Respiratory syncytial virus (RSV) is the leading cause of acute lower respiratory tract infections in infants and toddlers.¹ Up to 70% of children are infected during their first year of life² and 1–3% of the annual birth cohort are hospitalised because of RSV infection.^3–,⁶ The need for hospitalisation is a useful marker of severity, has emerged as the primary endpoint in clinical trials of RSV prophylaxis,^7–,⁹ and is a major cost driving event.¹⁰ Major host factors associated with an increased risk for hospitalisation associated with RSV are prematurity,^2,4,11 bronchopulmonary dysplasia (BPD),^2,4,11 and congenital heart disease (CHD).¹² Population based RSV hospitalisation rates for infants with prematurity and those with BPD have been established,^4–,⁸ and provided the rationale for studying and introducing RSV immunoprophylaxis using the monoclonal antibody palivizumab in some countries.¹³ Considerably less data are available for CHD^4,6 and none provide hospitalisation rates for children with haemodynamically significant CHD. This distinction is important because palivizumab was studied exclusively in patients with haemodynamically significant CHD.⁹ In recently published national recommendations for Great Britain¹⁴ and the USA,¹⁵ its use was therefore restricted to this indication. The present study reports population based RSV hospitalisation rates in children with haemodynamically significant CHD, taking advantage of a long term surveillance programme of RSV hospitalisations^3,16 at an institution serving a precisely defined paediatric population.

METHODS

RESULTS

RSV hospitalisations

During six consecutive years, 813 children (456 males) were hospitalised because of RSV infection. Table 1⇓ shows major clinical and outcome variables. Eighty four patients (10%) were >24 months of age and were excluded. CHD, BPD, prematurity, and age <1 month were recorded in 10 (1.4%), 16 (2.1%), 60 (8.2%), and 90 (12.3%) of the remaining 729 patients, respectively. Five (50%) and 462 (64%) children with and without CHD, respectively, were <6 months of age. There was biannual periodicity of RSV hospitalisation frequencies reflecting the pattern of alternating severity of RSV epidemics in this region (fig 1A⇓).¹⁶ There was no correlation between the severity of RSV epidemics and the distribution of risk factors (fig 1B⇓) or the clinical course of RSV hospitalisations (data not shown).

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Table 1

 Clinical course of RSV hospitalisations in 729 children less than 24 months of age stratified according to risk factors

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Figure 1

 Epidemiology of RSV hospitalisations in the Canton of Bern, Switzerland. (A) Frequency of RSV hospitalisations in each study year in children <24 months of age. (B) Distribution of risk factors among patients hospitalised for RSV infection in each study year. CHD, congenital heart disease; BPD, bronchopulmonary dysplasia.

CHD was diagnosed in 407 of 54 947 (0.74%) live born infants during the study period. There were 10 RSV hospitalisations in CHD patients (table 2⇓). Complete surgical correction had already been accomplished at the time of RSV infection in three patients (coarctation, coarctation plus ASD, and ASD plus PDA in one patient each). None of these patients had pulmonary arterial hypertension. The remaining seven children had uncorrected CHD (VSD and complex cyanotic CHD in two patients each; ASD, cor triatriatum with mitral valve stenosis, atrioventricular canal, and Epstein’s anomaly in one each). Pulmonary arterial hypertension and cyanosis were present in five and two of these patients, respectively. Haemodynamically insignificant cardiac malformations were recorded in 11 patients (VSD in eight patients; ASD in three; PDA in one) assigned to the non-CHD group.

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Table 2

 RSV hospitalisation rates in children with and without CHD

DISCUSSION

In this six year study we established that in the Canton of Bern, Switzerland, RSV hospitalisation rates in children <24 months of age with CHD (tables 2⇑ and 3⇑) were markedly lower than previously reported figures from the USA (table 3⇑)⁴ and from Sweden.⁶ These discrepancies warrant comparative analysis of the methods used for case catchment and ascertainment in these studies. The method used in our study is likely to yield reliable RSV hospitalisation rates, because (1) cases were identified prospectively using a standardised diagnostic algorithm at a single study site, which (2) served a precisely defined geographical area, which permitted generation of accurate data on both the incidence of CHD and the live birth cohort, and (3) the six year observation period eliminated the effect of year to year fluctuation of hospitalisation rates.¹⁶ In addition, both the incidence of CHD (0.74%) in the general population^19,20 and the overall infant RSV hospitalisation rate of 1.2% are consistent with established figures,^5,6,21,22 lending further support to the accuracy of data acquisition.

