Association of early viral lower respiratory infections and subsequent development of atopy, a systematic review and meta-analysis of cohort studies.

INTRODUCTION: Existing evidence on the relationship between childhood lower respiratory tract infections (LRTI) and the subsequent atopy development is controversial. We aimed to investigate an association between viral LRTI at <5 years and the development of atopy at > 2 years.
METHODS: We conducted a search at Embase, Pubmed, Web of Science, and Global Index Medicus. We collected data from the included articles. We estimated the odds ratio and the 95% confidence intervals with a random effect model. We determined factors associated with atopy development after childhood LRTI using univariate and multivariate meta-regression analyses. We recorded this systematic review at PROSPERO with the number CRD42018116955.
RESULTS: We included 24 studies. There was no relationship between viral LRTI at <5 years and skin prick test-diagnosed-atopy (OR = 1.2, [95% CI = 0.7-2.0]), unknown diagnosed-atopy (OR = 0.7, [95% CI = 0.4-1.3]), atopic dermatitis (OR = 1.2, [95% CI = 0.9-1.6]), hyperreactivity to pollen (OR = 0.8, [95% CI = 0.3-2.7]), food (OR = 0.8, [95% CI = 0.3-2.5]), or house dust mite (OR = 1.1, [95% CI = 0.6-2.2]). Although not confirmed in all studies with a symmetric distribution of the 23 confounding factors investigated, the overall analyses showed that there was a relationship between childhood viral LRTI at < 5 years and serum test diagnosed-atopy (OR = 2.0, [95% CI = 1.0-4.1]), allergic rhinoconjunctivitis (OR = 1.7, [95% CI = 1.1-2.9]), hyperreactivity diagnosed by serum tests with food (OR = 5.3, [1.7-16.7]) or inhaled allergens (OR = 4.2, [95% CI = 2.1-8.5]), or furred animals (OR = 0.6, [95% CI = 0.5-0.9]).
CONCLUSION: These results suggest that there is no association between viral LRTI at < 5 years and the majority of categories of atopy studied during this work. These results, however, are not confirmed for the remaining categories of atopy and more particularly those diagnosed by serum tests. There is a real need to develop more accurate atopy diagnostic tools.

Introduction

Atopy is a genetic predisposition to the development of allergic diseases such as atopic dermatitis, atopic eczema, atopic asthma, atopic conjunctivitis or allergic rhinitis [1]. Atopy also includes increased hypersensitivity to inhaled or food allergens, with the development of IgE mediated by Th2 cells [2]. Atopic diseases is associated to a significant morbidity and a very important economic burden for society[3]. Atopic disease prevalence has experienced in recent decades an exponential increase in the world [4,5].

Common viruses associated with lower respiratory tract infections (LRTI) include Influenza, Rhinovirus, Respiratory Syncytial Virus (HRSV), Metapneumovirus, Parainfluenzavirus, Enterovirus, Adenovirus, Bocavirus, and Coronavirus [6,7]. Data have showed the association between HRSV LRTI and subsequent wheezing or asthma [8-11]. With the advent of molecular assays, the description of childhood infections caused by non-HRSV has further demonstrated the implication of these diseases in long-term sequelae [12,13]. A meta-analysis by Liu et al., have demonstrated the association between childhood RV infections and the subsequent development of asthma [13]. A systematic review showed that pneumonia mainly due to Adenovirus was linked to sequelae including obstructive pulmonary disease or chronic bronchitis [12]. The subgroup analyses in this latter however found that the 3 included studies with Mycoplasma pneumoniae pneumonia were not associated with long-term sequelae [12].

Studies on the prevalence of atopy among people presenting with viral LRTI in childhood have shown divergent results [14-16]. Some studies have reported an increased risk of allergic sensitization after viral LRTI in childhood [14,17]. Protection against allergic sensitization through the stimulation of Th-1 cytokine production has been suggested by other studies [16]. Maximum confusion has been demonstrated by other studies that have shown no influence of childhood viral LRTI in the development risk of subsequent atopy [15,18,19].

