediatric wards of Kilifi District Hospital (KDH), a rural hospital on the Indian Ocean coast of Kenya. Since 2001, data on all pediatric admissions and discharges of children at KDH have been prospectively collected in real time through an integrated online data management system in FileMaker Pro (FileMaker, Inc., Santa Clara, CA, USA). Starting from April 16, 2002, we linked admission records to the individual residence status of each child at the date of illness onset within the Kilifi Health and Demographic Surveillance System (KHDSS). The KHDSS covers a population of ≈250,000 living close to the hospital; ≈60% of pediatric admissions of children at KDH originate from KHDSS residents (13,14). The KHDSS fieldworkers enumerate births, deaths, and migrations (i.e., into, out of, and within the study area) every 4 months.

Since January 2002, continuous surveillance for RSV has been conducted among all children <60 months of age admitted to KDH for LRTI (15). A nasal specimen (nasal wash by bulb or nasopharyngeal aspirate) is collected from each patient by trained medical assistants soon after admission (15,16) and assayed for RSV antigen by immunofluorescence antibody testing (Imagen Respiratory Syncytial Virus Kit; Oxoid Ltd., Hampshire, UK; or Light Diagnostics Respiratory Viral Screen DFA Kit; Millipore, Temecula, CA, USA), according to the manufacturer’s instructions.

For our study, the cohort was defined as residents of KHDSS admitted to KDH during the first year of life during RSV epidemics from April 16, 2002, through May 31, 2010. We classified the cohort into those who did or did not have LRTI on their first (index) admission. Among those with LRTI, we further subdivided the children on the basis of RSV immunofluorescence antibody test results. Children with LRTI not tested for RSV were examined in preliminary analyses and consolidated into the negative RSV test group. The 3 exposure groups in the cohort were the RSV LRTI group, the other LRTI group, and the non-LRTI group. Infants were excluded if they were admitted on the day of birth; had features of severe malnutrition (i.e., severe wasting, bipedal edema, or mid-upper arm circumference <11 cm); were born with low birthweight (<2.5 kg); had underlying congenital diseases; or remained in the hospital for >2 weeks. Evidence suggests that infants in these categories are at a higher risk for readmission and postdischarge death (17).

We used the linked databases of the KDH and KHDSS to determine which cohort members were subsequently readmitted to the hospital or died before their fifth birthday. The primary outcome was readmission to KDH for pneumonia. As secondary outcomes, we examined pneumonia with concurrent wheezing (a marker of hyperreactive airways), all-cause, and nonpneumonia readmissions, as well as all-cause mortality. The Kenya Medical Research Institute Scientific Steering Committee and the National Ethical Review Committee granted ethical approval for this study.

Using detailed hospital-based data linked to a closely monitored population, we found no difference in the incidence of pneumonia hospitalization among children previously admitted for RSV-associated LRTI in infancy compared with those admitted for non-RSV associated LRTI. However, we did find elevated incidence of readmission for pneumonia among children admitted as infants for LRTI, with or without RSV diagnosis, compared with children admitted as infants for a non-LRTI condition. The magnitude of this association was highest among children admitted in the first 3 months of life and decreased to nonsignificant levels in children >3 months of age at the first admission. Although the association between LRTI during infancy and readmission for pneumonia was unaffected by RSV status at first admission, the association between readmission for pneumonia with wheeze was greater among children whose previous admission was for RSV LRTI (5-fold) compared with children whose previous admission was for LRTI without RSV (3-fold). Only children who were admitted for LRTI at <3 months of age had higher incidence of all-cause readmission compared with those admitted for non-LRTI. The association was lost, with no effect modification by age, when pneumonia admissions at the index admission were excluded; this finding indicates that the later pneumonia was the main driver of the increased incidence of subsequent readmissions and the observed effect modification by age at index admission.

Although this study involves a retrospective analysis, it is based on a large, unique dataset from sub-Saharan Africa in which detailed and consistent data were collected prospectively. KDH is the main inpatient facility in this rural district of Kenya. Previous reports indicate a distance decay in access to KDH, but this would only influence the relative incidence rates between study groups if there was a differential in access by study groups (14,15). Although Cox regression would have provided a more flexible analysis method, the proportional hazards assumption was violated, and we therefore used Poisson regression with Lexis expansion. Alternative analyses accounting for death as a competing risk yielded no qualitative differences in the study results. To account for the time-dependent incidence (seasonal changes) of exposure to LRTI pathogens, we set the analysis time based on the calendar time in the survival analysis. Seasonal variation in exposure was also minimized by restricting cohort recruitment to RSV epidemic periods only.

