Recruitment, surveillance and loss to follow-up characteristics
A total of 635 children (51% male) were enrolled into the study at or near birth from KDH in two phases; January to May 2002, and December 2002 to July 2003 (). 535 (84%) of the children were recruited in the maternity ward of KDH. 47% of the cohort resided within Kilifi Township. Follow up over three epidemics for each phase realised a total of 1187 cyo ( panels a-b). The mean age of a child at exit from the study was 22 months (median 25 months, ). Of the recruits 199 (31%) exited prior to the end of the study (a rate of 17% of the cohort per annum). In 16 (8%) of these the cause was death of the child; eleven occurring in the first year of life (562 cyo), ie 20/1000 infant mortality.
Figure 1 Infection and disease within a birth cohort from Kilifi District, Kenya. Panels on the left show data for cohort children recruited in the first phase (Jan-May 2002), and on the right second phase recruits (Dec 2002 – July 2003). Panels a-b show, (more ...)
The intensity of surveillance was 29 visits /cyo (1 per 13 days), with an average interval between visits of 9 days within RSV epidemic periods and 18 days between. On average, for each child there were 22 home visits and 6 clinic visits, per year (these rates were highly homogeneous). The rate of clinic presentations within and between epidemics did not change (RR 1.02, 95%CI 0.98-1.07, P=0.324). There were 8716 visits fulfilling the criteria for a nasal specimen, of which 8492 (97%) were collected ( 7 per cyo). Blood slides were indicated in 5113 visits, of which 570 (11.1%) were parasite positive, and 490 (9.6%) had an accompanying diagnosis of malaria, representing 1.4% of all visits. Laboratory IFAT results were obtained for 8471 of the nasal samples, yielding 409 (4.8%) RSV antigen positive episodes, comprising 130 from active visits, 268 from clinic visits and 11 from admissions to KDH. A diagnosis of malaria was made in 86/1008 (8.5%) RSV negative LRTI diagnoses, with 12 severe LRTI and 10 hospitalised.
RSV infections in the birth cohort
Of the 409 separate RSV episodes, 326 were the first observed in a particular child and hereafter denoted as primary cases, and 83 were repeat infections. There were four distinct RSV epidemics ( panels a-b) occurring with approximate annual periodicity (intervals between the epidemics were 9, 14 and 10 months) with the majority of cases in the first quarter of the year, and not associated with any meteorological measures. Over the 4 calendar years of observation (2002-2005), there were 70 out of 208 weeks (or 0.34 of the year on average) defined as epidemic (see legend to ). The proportion of the cohort observation period that was within defined epidemic periods was 0.44 indicating an over-sampling from within epidemics.
Crude incidences (/1000 cyo) for total, primary and re-infections are 345 (cyo 1187), 394 (827), and 230 (361), respectively. Corresponding adjusted incidence estimates (ie weighted for epidemic over-sampling) are 261 (95%CI 236-287), 298 (264-337) and 169 (134-214). There was no statistically significant difference in the incidence of RSV infections by age group (infants 0-11m versus children 12-30m) or by sex. The incidence of re-infections was approximately half that for primary infections, regardless of age.
RSV associated disease in the cohort
Out of the 409 RSV episodes, 275 (67%) appeared confined to the upper respiratory tract and 134 (33%) involved the lower respiratory tract, of which 66 (49%) were assigned severe. Of all RSV cases, 11 (3%), all severe LRTI, were admitted to KDH none of whom had a co-bacterial infection. No RSV infection coincided with the death of the child. A concurrent malaria diagnosis was made in 6 (1.5%) of 409 RSV infections, of which two had LRTI, one of which was severe and none were hospitalised.
The risks of LRTI, severe LRTI and hospital admission following primary RSV infection were 35%, 18% and 3%, respectively, and correspondingly for repeat RSV infection were 24%, 8% and 2%. Stratifying by age group (), following primary infection the peak disease risk tends to be in children under 6 months of age, followed by a trend for decline with increasing age. For LRTI this trend is gradual with the risk never declining to less than 20% (ie around 40% of the peak risk) even in children aged 24 months or over. The risk of severe LRTI following RSV infection appears to decline only from age 9-11m and most significantly in the age group 18-30m. In relation to repeat infection, the data indicate a substantial risk of LRTI, particularly in children ≥18m, (25.4%, 95%CI 15.3-37.9), and of severe LRTI (9.5%, 95%CI 3.6-19.6), although numbers are too few in the first 18months to identify any trend with age. Two children aged 18-30m were, however, admitted to hospital.
Risk of RSV associated LRTI, severe LRTI and hospitalisation, by age group and infection history, in a birth cohort from Kilifi District, Kenya
Adjusted incidence estimates, by age group, for RSV associated LRTI, severe LRTI and hospitalisation are presented in . For all disease categories, peak incidence occurred in infants under 6 months of age, and is significantly lower in the older age group (6-30m) for LRTI (IRR 0.494 P=0.002, 95%CI 0.318-0.768) and severe-LRTI (IRR 0.347 P<0.001, 95%CI 0.198-0.610). For infants (0-11m) adjusted incidence (95%CI) of LRTI, severe LRTI and admission is 104 (79-137), 66 (47-91), and 13 (5-34) respectively. Corresponding estimates for children aged 12-30m are 77 (39-151), 22 (9-56), and 7 (1-61) respectively. There was no relationhip between incidence and sex of the child or low birth weight (<2.5kg).
Adjusted RSV incidence (/1000 cyo) by age group and severity of associated disease, in a birth cohort from Kilifi District , Kenya
RSV disease as a proportion of all-cause LRTI and hospital admissions
The temporal occurrence of RSV associated LRTI and severe LRTI relative to all-cause LRTI and severe LRTI is recorded in (panels c-d and e-f, respectively). RSV was identified in 13% of LRTI, 19% of severe-LRTI and 5% of admissions. Stratified by age () the data show a higher risk of RSV in cases of LRTI, severe LRTI and hospitalisations in infants compared with older children, which is statistically significant only for LRTI.
Proportion of LRTI, severe-LRTI and hospital admissions associated with RSV in a birth cohort from Kilifi District, Kenya
The characteristics of RSV repeat infections
The distribution of total number of clinical RSV infections per individual was 254 with one, 64 with two, 6 with three, and 1 each with four and five. Of the 72 children with more than one RSV episode, 19 (26%) had a repeat infection that involved the lower respiratory tract and 6 (8%) had severe LRTI. In 10 (14%) a repeat infection was more severe than the primary episode. Of the 83 repeat infections 19 (23%) occurred within the same epidemic with median interval between re-infections of 24 days (range 18-66 days). There were five children re-infected within the first 6 months of life (one twice). Of these six repeat infections four resulted in LRTI (one severe), five occured within a single epidemic with an interval between episodes of 19-63 days, and one occurred in the succeeding epidemic (gap 113 days). Of the eight children with 3 or more RSV infections four were admitted at least once, however none had an RSV-associated hospital admission, and none had in-patient reports that would indicate an immunocompromised condition.