The resolution of the question of the association between viral LRTI in childhood and the subsequent development of atopy could serve as a basis for preventive measures and management of atopic diseases [20-22]. The purpose of this systematic review and meta-analysis of Long-term sEquelAe of lower Respiratory tract infections iN Early childhood (A LEARNED study) was to investigate the association between viral LRTI at <5 years and the atopy development at > 2 years.

Methods

Research design

This systematic review was registered in PROSPERO (Registration number: CRD42018116955). The study was conducted following the Centre for Reviews and Dissemination guidelines [23] and reported according to the PRISMA (Preferred reporting items for systematic review and meta-analysis) guidelines (S1 Table) [24].

Inclusion criteria

Study participants were children with a history of laboratory confirmed viral LRTI before 5 years. Viral LRTI was considered using the definition proposed by the authors of the included studies. Children with viral LRTI, as reference cases, were compared to control children who had no history of LRTI in childhood. Studies including only participants with medical conditions (premature birth, immunodeficiency or other comorbidities) were excluded. The exposure in this systematic review was a viral LRTI in children at <5 years. The outcome of this systematic review was the development of atopy at> 2 years including atopic diseases and sensitization to food and atmospheric allergens. Atopic status was determined by skin prick tests (SPT) and total or allergen-specific serum IgE antibody assessed by immunoassays. Included studies were prospective and retrospective cohorts with a minimum follow-up duration of one year. Atopic diseases were diagnosed clinically. We considered atopy category whose data on outcomes were available in three or more studies.

Online search strategy and study selection

The Pubmed, Excerpta Medica Database, Web of Science, and Global Index Medicus databases were queried for articles published from inception through July 15, 2019. All languages and geographic areas were considered for this systematic review. The combination of terms used for the bibliographic search is listed in Table 1. We manually screened the included studies and relevant review reference lists to locate additional articles. Two independent investigators (KS and AFM) reviewed the titles and abstracts of the articles found by the electronic and manual search [25]. We summarized the selection process of potentially relevant articles on a PRISMA flowchart. The disagreements between the two investigators were resolved by discussion and consensus.

Table 1

Search strategy in Pubmed.

Field	Key words
#1 (Atopy)	Atop* OR Allerg* OR Asthma* OR hypersensitivity OR "immunoglobulin E" OR "Ig E"
#2 (LRTI)	LRTI OR ALRTI OR "Lower Respiratory Tract Infections" OR ALRI OR "Acute Lower Respiratory Infections" OR "Acute Lower Respiratory Tract Infections" OR SARI "Severe Acute Respiratory Infections" OR "Severe Acute Respiratory Illness" OR Bronchiolitis OR Pneumonia
#3 (Virus)	Virus* OR "viral infect*" OR HRSV OR RSV OR "Human Respiratory Syncytial Virus" OR "Respiratory Syncytial Virus" OR HMPV OR MPV OR "Human Metapneumovirus" OR Metapneumovirus OR HAdV OR AdV OR Adenovirus OR "Human Adenovirus" OR HBoV OR BoV OR Bocavirus OR HCoV OR CoV OR Coronavirus OR 229E OR OC43 OR NL63 OR HKU1 OR HPIV OR Parainfluenzavirus OR PIV-1 OR PIV-2 OR PIV-3 OR PIV-4 OR HPIV-1 OR HPIV-2 OR HPIV-3 OR HPIV-4 OR Enterovirus OR Coxsackievirus OR Echovirus OR Parechovirus OR Rhinovirus OR Rhinoviruses OR Influenza
#4	#1 AND #2 AND #3

Data extraction

Two researchers (KS and AFM) independently extracted data from full text of included articles. The following data was collected (title, first author, year of publication, time of data collection, country, participants interview period, LRTI type, LRTI rank, LRTI period, age at LRTI, virus associated with the LRTI, control age, control gender, total number of cases and controls, numbers with atopy at follow up, and data on confounders). The discrepancies were resolved by discussion and a consultation of a third arbitrator (RN) if necessary.

