Introduction

Epidemiological studies have shown that up to 50% of children have at least one episode of wheezing before their third birthday [1–3]. This wheezing is responsible for hospitalization rates in children of up to 8% [1].

Several studies have shown that hospitalization for early Human Respiratory Syncytial Virus (HRSV) bronchiolitis was a predictor of subsequent wheezing episodes [4,5]. The association between HRSV-bronchiolitis and long-term wheezing is now clearly established by multiple original studies and meta-analyses [4,5]. The current residual questions are to known whether the HRSV-LRTI are for subsequent wheezing: 1) a marker of susceptibility, 2) a causal agent, or 3) both a marker of susceptibility and a causal agent. The responses to these residual shadow points now relate to the multiple confounding factors or ideally the response to the causal effect between the HRSV-bronchiolitis and wheezing which can only be addressed by interventional studies with prophylactic means such as palivizumab or very soon with anti-HRSV vaccines approval [6]. A recent meta-analysis failed to provide acceptable evidence for the causal relationship between childhood HRSV infections and long-term respiratory morbidity [7]. This question of wheezing after bronchiolitis in childhood have also been incompletely explored in multiple aspects including the age of children at the time of bronchiolitis development, bronchiolitis due to non-HRSV viruses, non-bronchiolitis Lower Respiratory Tract Infections (LRTI), and the influence of confounding factors [8–10]. The introduction of molecular diagnostic tests has led to better definition of the role of respiratory virus in bronchiolitis [11]. It is now recognized that Human Metapneumovirus (HMPV), Human Bocavirus (HBoV) or even Rhinovirus (RV) are among common viruses involved in bronchiolitis [12–16]. It has also been shown that childhood RV infections are associated with subsequent wheezing [17,18]. Apart from HRSV and RV, there is no systematic review with respect to the association between childhood LRTI due to other common respiratory virus and later wheeze. In addition to bronchiolitis, other low respiratory infections are very common in childhood [19,20]. To date, however, there is no systematic review on the influence of non-bronchiolitis respiratory infections in infancy on long-term wheezing. There are several confounding factors that have not yet been explored concerning their effect on post bronchiolitis wheezing [21–25]. These confounding factors include atopic predisposition [26–34], reduced premorbid lung function [35], smoking exposure, breastfeeding [34,36], premature birth, low birth weight, or overcrowding [36,37]. These confounding factors may act synergistically with low respiratory infections in childhood and all these mechanisms remain to be elucidated [38].

Early recognition of children at risk of developing long-term wheezing may be important for many prevention and management policies [39,40]. The aim of this study was to evaluate, in a meta-analysis and sensitivity analyses including studies comparable for sociodemographic and clinical confounding factors, wheezing as a long-term sequela of viral LRTI in children.

Methods

Results

Study selection

The search strategy identified 1962 articles. We eliminated 1425 articles unrelated to the objectives of the study. We reviewed a total of 139 complete articles to determine their eligibility for meta-analysis. Among these items, we excluded 121 for multiple reasons (S4 Table) and included 18 in this study (Fig 1) [52–69]. The 18 citations represented 22 individual studies since 3 references included data collected at 2 different ages and one study included data for 2 different viruses [54,55,61,68].

Fig 1

Flow chart for the systematic literature search.

Meta-analysis results

Association between LRTI in infancy and wheezing later

Findings from the meta-analysis showed that the rate of wheezing was significantly higher in patients with childhood LRTI than in controls: OR = 3.0, 95% CI = 2.3–3.9 (Fig 2). All wheezing categories (any wheezing: OR = 3.2, 95% CI = 1.9–5.3, I² = 0.0%; current wheezing: OR = 3.1, 95% CI = 1.5–6.2, I² = 72.3%; recurrent wheezing: OR = 3.0, 95% CI = 2.2–4.2, I² = 44.0%; wheezing in the last 12 months: OR = 3.0, 95% CI = 1.8–5.0 were significantly more common in older LRTI patients compared to the control group.

Fig 2

Forest plot of wheezing in children with and whitout LRTI in infancy.

Sensitivity analysis

We assessed the constancy of our results through multiple sensitivity analyses including studies reporting only the first episode of LRTI, physician-diagnosed wheezing, and studies comparable between cases and controls for multiples confounding factors (S8 and S9 Tables). Table 1 presents the results of these different sensitivity analyses. The results of the sensitivity analyses were consistent with those of the overall findings for studies reporting only the first episode of LRTI and studies with studies comparable between cases and controls for almost all confounding factors. We found no publication bias in the overall analyses (p-value Egger test = 0.282). Funnel graph showed no asymmetry (S1 Fig). Significant heterogeneity was observed in overall analyses (I2: 47.4% 95% = 13.5–68; p-value heterogeneity: 0.008).

