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Discussion
Three important observations made in our study were that HRV/ENT acute respiratory infections were very commonly detected in our patient population; children with HRV/ENT infections had more severe outcomes compared to those with other common respiratory viruses; and children with underlying cardiorespiratory or immunocompromised/metabolic conditions were more likely to present with HRV/ENT infections.
The proportion of single HRV/ENT infections reported in our study (30·4%) was significantly higher than in studies which used conventional diagnostic methods (5%), but comparable to those in which molecular tests were used, including studies of children with ARTIs (27·2%) and infants with bronchiolitis (29%). These discrepancies can be attributed to the higher sensitivity and broader range of virus detection by molecular-based methods.
Similar to others studies, children infected by HRV/ENT alone were younger compared to those with FLU infections but older compared to those with RSV infections. In our study, children with HRV/ENT infections presented with higher rates of underlying cardiorespiratory and immunosuppressive conditions compared to those with any other single viral infection. Our findings are similar to those described in adults admitted with HRV/ENT respiratory infections, in whom high rates of underlying immunosuppressive conditions were identified, thus suggesting that these patients may be at higher risk of HRV/ENT infections. The extent to which severity of respiratory illness is attributed to HRV/ENT or to other underlying conditions is yet unclear.
Notwithstanding the high proportion of underlying comorbidities identified among our HRV/ENT population, HRV-/ENT-positive status was identified as a significant independent predictor for hospital admission and resulted in an increased clinical disease severity among inpatients compared with either RSV or FLU, while controlling for underlying comorbidities and age. Furthermore, we found significantly longer duration of hospitalization among children admitted with HRV/ENT infections compared to those admitted with FLU infections. Also, higher rates of pneumonia were observed among children with single HRV/ENT infections compared to those with RSV single viral infections as suggested by a previous study by Malcolm et al. Finally, half of the deaths observed among the four HRV-/ENT-infected children with underlying conditions may have resulted from their HRV/ENT respiratory illnesses as no other viral, bacterial, or fungal pathogens were documented. All these findings contrast with recently published studies which reported equivalent disease severity between subjects with HRV/ENT infections and those with other common viral infections. These studies, however, had major limitations, which may have resulted in not detecting a true difference. Firstly, the studies were conducted in inpatients only. One can speculate that hospitalized patients share a level of comorbidity leading to more similar outcomes regardless of the virus involved. Furthermore, most of these studies compared HRV/ENT infections to all other viruses combined and did not adjust for underlying comorbidities. While treatment of FLU-A-positive children with oseltamivir might have been expected to improve their prognosis, no children included in this study received oseltamivir, as specimens were collected before the implementation of guidelines advocating for oseltamivir treatment of high-risk children Thus, the difference in outcomes between HRV/ENT and treated FLU-A may be even more pronounced than found in our study.
An important strength of our study was the inclusion of outpatients, thus enabling the use of hospital admission as a measure of clinical severity. Furthermore, the adjustment for underlying comorbidities in multivariable analysis reinforced the association between HRV/ENT and clinical outcomes. Given our low rate of bacterial coinfections, no adjustment for this variable was made in multivariable analyses. Finally, we had adequate sample size to compare HRV/ENT to a number of different viruses. Potential limitations of our study relate to its retrospective design. However, we believe that most of our patient-related important outcomes could be well assessed though chart review. Similarly, the observational nature of our study may have led to selection bias as not all consecutive patients were tested for respiratory viruses as a result of limited resources. Random sampling ensured an unbiased selection of samples tested by molecular assays. Furthermore, the criteria for using virologic diagnostics as part of routine patient care may have varied during the study. For instance, viral culture was only routinely used from November 2007 to April 2008, which may have affected the comparisons of illness severity between different viruses. Third, we assessed the presence or absence of viruses, but did not measure their viral load; higher viral loads in acutely ill subjects compared with asymptomatic children might have further strengthened the association between HRV/ENT and severe disease as rhinoviruses are also commonly identified in community-based controls. Future research should measure viral loads and use sequencing for genotyping analysis to differentiate HRV from enterovirus and to speciate HRV. Recent studies suggest that human rhinovirus species A and C (HRV-A and HRV-C) may be associated with greater clinical severity compared with HRV-B species. Finally, our estimation of bacterial coinfection may have been underestimated as adequate respiratory samples such as BAL are rarely performed in children and pneumonia rarely result in positive blood cultures. Also, URT samples are not necessarily representative of LRT disease. This limitation inherent to studies assessing the severity of respiratory illnesses in children may be overcome in future prospective studies, conducted among children with specific underlying comorbidities (e.g., immunocompromised children), which would include validated molecular assays for detection of both viral and bacterial pathogens from URT samples in all children with ARTI.
In conclusion, our findings provide new insight into the burden and severity of HRV/ENT infections and reinforce the need for routine diagnosis in hospital settings. HRV/ENT infections were very common and associated with more severe disease than other common viruses such as FLU or RSV highlighting the need for development and testing of specific antiviral drugs.
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