Quality assessment of included studies

In accordance with Newcastle-Ottawa Scale (NOS) criteria including patient selection, comparability of groups, and outcome evaluation, two independent researchers (KS and AFM) assessed the quality of all included studies [26] (S2 Table). To reach consensus, all the differences were discussed between the two researchers.

Data synthesis and analysis

We estimated Odds ratio (OR) as a measure of the association between childhood viral LRTI and subsequent atopy development. We evaluated the publication bias by visual inspection of funnel diagram and Egger test. We estimated heterogeneity between studies by the Q test and the I2 statistic [27,28]. We considered heterogeneity as significant between studies for p-value <0.1 or I2> 50%. We conducted sensitivity analyses with studies with a low risk of bias, studies including only inpatients or the first episode of viral LRTI. We performed subgroup analyses on the basis of the type of LRTI, WHO region, age at LRTI, age at follow up, and type of virus detected in LRTI. We applied a multivariate metaregression with a stepwise manual selection procedure to identify factors associated with the variation of overall risk of atopy. We successively removed from the model variables by considering the signification of the p-value and information criteria for the model like log-likelihood, deviance, Akaike information criterion (AIC), Bayesian information criterion (BIC), and corrected Akaike Information Criterion (AICc). We reported the explained heterogeneity (R2) by variables included in models. A variable with P value < 0.05 was considered statistically significant in the final model. We assessed the influence of confounding factors by conducting a sensitivity study that included only equitably distributed studies for each risk factor between reference cases and controls. For each potential confounding factor, we assessed the distribution between reference cases and controls by recalculating the p values using the exact tests of Fisher and Chi-2. The two p values> 0.05 of Fisher's exact test and Chi-2 indicated a symmetric distribution of the confounding factor between reference cases and controls.

Results

Literature search and characteristics of included studies

We synthesized the study selection process in Fig 1. The electronic (4634 articles) and manual (23 articles) searches identified 4657 articles. The first selection by titles and abstracts resulted in the exclusion of 4249 irrelevant articles. We read and fully reviewed the complete texts of the remaining 330 articles. We excluded a total of 309 articles for multiple reasons including mismatch of the study population (no control group, inclusion of non-viral LRTI and non-LRTI infections, and inclusion of only patients with underlying medical conditions), the type of study not appropriate (case report, comment on study, editorial, and review), lack of data on outcomes, conference abstract or complete texts not found, and irrelevance of the articleSupplementary. We finally included 22 articles (24 studies) in the qualitative and quantitative synthesis of this systematic review [29-50]. We showed the individual characteristics of the publications included in S3 Table. Most studies were conducted in Europe, detected HRSV, had a low risk of bias, included hospitalized children under 1 year of age with their first episode of bronchiolitis, had followed children between 5–10 years old, and were prospective. Children with a history of viral LRTI in childhood were recruited between 1960 and 2014 and articles were published between 1981 and 2017.The individual NOS score from the included studies are presented in S4 Table.

Fig 1

Study selection.

Comparison of reference cases with controls

The frequency of post-LRTI atopy was similar between reference cases and controls in most categories (atopy diagnosed with SPT, OR = 1.2, 95% CI = 0.7–2.0; atopy diagnosis unknown/not reported, OR = 0.7, 95% CI = 0.4–1.3; atopic dermatitis, OR = 1.2, 95% CI = 0.9–1.6; pollens, OR = 0.8, 95% CI = 0.3–2.7; food allergy, OR = 0.8, 95% CI = 0.3–2.5; and house dust mite, OR = 1.1, 95% CI = 0.6–2.2) (Fig 2, S1 Fig). With regard to atopy assess by serum test, we observed significant differences in favor of reference cases including positive serum test (OR = 2.0, 95% CI = 1.0–4.1), food positive serum test (OR = 5.3, 95% CI = 1.7–16.7), and inhalant positive serum test (OR = 4.2, 95 CI % = 2.1–8.5). In 8 studies, allergic rhinoconjunctivitis was significantly more frequently reported in reference cases than in controls (OR = 1.7, 95% CI = 1.0–2.9). Positivity for furred animals was significantly more frequent in controls compared to reference cases (OR = 0.6, 95% CI = 0.5–0.9). The overall effect remained unchanged for the majority of our results when assessed by sensitivity analyses of the impact of LRTI rank, hospitalization, and study quality (Table 2). The effect observed in the main analysis of the positive serum test was lost for studies reporting the first episodes of LRTI (OR = 2.0, 95% CI = 0.6–6.7) and hospitalized children (OR = 2.5, 95% CI = 0.9–6.5). In contrast to the association observed between LRTI history and development of allergic rhinoconjunctivitis (OR = 1.7, 95% CI = 1.1–2.9), no effect was observed for studies reporting the first episode of LRTI (OR = 1.4, 95% CI = 0.5–3.6). The significant preponderance of furred animal positivity in controls compared to reference cases was lost in studies including only the first LRTI episodes (OR = 0.5, 95% CI = 0.3–1.0).