Table 1

Wheezing in children with LRTI in infancy and control without respiratory diseases.

Wheezing	OR (95%CI)	95% Prediction interval	N Studies	N LRTI cases	N controls	H (95%CI)	I2 (95%CI)	P heterogeneity	P Egger test
Overall	3 [2.4–3.9]	[1.4–6.7]	22	1239	18649	1.4 [1.1–1.8]	47.4 [13.5–68]	0.008	0.282
Sensitivity analyses
First episode of LRTI	2.8 [2.1–3.7]	[1.3–6.1]	15	958	18316	1.4 [1–1.9]	46.7 [2.8–70.8]	0.024	0.582
Physician-diagnosed wheezing	3 [1.9–5]	[0.9–10.8]	7	363	340	1.5 [1–2.3]	55.4 [0–80.9]	0.036	0.993
Studies comparable for allergic rhinitis	3.4 [1.6–7.4]	[0–7574.6]	3	131	136	1.7 [1–3.1]	64.5 [0–89.8]	0.06	0.094
Studies comparable for antiasthmatic treatment	3.1 [1.7–5.7]	NA	1	130	111	NA	NA	1	NA
Studies comparable for asthma admissions	4.5 [1.5–13.3]	NA	1	32	30	NA	NA	1	NA
Studies comparable for asthma in children	1.3 [0.7–2.5]	NA	1	74	74	NA	NA	1	NA
Studies comparable for asthma in father	6 [2.6–14.3]	NA	2	55	60	1	0	0.38	NA
Studies comparable for asthma in mother	6 [2.6–14.3]	NA	2	55	60	1	0	0.38	NA
Studies comparable for asthma in parents	3.4 [2.3–5.1]	[1.4–8.4]	4	187	371	1 [1–2.6]	5.2 [0–85.5]	0.367	0.555
Studies comparable for asthma in siblings	6 [2.6–14.3]	NA	2	55	60	1	0	0.38	NA
Studies comparable for atopic dermatitis	3.1 [2–4.8]	[1.1–8.6]	7	295	361	1.3 [1–2]	39.1 [0–74.4]	0.131	0.131
Studies comparable for atopy in children	3 [1.4–6.4]	[0.2–53.4]	4	149	154	1.7 [1–2.9]	64.8 [0–88]	0.037	0.168
Studies comparable for atopy in father	6 [2.6–14.3]	NA	2	55	60	1	0	0.38	NA
Studies comparable for atopy in mother	3.6 [2.4–5.6]	[0.2–59.1]	3	210	576	1.1 [1–3.5]	22.6 [0–91.9]	0.275	0.415
Studies comparable for atopy in parents	3.3 [2.3–4.7]	[2–5.3]	7	273	417	1 [1–1.8]	0 [0–70.1]	0.438	0.357
Studies comparable for atopy in siblings	10 [2.4–41.2]	NA	1	23	30	NA	NA	1	NA
Studies comparable for current asthma	5.8 [2.2–15.2]	NA	1	35	64	NA	NA	1	NA
Studies comparable for current atopy	5.9 [3.1–11.3]	[0.1–382.6]	3	90	124	1 [1–1.9]	0 [0–73.2]	0.679	0.794
Studies comparable for current eczema	5.8 [2.2–15.2]	NA	1	35	64	NA	NA	1	NA
Studies comparable for family history of atopy	2 [0.6–7.1]	NA	1	17	25	NA	NA	1	NA
Studies comparable for heredity for asthma	3.3 [2–5.2]	[0.2–66.1]	3	141	279	1 [1–1]	0 [0–0]	0.97	0.605
Studies comparable for heredity for atopy	3.3 [2–5.2]	[0.2–66.1]	3	141	279	1 [1–1]	0 [0–0]	0.97	0.605
Studies comparable for history of asthma	2.9 [1.3–6.2]	NA	2	111	140	2 [1–4.1]	74 [0–94.1]	0.05	NA
Studies comparable for history of atopy	4.6 [2.8–7.5]	[0.2–110.8]	3	192	17039	1.3 [1–2.4]	42.2 [0–82.5]	0.177	0.652
Studies comparable for history of eczema	2.9 [1.3–6.2]	NA	2	111	140	2 [1–4.1]	74 [0–94.1]	0.05	NA
Studies comparable for history of pertussis	3.3 [1.9–5.6]	NA	2	94	186	1	0	0.812	NA
Studies comparable for male gender	3.2 [2.4–4.3]	[1.4–6.9]	15	768	1279	1.3 [1–1.8]	45 [0–70]	0.03	0.307
Studies comparable for maternal smoking	4.7 [2.5–8.9]	[1.2–19]	4	127	101	1 [1–1.9]	0 [0–71.5]	0.657	0.466
Studies comparable for maternal smoking during pregnancy	1.8 [0.9–3.4]	NA	1	76	76	NA	NA	1	NA
Studies comparable for parental smoking	5.8 [2.2–15.2]	NA	1	35	64	NA	NA	1	NA
Studies comparable for paternal smoking	3.9 [2.4–6.3]	[0.2–90.4]	3	185	171	1.1 [1–3.3]	12.3 [0–90.9]	0.32	0.247
Studies comparable for pets at home	3.1 [2.4–4.1]	[2.3–4.3]	9	520	1116	1.1 [1–1.5]	13 [0–54.9]	0.326	0.18
Studies comparable for premature birth	3.9 [1.9–8]	[0–381.1]	3	104	71	1 [1–1.2]	0 [0–26.8]	0.868	0.315
Studies comparable for siblings in the house	5.8 [2.2–15.2]	NA	1	35	64	NA	NA	1	NA
Studies comparable for smoke exposure	2.6 [1.9–3.5]	[1.3–5.1]	9	580	1189	1.2 [1–1.8]	34.4 [0–69.8]	0.142	0.246
Studies comparable for age at interview (years)	7.8 [3.5–17.3]	[0–1362.5]	3	90	95	1.3 [1–2.2]	36.6 [0–79.8]	0.207	0.671
Studies comparable for age at recrutment (months)	4.5 [2.4–8.4]	[0.1–256.7]	3	142	111	1 [1–1.7]	0 [0–64.9]	0.744	0.291
Studies comparable for birth weight (grams)	5.2 [2.2–12.2]	[0–1284.3]	3	107	76	1.4 [1–2.7]	51 [0–85.8]	0.13	0.333
Studies comparable for breastfeeding period (months)	3.3 [1.9–5.6]	NA	2	94	186	1	0	0.812	NA
Studies comparable for height at interview (cm)	3.4 [2.5–4.6]	[2.3–5]	7	424	1015	1.2 [1–1.8]	27.1 [0–68.4]	0.221	0.328
Studies comparable for number of siblings	3 [2–4.5]	[1.2–7.2]	4	188	372	1 [1–1.2]	0 [0–34.1]	0.874	0.961
Studies comparable for weight at interview (kg)	3.2 [2.3–4.3]	[2–4.9]	6	378	923	1.1 [1–2.2]	16.4 [0–78.8]	0.308	0.492

