Educational Aims
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The reader will come to:
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Understand the importance of differentiating between respiratory syncytial virus (RSV) and rhinovirus (RV)-induced bronchiolitis and the need for more phenotype-specific management for bronchiolitis.
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Review key studies assessing viral-dependent clinical and atopic features in infants with RSV and RV-induced bronchiolitis.
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Understand that despite minor differences in clinical and atopic features between RSV and RV-induced bronchiolitis, microbiological testing remains crucial for distinguishing the viral etiology of bronchiolitis.
Abstract
Background
Bronchiolitis is a leading cause of infant hospitalization, linked to respiratory syncytial virus (RSV) and rhinovirus (RV). Guidelines lack specific viral testing for bronchiolitis management. To establish effective management strategies, it is crucial to assess whether specific respiratory virus types are correlated with distinct examination features.
Methods
Through a systematic search of three databases, 21 studies were qualitatively analyzed, with 18 used for meta-analysis. Various outcomes like wheezing on auscultation, fever, atopic traits, and infection severity were evaluated.
Results
RSV-positive bronchiolitis was associated with a higher need for oxygen supplementation (OR 1.78, 95% CI 1.04–3.02) in 5 studies, while RV-positive bronchiolitis was more frequently linked to personal history of eczema (OR 0.60, 95% CI 0.41–0.88) in 6 studies. No significant differences were observed in the other outcomes examined.
Conclusions
Bronchiolitis caused by RSV or RV presents with similar clinical features. Despite the associations between RSV-positive bronchiolitis and need for oxygen supplementation, and RV-positive bronchiolitis and a history of eczema, our study shows that viral etiology of bronchiolitis cannot be determined solely based on clinical presentation.
Tailored management strategies, informed by accurate viral testing, seem crucial in clinical practice for enhancing patient outcomes in severe bronchiolitis.
Introduction
Bronchiolitis, a prevalent lower respiratory infection in children under the age of two, is a heterogeneous disease and a significant cause of infant hospitalization in the United States and Europe . However, emerging evidence is challenging the traditional notion of bronchiolitis as a single disease with a uniform pathobiology . Respiratory syncytial virus (RSV) and rhinovirus (RV), the primary viral culprits, have been identified as crucial factors in bronchiolitis severity and long-term complications like asthma .
Differentiating between RSV and RV-induced bronchiolitis is essential due to their distinct long-term prognosis, implications for management, and potential to guide targeted treatments . Unfortunately, current respiratory viral testing capabilities, particularly in RV detection, are limited, hindering accurate and timely diagnosis. Furthermore, inconsistent bronchiolitis diagnostic criteria across literature and international guidelines further complicate patient management . Additionally, increased phenotypic heterogeneity is a hurdle in applying effective treatments of bronchiolitis and asthma prevention strategies.
To address these knowledge gaps, a comprehensive systematic review is needed to elucidate the unique clinical profiles of RSV and RV-induced bronchiolitis in children under two years. By characterizing the clinical manifestations and exploring the association between respiratory virus type and clinical features, including atopic traits, this systematic review aims to enhance our clinical understanding of the disease and guide targeted management strategies.
Methods
Search strategy
Three bibliographic databases were searched (MEDLINE through PubMed, Web of Science via webofscience.com , and Cochrane Library) from inception to March 29, 2022. Search terms in each database included all subject headings, abstracts, and/or full texts associated with bronchiolitis, wheezing, and viral respiratory infection. The full PubMed search strategy is available in the Online Supplement. Reference lists were checked for any additional relevant studies. All extracted citations were imported into the EndNote® reference manager (Version X9, Clarivate Analytics, 2018). After removing the duplicates, two reviewers (DA and IO) working independently screened the retrieved titles and abstracts. Subsequently, all potentially relevant publications were assessed in full text. At each stage, uncertainty about the eligibility of studies was resolved through discussion and obtaining consensus by other reviewers (WF, AA, MR, TJ), if necessary. The review followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines . It was registered in the National Institute for Health Research’s PROSPERO (CRD42020218777).