Fig 2

Comparison of atopy in people with and without LRTI in infancy.

Table 2

Atopy development in children with and without lower respiratory tract infections in infancy.

	OR (95%CI)	95% Prediction interval	H¶ (95%CI)	N Studies	N LRTI cases	N controls	I2§ (95%CI)	P heterogeneity	P Egger test
Atopy diagnosed by SPT
- Overall	1.2 [0.7–2.0]	[0.1–9.2]	2.3 [1.9–2.9]	16	1083	7651	81.8 [71.4–88.3]	< 0.001	0,125
- First episode of LRTI	1.0 [0.6–1.8]	[0.2–5.6]	1.6 [1–2.6]	5	283	6612	59.7 [0–85]	0,042	0,193
- Hospitalized	1.4 [0.7–2.8]	[0.1–16]	2.4 [1.8–3.1]	12	577	827	82.3 [70.3–89.4]	< 0.001	0,39
- Low risk of bias	1.2 [0.7–2.1]	[0.1–10]	2.4 [1.9–3]	15	1046	7614	82.7 [72.7–89.1]	< 0.001	0,076
Positive serum test
- Overall	2.0 [1.0–4.1]	[0.2–20.4]	2.3 [1.6–3.3]	7	636	780	81.4 [62.5–90.7]	< 0.001	0,165
- First episode of LRTI	2.0 [0.6–6.7]	NA	NA	1	70	43	NA	1	NA
- Hospitalized	2.5 [0.9–6.5]	[0.1–87.1]	2.5 [1.7–3.8]	5	247	418	84.1 [64.3–92.9]	< 0.001	0,188
- Low risk of bias	2.0 [1.0–4.1]	[0.2–20.4]	2.3 [1.6–3.3]	7	636	780	81.4 [62.5–90.7]	< 0.001	0,165
Atopy diagnosis unknown/not reported
- Overall	0.7 [0.4–1.3]	[0–41.3]	1 [1–2.6]	3	70	99	0 [0–84.9]	0,503	0,872
- First episode of LRTI	1.0 [0.2–4.6]	NA	NA	1	15	15	NA	1	NA
- Hospitalized	0.6 [0.3–1.3]	NA	1 NA	2	55	84	6.7 NA	0,301	NA
- Low risk of bias	0.5 [0.2–1.5]	NA	1 NA	2	35	35	5.3 NA	0,304	NA
Allergic rhinoconjunctivitis
- Overall	1.7 [1.1–2.9]	[0.4–7]	1.6 [1.1–2.3]	8	377	607	59.3 [11.1–81.3]	0,016	0,615
- First episode of LRTI	1.4 [0.5–3.6]	NA	1 NA	2	55	60	0 NA	0,993	NA
- Hospitalized	1.7 [1.1–2.9]	[0.4–7]	1.6 [1.1–2.3]	8	377	607	59.3 [11.1–81.3]	0,016	0,615
- Low risk of bias	1.7 [1.1–2.9]	[0.4–7]	1.6 [1.1–2.3]	8	377	607	59.3 [11.1–81.3]	0,016	0,615
Atopic dermatitis
- Overall	1.2 [0.9–1.6]	[0.8–1.8]	1.3 [1–1.7]	15	930	1191	37.9 [0–66.4]	0,068	0,154
- First episode of LRTI	1.4 [0.8–2.5]	[0–63.8]	1 [1–2.6]	3	128	133	0 [0–85.3]	0,492	0,455
- Hospitalized	1.2 [0.9–1.6]	[0.8–1.8]	1.3 [1–1.7]	15	930	1191	37.9 [0–66.4]	0,068	0,154
- Low risk of bias	1.3 [0.9–1.8]	[0.6–2.8]	1.3 [1–1.9]	13	858	1090	45.1 [0–71.3]	0,039	0,224
Pollens
