To the Editor—We read with interest the article by Haddadin et al in this issue of Clinical Infectious Diseases [1]. As part of a prospective surveillance study, the authors enrolled a cohort of 898 children aged <5 years who presented with fever and/or respiratory symptoms to the emergency department or were hospitalized. Of those, 191 children had confirmed respiratory syncytial virus (RSV) infection, with a median age of 10 months (4.1–21); 34% had underlying medical conditions, and 79% of cases were caused by RSV A. The investigators found that in addition to younger age, a clinical disease severity score (CDSS), previously published by Garcia-Mauriño et al [2], was the more consistent parameter associated with severe disease, with an area under the curve of 0.849 (95% confidence interval, .629–.977; P < .001), while semiquantitative viral loads (cycle threshold values) were narrowly associated with severity. The study emphasizes the burden of RSV infection in older children, the value of clinical tools to assess disease severity, and the importance of combining detailed clinical and virologic data to unravel the factors that contribute to severe disease in these children.
We have extensively applied the CDSS used by Haddadin et al in our previous studies to assess disease severity in young infants with RSV infection [2–8]. The original CDSS was developed by Tal et al [9], which we modified to capture lung auscultation in a broader perspective, as wheezing is frequently absent in younger infants, and to also include the ability of the infant to feed, a parameter that is missing from previous scores but critical when evaluating infants and deciding the need for hospitalization.
Using the aforementioned score (RSV-CDSS), we recently analyzed the role of quantitative RSV loads in a large cohort of previously healthy children aged <2 years (90% <12 months) prospectively enrolled in the outpatient setting (n = 130) or hospitalized with moderate to severe disease (n = 404; Table 1). In this cohort, we found that viral loads were higher in infants with mild disease (ie, lower CDSS). Importantly, using polynomial and restricted cubic spline regression, we found that the association between age and RSV loads was roughly linear and differed according to age [6]. There was a decline in viral loads with increasing age among RSV inpatients and little association between age and viral loads in RSV outpatients.
Table 1.
Demographic, Clinical, and Virologic Parameters in Children With Respiratory Syncytial Virus Infection
| Characteristic | Mild | Moderate | Severe | P Value |
|---|---|---|---|---|
| (CDSS 0–5) | (CDSS 6–9) | (CDSS 10–15) | ||
| n = 308 | n = 164 | n = 62 | ||
| Demographics | ||||
| Age, months | 3.4 (1.60–7.79) | 3.4 (1.75–7.72) | 2.2 (1.28–5.09) | .009 |
| Age group, months | .07 | |||
| <6 | 209 (68) | 113 (69) | 53 (86) | |
| 6 to <12m | 62 (20) | 32 (19) | 7 (11) | |
| 12 to <24 | 38 (12) | 19 (12) | 2 (3) | |
| Sex, male | 170 (55.2) | 79 (48.2) | 36 (58.1) | .25 |
| Race | .86 | |||
| White | 190 (61.7) | 109 (66.5) | 40 (64.5) | |
| Black | 70 (22.7) | 31 (18.9) | 12 (19.4) | |
| Other | 48 (15.6) | 24 (14.6) | 10 (16.1) | |
| Vaginal delivery | 209/295 (70.8) | 108/159 (67.9) | 49/61 (80.3) | .19 |
| Breastfed | 163/293 (55.6) | 60/139 (43.2) | 24/57 (42.1) | .02 |
| Daycare attendance | 85/294 (28.9) | 40/139 (28.8) | 14/57 (24.6) | .79 |
| Smoke exposure | 96/295 (32.5) | 54/139 (38.8) | 20/57 (35.1) | .43 |
| Immunizations | 261/301 (86.7) | 141/162 (87.0) | 54/62 (87.1) | .99 |
| Asthma (family history) | 142/308 (46.1) | 77/164 (47.0) | 36/62 (58.1) | .22 |
| Clinical parameters | ||||
| Days of symptomsa | 4.0 (3.0–6.0) | 4.0 (3.0–5.0) | 4.5 (3.0–6.0) | .35 |
| Status | <.001 | |||
| Inpatient | 190 (61.7) | 152 (92.7) | 62 (100) | |
| Outpatient | 118 (38.3) | 12 (7.3) | 0 (0) | |
| Length of stay, days | 1.90 (1.20–2.82) | 2.60 (1.70–3.80) | 4.10 (3.30–7.32) | <.001 |
| Viral load data | ||||
| RSV type | .72 | |||
| A | 159 (52) | 91 (56) | 32 (52) | |
| B | 148 (48) | 73 (44) | 30 (48) | |
| RSV loads, log10 copies/mL | 7.73 | 7.41 | 7.18 | <.001 |
| (6.91–8.32) | (6.69–8.09) | (6.09–7.87) |
Abbreviations: CDSS, clinical disease severity score; RSV, respiratory syncytial virus.
aDuration of illness at study enrollment. Categorical data are expressed as frequencies (%) and analyzed using the Fisher or χ2 test. Continuous data are expressed as median (25%–75% interquartile range) and analyzed using the Kruskal-Wallis with Dunn test to adjust for multiple comparisons. Values in bold indicate significant 2-sided P values.
The complex relationships between age, RSV loads, and disease severity may explain the differences observed between the Haddadin cohort and the cohort analyzed in our study, as the median age of infants with severe disease in our cohort was significantly lower (2.2 months [1.3–5.1]) and children with chronic medical conditions were excluded.
Taken together, these studies emphasize the great burden of RSV in infants and young children, the value of the RSV-CDSS to assess disease severity across different ages, and the importance of age not only in terms of severity but on RSV loads. Further studies that include prospective longitudinal cohorts to further assess the value of the CDSS; the interactions between age, viral loads and severity; and whether they correlate with long-term outcomes are warranted.
Notes
Acknowledgments. We thank all members of the clinical research team at Nationwide Children’s Hospital (NCH) for their extraordinary efforts to help enroll our patients and especially our patients and their families for their participation in the study.
Financial support. This work was supported in part by the National Institutes of Health (NIH)/National Institute of Allergy and Infectious Diseases (grant AI112524), Janssen, and with intramural funds at NCH.
Disclaimer. The funding agencies had no input in data analyses and interpretation of study findings.
Potential conflicts of interest. A. M. and O. R. have received research grants from Janssen. A. M. has received fees for participation on advisory boards from Janssen, Roche, Sanofi, and Merck and grants from NIH. O. R. has received fees for participation on advisory boards from Sanofi/MedImmune, Merck, and Pfizer and fees for lectures from Pfizer and Merck; those fees were not related to the research described in this letter. O. R. has received grants to the institution from the Bill & Melinda Gates Foundation, Ohio Children’s Hospital Association, and NIH outside the submitted work. All remaining authors: No reported conflicts of interest. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.
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