CI: Confidence interval; OR: Odds ratio; NA: Not applicable.

Discussion

This systematic review of studies with LRTI patients in nearly half a century gives four main results. Children who experienced an episode of viral LRTI at ≤ 3 years of age were 3 times more likely than controls to develop wheezing later. This increased risk of wheezing in children with a history of viral LRTI was not influenced by the rank of LRTI episode, physician-diagnosed wheezing and studies comparable for the investigated confounding factors.

These results are consistent with previous systematic reviews that had already demonstrated an increased risk of wheezing among old bronchiolitis patients [8–10]. Kneyber et al have demonstrated in a quantitative analysis that hospitalized children with bronchiolitis episodes due to HRSV at <1 year of age had an increased risk of wheezing compared to controls [70]. Fauroux et al in a systematic review without meta-analysis of data published between 1995 and 2015 in Western countries reported that children hospitalized for HRSV infections were at high risk of developing recurrent wheezing until age 25 years old [71]. Shi et al in a recent meta-analysis showed that childhood HRSV infection was significantly associated with wheezing later in former LRTI cases compared to healthy individuals or controls without respiratory infection in infancy [8].

Although represented by a single study in this review, pneumonia was not associated with a risk of subsequent wheezing. A previous meta-analysis showed that childhood pneumonia mainly linked to adenoviruses was associated with respiratory sequelae in hospitalized and non-hospitalized children, including restrictive pulmonary disease, obstructive pulmonary disease, bronchiectasis and chronic bronchitis [72]. Asthma, considered by most authors as ≥ 3 episodes of wheezing, were however not associated with pneumonia in the meta-analysis [72]. Although the type of LRTI was a significant source of heterogeneity during this work, we are unable to draw a definitive conclusion about this parameter because the pneumonia category was represented by a single study and the category LRTI not specified is very heterogeneous to allow an objective interpretation. Previous reports have shown that the strength of the association between LRTI in childhood and wheezing later diminished with age with persistence into adulthood [18,70,71,73–77]. These previous reports suggest that the factor responsible for wheezing loses its influence with age, which could be small airways. Unfortunately, in this report, we have only recorded 2 studies with patients > 10 and are therefore unable to comment on the decrease in the strength of the association between LRTI in childhood and the subsequent wheezing risk.