- Overall	0.8 [0.3–2.7]	[0–773146.5]	2.3 [1.3–4.1]	3	134	223	81.6 [42.8–94.1]	0,004	0,214
- Hospitalized	0.8 [0.3–2.7]	[0–773146.5]	2.3 [1.3–4.1]	3	134	223	81.6 [42.8–94.1]	0,004	0,214
- Low risk of bias	0.8 [0.3–2.7]	[0–773146.5]	2.3 [1.3–4.1]	3	134	223	81.6 [42.8–94.1]	0,004	0,214
Food allergy
- Overall	0.8 [0.3–2.5]	[0–26.7]	1.3 [1–2.3]	4	195	292	43.2 [0–81]	0,152	0,297
- First episode of LRTI	0.8 [0.2–3.8]	NA	1 NA	2	55	60	0 NA	0,814	NA
- Hospitalized	0.8 [0.3–2.5]	[0–26.7]	1.3 [1–2.3]	4	195	292	43.2 [0–81]	0,152	0,297
- Low risk of bias	0.8 [0.3–2.5]	[0–26.7]	1.3 [1–2.3]	4	195	292	43.2 [0–81]	0,152	0,297
Furred animals
- Overall	0.6 [0.5–0.9]	[0.4–0.9]	1 [1–1.7]	9	382	7179	1 [0–65.1]	0,426	0,152
- First episode of LRTI	0.5 [0.3–1.0]	[0–44.7]	1 [1 – 1]	3	103	6674	0 [0–0]	0,913	0,004
- Hospitalized	0.6 [0.5–0.9]	[0.4–0.9]	1.1 [1–1.5]	8	334	565	13.3 [0 – 56]	0,326	0,1
- Low risk of bias	0.6 [0.5–0.9]	[0.4–0.9]	1 [1–1.7]	9	382	7179	1 [0–65.1]	0,426	0,152
House dust mite
- Overall	1.1 [0.6–2.2]	[0.2–6.8]	1.4 [1–2.4]	5	255	6961	52 [0–82.4]	0,08	0,552
- First episode of LRTI	0.7 [0.3–1.6]	NA	1 NA	2	122	6738	0 NA	0,385	NA
- Hospitalized	1.6 [0.8–2.9]	[0.4–6]	1.3 [1–2.2]	4	206	296	41.1 [0–80.1]	0,165	0,032
- Low risk of bias	1.1 [0.6–2.2]	[0.2–6.8]	1.4 [1–2.4]	5	255	6961	52 [0–82.4]	0,08	0,552
Positive serum test Food
- Overall	5.3 [1.7–16.7]	[0–1015892.4]	1.9 [1–3.5]	3	130	263	71.5 [3.4–91.6]	0,03	0,369
- Hospitalized	5.3 [1.7–16.7]	[0–1015892.4]	1.9 [1–3.5]	3	130	263	71.5 [3.4–91.6]	0,03	0,369
- Low risk of bias	5.3 [1.7–16.7]	[0–1015892.4]	1.9 [1–3.5]	3	130	263	71.5 [3.4–91.6]	0,03	0,369
Positive serum test Inhalants
- Overall	4.2 [2.1–8.5]	[0–402.8]	1.1 [1–3.3]	3	130	263	10.5 [0–90.7]	0,327	0,814
- Hospitalized	4.2 [2.1–8.5]	[0–402.8]	1.1 [1–3.3]	3	130	263	10.5 [0–90.7]	0,327	0,814
- Low risk of bias	4.2 [2.1–8.5]	[0–402.8]	1.1 [1–3.3]	3	130	263	10.5 [0–90.7]	0,327	0,814

SPT: Skin prick test; LRTI: Lower respiratory tract infections; N: Number; 95% CI: 95% Confidence Interval; NA: Not Applicable

¶H is a measure of the extent of heterogeneity, a value of H = 1 indicates homogeneity of effects and a value of H >1indicates a potential heterogeneity of effects.