Eligibility criteria
Main eligibility criteria included publication in the English language, the age group under two years old, the clinical presentation described either as bronchiolitis, acute wheezing episode, or acute lower respiratory tract infection, assessment at the hospital setting (emergency department [ED] and/or ward) or as outpatients assessed by the study investigators, comparison of at least two groups of patients with confirmed viral etiology proof the illness with RSV and RV. Exclusion criteria included duplicate publications and multiple publications regarding the same study group, non-human studies, studies including children presenting with confirmed respiratory infection with only one viral agent (e.g., only RSV-positive cases), studies including children over two years old without a subgroup analysis for patients under the age of two years, or studies with no data on clinical features of interest, study protocols, editorials or review papers, and conference abstracts. Actions were taken to contact corresponding authors when additional clarification and further data were required.
Our primary objective was to investigate whether specific clinical features and patient history could differentiate the viral etiology of bronchiolitis. The analysis focused on several key features:
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Presence of wheezing on auscultation.
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Occurrence of fever.
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Severity of infection, as indicated by admission to the paediatric intensive care unit (PICU).
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Personal history of atopy in the child.
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Parental history of atopy or asthma.
- (f)
Additional features identified in the studies that could aid in distinguishing the viral agent during the patient’s clinical presentation. These additional features encompassed observations such as crackles on auscultation, weight at enrollment, severity scores, length of hospitalization, hypoxia, need for oxygen supplementation, ventilation support, and mortality rate.
Study extraction and quality assessment
Data were extracted from each included study for the following parameters: (a) study origin, (b) participant details, (c) number of patients with detected RSV or RV, (d) details on wheezing at baseline, patient and parental history of atopy, the severity of the bronchiolitis episode assessed per viral etiology, (g) mean and the median age at baseline, and (h) potential confounding factor (s) such as prematurity or other comorbid medical conditions.
Two independent reviewers (DA, IO) assessed the risk of bias in each of the included studies without being blinded to the authors or journal. A modified Newcastle Ottawa Quality assessment scale (NOS) for cross-sectional studies was used to evaluate the quality of included studies ( Appendix S2, Online Supplement ). Encountered discrepancies were resolved through discussion with all the reviewers. We considered a study awarded nine or more points as a high-quality study in the current review.
Data analysis and synthesis
Data collection and curation were performed using a Microsoft Excel program. Review Manager (RevMan) v5.3 software from the Cochrane Collaboration (London, UK) was used to perform meta-analyses, generate forest and funnel plots, and calculate the I 2 statistic. Dichotomous variables were expressed using pooled statistics of odds ratio (OR) and their 95% confidence interval (CI), with a random-effects model using a Mantel-Haenszel method depending on heterogeneity. Heterogeneity was assessed using the I 2 statistic defined by the Cochrane Handbook for Systematic Reviews . I 2 value >50% indicated substantial heterogeneity. Several sensitivity analyses were conducted to test the robustness of the main findings and assess the potential sources of heterogeneity. First, a fixed-effect meta-analysis was conducted to evaluate the consistency of the main results from a random-effect model. Second, to investigate the impact of study quality, we performed sensitivity analyses by prospective and retrospective character of the study. At last, the individual study estimates one at a time were excluded to examine the impact of each study on the overall OR.
Results
Description of the studies and their risk of bias
Following the systematic search, we obtained 1441 publications. The PRISMA flow chart is shown in Fig. 1 . We excluded 1307 (91%) studies after screening the titles and abstracts for duplications and for not meeting our inclusion criteria. After we reviewed the full texts of the remaining 134 (9%) studies, 89 (66%) studies were excluded because they had inappropriate study design, including the not eligible age group, lower respiratory tract infection not limited to bronchiolitis, no data on any of our clinical outcome, information only on either RSV or RV-induced infection, or mechanistic study design, 11 (8%) were excluded because they were reporting the results from the same study group as the included studies, and 13 (10%) were excluded because their full-texts were either not available or in a language other than English. Thus, we included 21 (16% of the assessed full-texts) studies in our qualitative evaluation, and 18 (13%) studies in our quantitative evaluation .