The development of molecular diagnostic tests has made it possible to reassess the role of respiratory viruses in bronchiolitis and the description of new viruses [11]. Systematic reviews have shown that infections with no-HRSV respiratory viruses in childhood are also associated with an increased risk of developing wheezing sequelae [18,71]. Liu et al. showed the involvement of RV infections during the first 3 years of life in the subsequent wheezing in a meta-analysis including cohorts with and without controls [18]. The results of this systematic review, also, indicate that viral LRTI generally was associated with a risk of subsequent wheezing.

Studies have contributed to show that the index children with a family history of asthma had a greater risk of developing post-bronchiolitis wheezing [5]. Kneyber et al. in a quantitative analysis showed that family history of atopy/asthma were similar between index cases and controls [70]. In this systematic review, studies with confounding factor comparable in index cases and controls showed concordant results in the incidence of subsequent wheezing (Table 1). Studies have shown that male sex is a predictive factor of wheezing as a result of bronchiolitis [78,79]. In this systematic review, in the 15 studies with gender comparable between cases and controls, there were no difference in the association between early LRTI and subsequent wheezing. Studies have shown that maternal smoking was a predictor of subsequent wheezing [80]. In this meta-analysis, 4 included studies comparable for maternal smoking exposure in index cases compared to controls did not appear to affect the global effect observed. In this meta-analysis also studies comparable for the family atopy, family asthma, preponderance of overcrowding, daycare attendance, premature birth or breastfeeding did not affect the incidence of wheezing after bronchiolitis. Several plausible alternative hypotheses may be involved in post-bronchiolitis wheezing [31,81,82]. The decrease in pulmonary function very early in life has also been reported by several authors as a predisposing factor for bronchiolitis and post-bronchiolitis wheezing [35,83–85]. Despite these multiple other factors, bronchiolitis has always been shown to be a very important predictor of subsequent wheezing.

The main limitation of this systematic review is the small number of studies in some categories of our subgroup analyses. These categories included non-bronchiolitis LRTI and non-HRSV LRTI. The results of this subgroup analyses should therefore be considered with caution. The statistical significance of the symmetric or asymmetric distribution of confounders between cases and controls is largely a function of sample size. Although we used both parametric and nonparametric tests, studies with large samples have the power to detect much smaller differences between cases and controls than small studies do. We were not able to evaluate the influence of premorbid pulmonary function, the presence of co-morbidities or co-infections on the development of subsequent wheezing, as this information was missing in the majority of studies included. Despite these weaknesses, this systematic review has several strengths that include overall results consistent with multiple sensitivity analyses (consideration of the first episode of LRTI, physician-diagnosed wheezing and studies comparable for various confounding factors). No publication bias was recorded in global analyses. We conducted a comprehensive search strategy with no restriction in geographic, temporal, LRTI type, and LRTI virus type that significantly increased the number of studies and increased the statistical power of the analyses. We have adopted a transparent protocol, pre-recorded and intervention of two investigators at every stage of the process. We conducted a thorough data collection and provided an exhaustive characteristic of individual included studies. We have assessed for the first time studies comparable for confounding factors for the determination of the association between neonatal viral LRTI and subsequent wheezing. We have transparently documented our method of defining the categories of multiple wheezing case definitions and confounding factors recorded in the included studies and the definitions considered in each category for this systematic review.

Evidence from this meta-analysis strongly suggests that viral LRTI at ≤ 3 years is one of the major predictors of wheezing. Despite the multiple studies conducted on the subject, the interaction between bronchiolitis and other predictors of subsequent wheezing is unknown. More controlled prospective studies are needed to resolve these confusions. Nearly all studies evaluating the long-term sequelae of bronchiolitis have focused primarily on hospitalized children [78,86,87]. One study demonstrated the involvement of mild infections induced by RV early life in the development of wheezing sequelae later [88]. It is important to implement other cohort studies to clarify the role of ambulatory bronchiolitis in developing long-term wheezing symptoms. It is also necessary to conduct additional longitudinal studies to further evaluate the role of non-HRSV respiratory viruses, especially RV and HMPV, in post-bronchiolitis wheezing. The above additional studies are expected especially from lower-middle income countries where data are very scarce.