§: I2 describes the proportion of total variation in study estimates that is due to heterogeneity, a value > 50% indicates presence of heterogeneity

Subgroup analyses and metaregression

In the subgroup analyses (S5 Table), a statistically significant association between childhood viral LRTI and subsequent atopy was observed only in the bronchiolitis subgroup for the categories of atopy diagnosed by serum test (OR = 3.1, 95% CI = 2.0–4.8; p < 0.001), and allergic rhinoconjunctivitis (OR = 2.3, 95% CI = 1.3–3.9; p = 0.021). Atopy diagnosed by SPT was in favor of controls in retrospective studies (OR = 0.6, 95% CI = 0.5–0.8, p = 0.014). The difference in the development of atopy by age group at the time of LRTI development was statistically significant for atopy diagnosed by serum tests (p = 0.002) and positive serum test for food (p = 0.019). Children with LRTI at <9 months were at increased risk for atopy diagnosed by serum tests (OR = 20.5, 95% CI = 4.4–95.9) and positive serum test for food (OR = 41.5, 95% CI = 5.2–330.0). The development of atopy according to the age of the patients varied significantly for atopy diagnosed by SPT (p = 0.004), atopy diagnosed by serum test (p = 0.004), positivity for house dust mite allergen (p = 0.046), and for positive serum test for food (p = 0.030). Atopy positivity by SPT varied transiently with an association between 2 and 5 years (OR = 3.3, 95% CI = 1.9–5.6) and then between 15 and 20 years (OR = 1.6, 95% CI = 1.1–2.4). Positivity to atopy by serum tests was not significantly associated only for patients 5 to 10 years (OR = 1.0, 95% CI = 0.5–2.1). Positivity to house dust mite allergen was only associated with patients aged 15 to 20 years (OR = 2.8, 95% CI = 1.0–7.6). The positivity to food allergens by serum test was inversely proportional to the age of the patients and the association was lost between 5 and 10 years (OR = 2.0, 95% CI = 0.7–5.3). There was no statistically significant difference by WHO region and viruses screened subgroups. In metaregression analyses, only the type of LRTI was admitted in the best multivariate model for the type of LRTI in the atopy diagnosed by SPT, atopy diagnosed by serum test, and allergic rhinoconjunctivitis (S6 Table). Follow-up delay of participants was positively associated with house dust mite and negatively associated with atopy diagnosed by serum test for food.

Confounding factors

A total of 84.8% (89/105) of the 23 confounding factors collected in the included studies had a symmetric distribution between reference cases and control participants (S7 Table). We conducted a sensitivity analysis that included only studies with symmetric distribution for these confounding factors for atopy categories with a significantly different distribution between reference cases and controls (atopy diagnosed by serum tests, positivity to food and inhalant allergens by serum tests, allergic rhinoconjunctivitis, and furred animals). The significant difference observed in the overall analysis was lost in the majority of these categories of atopy (S8 Table).

Heterogeneity and publication bias analysis

There was no heterogeneity in overall and sensitivity analyses for atopy with unknown or not reported diagnosis method, atopic dermatitis, food allergy, furred animals, and positive serum tests for inhalants (Table 2). The analyses of atopy diagnosed by SPT showed a publication bias (P Egger = 0.085). The funnel diagrams of the main analysis are presented in the S2–S12 Figs.

Discussion

Our results highlight that there is no relationship between a history of LRTI at < 5 years and atopy diagnosed by SPT, atopy diagnosed unknown/not reported, atopic dermatitis, and hyperresponsiveness to common allergens including pollen, food allergens or house dust mites. Our results on atopy diagnosed by serum tests, allergic rhinoconjunctivitis, and positivity by serum tests to food or inhaled allergens cannot be definite with an increased risk observed in the global analysis and not confirmed by the analyses in studies reporting confounding factors. The increased risks of developing atopy observed in some subgroup analyses were more frequent in case of bronchiolitis due to HRSV between 9–12 months and in prospective studies conducted in Europe.