Our findings are consistent with the results of similar studies in The Gambia (11,19) and elsewhere (6,9,11,20,21). Weber et al. reported a 3-fold increase in incidence of admission for pneumonia or wheezing in children with prior exposure to RSV infection compared with a community of age-matched neighborhood children (11). Their study suggested that the duration of increased risk for pneumonia after RSV LRTI in infancy waned by the end of the second year after discharge, a finding duplicated in our study. However, that study did not explore the differential incidence of pneumonia after non-RSV LRTI, nor did it explore the influence of age at first episode of LRTI. Our study also used a hospital-based comparison group for which risk for readmission with pneumonia might have been elevated.

Prospective studies in Europe and the United States reported that the effects of RSV in infancy on respiratory sequelae decreased sharply during the first year of follow-up and that, by 5 years after RSV infection, the association is insignificant (11,20,21). Other studies have reported persistence of increased respiratory disease up to 7 years (22) and 11 years (8) after RSV infection but not at 18 years after infection (5).

A second observational, age-matched, case–control study in The Gambia examining later lung problems in children after childhood (<5 years of age) admission for severe pneumonia reported inconclusive results (19). Even though the odds of lung disease were higher among the childhood pneumonia case-patients compared with controls (odds ratio 2.93, 95% CI 0.69–12.48), the study had severe limitations, including small sample size and potential bias (only 68 of 190 possible cases were traced).

Our findings suggest that, in addition to RSV infection, other etiologies of LRTI are associated with subsequent hospital admissions for pneumonia or wheeze. We offer 2 possible explanations for this. First, children with an inherent predisposition to subsequent pneumonia or wheezing episodes, such as those with smaller airways (23–26) or with atopy (27), may also be more susceptible to viral LRTI in early infancy. Second, viral LRTI in early infancy could lead to structural lung damage or immune paresis that causes further pneumonia episodes with or without wheeze. The latter explanation has been reported for reactive airway disease (mainly manifested as wheeze) in relation to RSV predisposition (28–32).

In our study, RSV infection appeared to protect against death, but this conclusion is best explained in reverse. In the comparison group, children admitted to a hospital for conditions other than RSV were more likely to die subsequently than were children admitted for RSV. However, unlike some other viruses that cause severe conditions, RSV causes a highly infectious disease that affects most children and does not associate specifically with markers of chronic ill health. A similar phenomenon has been observed with malaria parasitemia, which is associated with a reduced postdischarge mortality rate when compared with admissions for other conditions (17).

Findings of an increased mortality rate among children residing in areas with good access to KDH, as well as decreased incidence of subsequent pneumonia following admission to HDU, were unexpected and counterintuitive. Good access was mainly in urban and periurban administrative areas of Kilifi; because urbanization is associated with high HIV prevalence, some of the access-to-care effect may be attributable to HIV/AIDS, but our data lacked HIV results for all admissions to check this effect. The protective association between HDU treatment and later pneumonia may be explained because the HDU has no ventilators and mainly admits children with a nonrespiratory severe illness and because nonrespiratory disease does not have an association with later pneumonia.

We report that hospitalizations for severe LRTI in early infancy in Kenya are associated with increased risk for subsequent pneumonia. The phenomenon has been observed for RSV-associated severe LRTI but not for non-RSV severe LRTI. This raises questions about the underlying cause and, on a practical level, alerts clinicians that a child with LRTI in the first 3 months of life is at risk for readmission with severe respiratory disease over the period of 1–2 years after discharge. Parents of children with LRTI-related hospital admissions during infancy should be advised to be vigilant in the care of the child and to seek medical advice rapidly in the event of further respiratory symptoms. An effective outpatient follow-up for these children throughout early childhood might also be warranted. Larger cohorts and probe studies using interventions against LRTI in infancy (e.g., vaccines) will be pivotal for confirming the causality and the magnitude of the associations observed here and for determining the specificity of the infectious etiologies associated (or not associated) with later episodes of pneumonia.

Number and crude incidence rates per 1,000 child-years of various diagnoses by study group for readmission to Kilifi District Hospital, coastal Kenya; univariate Poisson regression analysis of risk factors for readmission with pneumonia, pneumonia with wheeze and all-cause mortality; and incidence rates of readmission with pneumonia over follow-up time by study group.