Importance of respiratory syncytial virus as a predictor of hospital length of stay in bronchiolitis

Introduction

Bronchiolitis is the most frequent lower respiratory tract infection in infants^1,2. One of the variables with more incidence in the financial burden of this disease is the hospital length of stay (LOS)³. The hight medical cost associates with prolonged LOS in bronchiolitis imposes an economic burden, especially in tropical middle-income countries⁴. LOS is a direct measure of the quality of health service⁵.

Some models have identified predictors of LOS such as age, underlying conditions (congenital heart disease, chronic lung conditions, immunocompromised states), low birthweight, male gender, clinical characteristics at admission, prematurity, detection of RSV⁶. However, many of these models lack accuracy⁷ or were made in patients without significant comorbidities^8,9. In this context, there is a critical need to explore predictors of LOS, improving their accuracy of current models. This information will allow risk management for healthcare and prioritize care strategies in groups with a high probability of prolonged hospital stay to reduce their impact on hospital costs and morbidity. This study aims to identify clinical variables associated with LOS of bronchiolitis in children in Colombia.

Methods

We conducted a retrospective cohort study that included all infants with bronchiolitis younger than two years of age admitted to tertiary centers in Rionegro, Colombia, from January 2019 to December 2019. The municipality of Rionegro had a total population of 101,046 inhabitants, with two tertiary referral hospitals¹⁰. Inclusion criteria were defined as children younger than two years of age admitted to the pediatric ward diagnosed with bronchiolitis, according to the national clinical guideline of bronchiolitis (first wheezing episode younger than 24 months of age)¹¹. Patients without lower respiratory compromise, with positive bacterial cultures on admission, confirmed whooping cough (culture or PCR) were excluded. The study protocol was reviewed and approved by the Institutional Review Board of the University of Antioquia (No 18/2015). Informed consent was obtained from all parents or caregivers of the patients included in the study, following the clinical research standards in Colombia, and prior approval by the ethics committee.

Results

Discussion

The main purpose of this study was to determine the independent clinical variables associated with LOS of bronchiolitis in children in tropical middle-income countries. Our study shows that RSV, age <6 months, comorbidities (CHD or neurological), BPD, chest indrawing, and C-reactive protein were independent predictors of LOS

Our results emphasize the importance of knowing the presence of RSV. While some predictors of LOS, such as age, comorbidities, and potentially initial signs of respiratory distress, can not be modified, others as detection of RSV are potentially modifiable by interventions such as futures vaccines or palivizumab in a high-risk population^14,15. Previous studies in populations with seasonality had revealed the importance of RSV as a predictor of hospital stay. DeVicenzo et al., in a sample of 141 infants <24 months old without previous chronic cardiac or lung disease or prematurity, in Tennessee described a longer LOS with a higher amount of RSV in secretions. A 1-log higher RSV load was associated with a 0.8-day longer hospitalization, reflects the higher RSV load that occur earlier in the disease¹⁴. Rodríguez-Martínez, in 303 infants with acute bronchiolitis in Bogota, also found that detection of RSV correlated with a hospital stay of 5 or more days (OR 1.92, CI 95% 1.02 to 3.73)³. In Qatar, Janahi et al., detected RSV in 51.2% of in 369 patients admitted to the pediatric ward for bronchiolitis, but no association was found between RSV and LOS¹⁶. Additionally, Masarweh et al., in a retrospective study of 4793 infants with bronchiolitis in a single tertiary medical center in Israel between 2001–2009, found that RSV isolation did not correlate with LOS¹⁷. In this evidence, only the Mansbach study used the PCR assay for viral detection, but the results with immunofluorescence assay with respect to the predictive value of RSV were similar to the PCR assay. Indeed, the main problem of the studies mentioned above was the serious statistical mistakes of analyzing the LOS. While we used a negative binomial regression model, due to the presence of overdispersed count data, to adjust for potential confounding variables to analyze LOS, studies by Rodriguez, Devicenzo, and Mansbach dichotomize the LOS to perform logistic regression, while Masarweh's study performed a linear regression; being both approaches not completely correct. The loss of information from dichotomizing a continuous outcome is well documented in the literature, and even worse, analyzing a variable that does not have a normal distribution with a linear regression invalidates this method of analysis¹⁸. These pitfalls in statistical analysis can explain the lack of accuracy of predictive models⁶. The regression models recommended are median, gamma, or Poisson regression, which have some type I error but avoid the mistakes previously mentioned with the logistic or linear regression model.

Othe variable potentially modifiable associated with LOS was age <6 months. Our findings are consistent with previous results reported in the literature and provide further evidence that younger infants are at a greater risk of requiring prolonged LOS³. This can be explained because the smaller caliber of the airways in younger infants and poor innate immune response to RSV in newborns, making younger infants more susceptible to severe forms of viral infections and prolonged LOS^19,20. Preventive strategies such as the use of palivizumab in a high-risk population or the use of future vaccines that confer immunity in children under 6 months against RSV; will constitute possibly effective interventions in reducing the economic burden of this disease.

Several predictive models had reports consistently the chest indrawing as predictive of prolonged LOS that is which is biologically plausible and expected due that this sign also is a universal marker of severity of the disease, as well as the presence of underlying conditions (congenital heart disease, chronic lung conditions, immunocompromised states)^{3,6–8,21–23} or C-reactive protein (CRP) as a biomarker of severity and bacterial co-infection in patients hospitalized for bronchiolitis^24–26

Our study has limitations. First, since this study was based on medical records review, we cannot include other variables such as environmental pollution and genetic factors, and residual confounding cannot be excluded. Second, respiratory syncytial virus was confirmed using direct immunofluorescence, which may underestimate the real burden of viral infection. However, despite this possible underestimation, RSV infection was positively associated, and it is possible that the magnitude of the IRR is even greater. The detection of other respiratory viruses was not homogeneous in all patients, so to avoid information bias we decided not to include them in the analysis. We cannot rule out that other respiratory viruses have equal or greater association with our dependent variable in the study. Third, the study was conducted in a tertiary referral hospital, and therefore the patients included represent the high spectrum of severity, limiting the generalization of results to other contexts. However, the similarity of our population in terms of clinical characteristics, risk factors, and seasonality of bronchiolitis in our country with previous reports suggest strength and consistency in our results^3,4

Conclusion

Our results show that in infants with bronchiolitis, RSV, age <6 months, comorbidities (CHD or neurological), BPD, chest indrawing, and C-reactive protein were independent predictors of LOS in a tropical middle-income country. As a potentially modifiable risk factor, efforts to reduce the probability of RSV infection can reduce the hight medical cost associates with prolonged LOS in bronchiolitis.

Data availability

Declarations

Abbreviations

incidence rate ratios (IRR)

hospital length of stay (LOS)

respiratory syncytial virus (RSV)

Nasopharyngeal aspirate (NPA

Bronchopulmonary dysplasia (BPD)

Chronic heart disease (CHD)