Among the study designs of the eligible studies, 17 (81%) were prospective , 3 (14%) retrospective observational , and one randomized controlled trial (5%) . All the included studies were published between 2002 and 2021 ( Table 1 ). Of these studies, four were done in the USA ; five in South America (including Brazil and Chile ); 11 in Europe (including Finland , France , Greece , Italy , Spain , Turkey ); and one in Asia (Qatar ).
| Study ID and country | Study Design | Population | Sample size with viral agent detected | Quality assessment scale * | |
|---|---|---|---|---|---|
| 1 | Papadopoulos et al. 2002, Greece | Prospective Observational | Inpatients with 1st or 2nd episode of bronchiolitis (<18 mo) | RV = 12 RSV = 50 | FAIR |
| 2 | Korppi et al. 2004, Finland | Prospective Observational | Inpatients with bronchiolitis (<24 mo) | RV = 26 RSV = 24 | GOOD |
| 3 | Pitrez et al. 2005, Brazil | Prospective Observational | Inpatients with the 1st episode of bronchiolitis (<6 mo) | RV = 6 RSV = 33 | FAIR |
| 4 | Jartti et al. 2006, Finland, the Vinku study | Randomized Controlled Trial | Children with the 1st episode of bronchiolitis (data received from author on the exclusively children < 24 mo) | RV = 30 RSV = 31 | GOOD |
| 5 | Marguet et al. 2009, France | Prospective Observational | Inpatients with the 1st episode of bronchiolitis (<12 mo) | RV = 15 RSV = 96 | GOOD |
| 6 | Midulla et al. 2010, Italy | Prospective Observational | Inpatients with bronchiolitis (<12 mo) | RV = 16 RSV = 60 | FAIR |
| 7 | Nascimento et al. 2010, Brazil | Prospective Observational | Patients with the 1st episode of bronchiolitis assessed in ED (<24 mo) | RV = 13 RSV = 36 | FAIR |
| 8 | Carroll et al. 2012, USA, the TRCI cohort | Prospective Observational | Patients with bronchiolitis (<12 mo) | RV = 41 RSV = 268 | FAIR |
| 9 | Luchsinger et al. 2014, Chile | Prospective Observational | Children with clinical signs of respiratory distress with crackles or wheezing, or hyperinflation in a chest radiograph assessed in hospital setting and outpatient clinic (<6 mo) | RV = 22 RSV = 74 RSV + RV = 28 | GOOD |
| 10 | Selvaggi et al. 2014, Italy | Retrospective Observational | Inpatients with bronchiolitis (<12 mo) | RV = 40 RSV = 78 | FAIR |
| 11 | Turunen et al. 2014, Finland, the Vinku-2 study | Prospective Observational | Children with the 1st wheezing episode assessed in hospital setting (<24 mo) | RV-positive RSV-negative = 71 RSV-positive RV-negative = 18 | FAIR |
| 12 | Jartti et al. 2014, the MARC-30, Finland | Prospective Observational | Inpatients with bronchiolitis (≤24 mo) | RV = 113 RSV = 172 | GOOD |
| 13 | Diaz et al. 2015, Chile | Prospective Observational | Children with bronchiolitis assessed in hospital/clinic setting (<24 mo) | RV = 27 RSV = 60 RSV + RV = 28 | GOOD |
| 14 | Mansbach et al. 2016, the MARC-30, USA | Prospective Observational | Inpatients with bronchiolitis (<24 mo) | RV = 277 RSV = 1302 | GOOD |
| 15 | García-García et al. 2017, Spain | Prospective Observational | Inpatients with bronchiolitis (<24 mo) | RV = 18 RSV = 116 | FAIR |
| 16 | Janahi et al. 2017, Qatar | Retrospective Observational | Inpatients with bronchiolitis (≤24 mo) | RV = 58 RSV = 160 | FAIR |
| 17 | Pierangeli et al. 2018, Italy | Prospective Observational | Inpatients with the 1st episode of bronchiolitis (<6 mo) | RV = 18 RSV = 53 | FAIR |
| 18 | Hasegawa et al. 2019, the MARC-35, USA | Prospective Observational | Inpatients with bronchiolitis (<12 mo) | Data received from authors: RV-positive RSV-negative = 92 RSV-positive RV-negative = 699 | GOOD |
| 19 | Arroyo et al. 2020, USA | Prospective Observational | Inpatients with the 1st episode of bronchiolitis (≤24 mo) | RV = 19 RSV = 11 | FAIR |
| 20 | Üzüm et al. 2020, Turkey | Retrospective Observational | Inpatients with moderate/severe bronchiolitis (<24 mo) | RV = 59 RSV = 23 | FAIR |
| 21 | De Paulis et al. 2021, Brazil | Prospective Observational | Children assessed in the hospital setting with 1st episode of bronchiolitis (<6 mo) | RV = 9 RSV = 49 | GOOD |
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