Comparison of the present study with the report by Boyce and co-workers,⁴ who found approximately fourfold greater hospitalisation rates in CHD patients (table 3⇑), yields a number of possible explanations for discrepant results. In their retrospective analysis of a large Medicaid population in Tennessee, these authors identified CHD patients using the ICD-9 codes 745, 746, and 747. This approach did not allow them to distinguish between haemodynamically significant and non-significant heart disease. Because haemodynamically significant CHD alone is a risk factor for RSV hospitalisation,²³ the accuracy of reported incidence rates may have been affected. Furthermore, the number of RSV hospitalisations in patients with and without CHD (that is, the numerators) may have been overestimated, because episodes coded specifically for “RSV infection” accounted for 6.3% of cases only.⁴ The remainder were coded for the diagnosis of “bronchiolitis”. Although corrections were made for influenza, other viruses such as parainfluenza virus, adenovirus, and human metapneumovirus may have accounted for an unknown proportion of cases.

Regardless of the methodological differences between these two studies, CHD patients of all age groups had an RR for RSV hospitalisation of approximately 2 compared with non-CHD patients (table 3⇑). It is thus conceivable that the differences in RSV hospitalisation rates are real and reflect true epidemiological differences. This notion is supported by the results from the two placebo controlled trials of RSV immunoprophylaxis. For instance, hospitalisation rates among CHD patients <6 months of age assigned to the placebo arm were 24%²⁴ and 12.2%,⁹ respectively. These figures are substantially greater than those found in the present study (2.5%), even if we take into account the fact that hospitalisation rates established in our study must be corrected by a factor of 2 for comparison. This adjustment is necessary because patients participating in these trials were observed prospectively during a six month period in winter, during which essentially all RSV infections occur.²⁴ Thus, true exposure occurs during approximately half of the number of child-years used as denominator in our study. Several reasons for these widely divergent RSV hospitalisation rates are conceivable. It has been shown that the severity of both RSV epidemics and RSV disease varies according to geographical location.^25,26 Small family size and low rates of day care attendance in Switzerland may reduce exposure to RSV during the first year of life. Also, different criteria for hospital admission may play a role.

Eriksson and co-workers⁶ reported the only currently available estimates on RSV hospitalisation rates in CHD patients from a European country. These investigators found hospitalisation rates between 2.8% and 6.4% depending on the severity of the annual RSV epidemic. Comparison with our data is hampered, however, because stratifications according to age and haemodynamic significance of CHD were not made.

The present study has several limitations. (1) We were unable to define the subpopulation of CHD patients who had not had corrective surgery at the time of RSV exposure. Thus, the number of children with CHD at increased risk of RSV hospitalisation may have been smaller, although surgical correction does not necessarily reduce the risk of RSV infection to baseline. This shortcoming, however, does not invalidate comparison of data (table 3⇑), because it was noted also in the two comparator studies.^4,6 (2) Catchment of RSV infections was incomplete because of less than optimal sensitivity (90–95%) of the RSV test system.²⁷ (3) Calculation of RSV hospitalisation rates in premature infants and children with BPD was not feasible, because reliable data on the respective birth cohorts were not available. (4) The number of RSV hospitalisations among CHD patients was so small that confidence intervals for hospitalisation rates were wide. (5) The study was conducted in a static, predominantly (70%) urban population with a very low level of poverty and unrestricted access to emergency healthcare. The results may not be applicable to populations with different characteristics.

Reliable data on RSV hospitalisation rates in CHD patients are needed more than ever before. Feltes and co-workers⁹ recently reported the results of a large, placebo controlled trial of RSV prophylaxis using palivizumab in children <24 months of age with haemodynamically significant CHD. Palivizumab was found to cause a risk reduction for RSV hospitalisation of 51% and 45%, respectively, among patients <6 months and <24 months of age. These efficacy data can be used to calculate the number of CHD patients needed to be treated with palivizumab for prevention of one RSV hospitalisation (table 4⇑). Taking into account the fact that palivizumab costs between €3500 and €5000 per patient, it is evident that this intervention would not be cost effective. Considering the low RSV hospitalisation rates and RR, unrestricted use of palivizumab thus appears to be of low priority in our CHD patient population, despite the fact that both the course of RSV hospitalisations and the case fatality rate were significantly less favourable compared with non-CHD patients, including children with BPD and prematurity (table 1⇑). The American Academy of Pediatrics recommends the use of palivizumab in children <24 months of age with haemodynamically significant CHD.¹⁵ The British Paediatric Cardiac Association, however, restricts palivizumab to patients <12 months of age.¹⁴ Our data would support this approach, because the RSV hospitalisation rate among CHD patients 12–24 months of age was lower than that of children <12 months of age without CHD.

In conclusion, RSV hospitalisation rates in patients with CHD were found to be low, and the risk of RSV hospitalisation was only twofold greater compared to non-CHD patients. Recommendations for use of palivizumab in CHD patients will need to weigh these epidemiological findings, which entail costs between €280 000 and >€1 000 000 for prevention of a single RSV hospitalisation, against the more severe course of RSV disease in these patients.