Association between early viral LRTI and subsequent wheezing development, a meta-analysis and sensitivity analyses for studies comparable for confounding factors

Introduction Consideration of confounding factors about the association between Lower Respiratory Tract Infections (LRTI) in childhood and the development of subsequent wheezing has been incompletely described. We determined the association between viral LRTI at ≤ 5 years of age and the development of wheezing in adolescence or adulthood by a meta-analysis and a sensitivity analysis including comparable studies for major confounding factors. Methods We performed searches through Pubmed and Global Index Medicus databases. We selected cohort studies comparing the frequency of subsequent wheezing in children with and without LRTI in childhood regardless of the associated virus. We extracted the publication data, clinical and socio-demographic characteristics of the children, and confounding factors. We analyzed data using random effect model. Results The meta-analysis included 18 publications (22 studies) that met the inclusion criteria. These studies showed that viral LRTI in children ≤ 3 years was associated with an increased risk of subsequent development of wheezing (OR = 3.1, 95% CI = 2.4–3.9). The risk of developing subsequent wheezing was conserved when considering studies with comparable groups for socio-demographic and clinical confounders. Conclusions When considering studies with comparable groups for most confounding factors, our results provided strong evidence for the association between neonatal viral LRTI and the subsequent wheezing development. Further studies, particularly from lower-middle income countries, are needed to investigate the role of non-bronchiolitis and non-HRSV LRTI in the association between viral LRTI in childhood and the wheezing development later. In addition, more studies are needed to investigate the causal effect between childhood viral LRTI and the wheezing development later. Trial registration Review registration: PROSPERO, CRD42018116955; https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42018116955.


Rationale
3 Describe the rationale for the review in the context of what is already known. 4-5 Objectives 4 Provide an explicit statement of questions being addressed with reference to participants, interventions, comparisons, outcomes, and study design (PICOS).

Protocol and registration 5
Indicate if a review protocol exists, if and where it can be accessed (e.g., Web address), and, if available, provide registration information including registration number.

5
Eligibility criteria 6 Specify study characteristics (e.g., PICOS, length of follow-up) and report characteristics (e.g., years considered, language, publication status) used as criteria for eligibility, giving rationale.

5-6
Information sources 7 Describe all information sources (e.g., databases with dates of coverage, contact with study authors to identify additional studies) in the search and date last searched.

6
Search 8 Present full electronic search strategy for at least one database, including any limits used, such that it could be repeated.

6
Study selection 9 State the process for selecting studies (i.e., screening, eligibility, included in systematic review, and, if applicable, included in the meta-analysis).
7 Data collection process 10 Describe method of data extraction from reports (e.g., piloted forms, independently, in duplicate) and any processes for obtaining and confirming data from investigators.

7
Data items 11 List and define all variables for which data were sought (e.g., PICOS, funding sources) and any assumptions and simplifications made. 6

Risk of bias in individual studies
12 Describe methods used for assessing risk of bias of individual studies (including specification of whether this was done at the study or outcome level), and how this information is to be used in any data synthesis. Risk of bias across studies 15 Specify any assessment of risk of bias that may affect the cumulative evidence (e.g., publication bias, selective reporting within studies).

Study selection
17 Give numbers of studies screened, assessed for eligibility, and included in the review, with reasons for exclusions at each stage, ideally with a flow diagram.

8
Study characteristics 18 For each study, present characteristics for which data were extracted (e.g., study size, PICOS, follow-up period) and provide the citations.

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Risk of bias within studies 19 Present data on risk of bias of each study and, if available, any outcome level assessment (see item 12). 9 Results of individual studies 20 For all outcomes considered (benefits or harms), present, for each study: (a) simple summary data for each intervention group (b) effect estimates and confidence intervals, ideally with a forest plot.

DISCUSSION
Summary of evidence 24 Summarize the main findings including the strength of evidence for each main outcome; consider their relevance to key groups (e.g., healthcare providers, users, and policy makers).
Limitations 25 Discuss limitations at study and outcome level (e.g., risk of bias), and at review-level (e.g., incomplete retrieval of identified research, reporting bias).

16
Conclusions 26 Provide a general interpretation of the results in the context of other evidence, and implications for future research.

FUNDING
Funding 27 Describe sources of funding for the systematic review and other support (e.g., supply of data); role of funders for the systematic review.