Our results are consistent with the quantitative analysis by Knyber et al. who concluded that there was no relationship between hospitalization for HRSV bronchiolitis at < 1 year and subsequent allergic sensitization [10]. Similar to the findings of this review, Kneyber et al. also concluded that HRSV infection in childhood was associated with allergic sensitization to food or inhaled allergens tested with serum tests. However, we have no definitive conclusion on this point since our analyses, taking into account studies with confounders, such as family history of atopy [51], did not confirm this finding. Similar to the findings of the present work, several studies have also shown divergent results between serum and skin tests [52-55]. There are many hypothetical reasons that may explain these observed differences between serum and skin test results. First, differences in the composition and/or concentration of skin and serum tests targets may lead to differences in the results of both tests [52]. In a context of immune immaturity, for example, insufficient migration of mast cells to the epidermis could lead to positive results for serum tests and false negative for skin tests. Serum tests also involve false positive results due to nonspecific binding with the antibodies used [56]. Technical differences in the handling of skin and serum tests may also be involved in the differences observed between the two methods [57]. The systematic review by Fauroux et al. reported for studies conducted between 1995 and 2015 in industrialized countries the controversial nature of the results on the association between infantile hospitalizations for HRSV LRTI and subsequent atopy [58]. Pérez-Yarza in a systematic review including children younger than 3 years with HRSV respiratory infection from 1985 to 2006 also suggested controversial findings about the subsequent risk of allergic sensitization development defined by positive skin or serum tests specific for common allergens [11].

Strengths and limitations

While this systematic review may help clarify the relationship between LRTI in childhood and subsequent atopy, the weaknesses of the work must be emphasized. More than three quarters of the included studies in this systematic review were from Europe. This suggests an important problem in the external validity of our results on a global scale, with the absence of America, South East Asia and Eastern Mediterranean.

This systematic review is the only one to date to address this topic with a strict atopy definition with the consideration of 11 different categories depending on the type of diagnosis used, allergic diseases and sensitization to common allergens. This systematic review includes a multitude of sensitivity analyses with studies reporting their first episode of LRTI, studies reporting children hospitalized for LRTI, and quality of studies. Other special strengths of this systematic review include the large size of the participants included, 5294 reference cases and 27091 controls, the long follow-up period of more than half a century of children from birth to about 30 years old and with several points of follow-up including all age groups. The data was carefully extracted from a structured questionnaire and we used an appropriate data analysis to consider 23 important confounding variables.

Conclusions

No relationship was found in this systematic review between viral LRTI at <5 years and the subsequent development of a SPT-diagnosed atopy, sensitization to common allergens or the development of atopic dermatitis. This conclusion was not confirmed for the association between viral LRTI at < 5 years and the subsequent development of serum test diagnosed atopy, serum test positive for food or inhaled allergens, allergic rhinoconjunctivitis, and sensitization to furred animals.

Thus, more longitudinal investigations adjusted to confounding factors are important to elucidate the implication of childhood LRTI in the development of atopy or allergy to food or inhalant assessed by serum tests, allergic rhinoconjunctivitis, and sensitization to furred animals. These findings should encourage research on the long-term burden of viral LRTI in childhood in non-European regions and non-HRSV viruses. Prospective randomized studies including intervention against the development of the LRTI would be ideal to rule out the residual confusion about the causal relationship between infantile LRTIs and the development of subsequent atopy. The imminent arrival of the vaccine against HRSV on the market or the prophylactic means such as palivizumab could be a way to carry out these interventional studies. To reduce the burden of atopy, there a real need of more accurate diagnosis tools and efforts should focus on other major risk factors including genetic predisposition, diet habits, air pollution, family size, and the use of vaccines or antibiotics.

PRISMA 2009 checklist.

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Items for risk of bias assessment.

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Individual characteristics of included studies.

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Risk of bias assessment.

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Subgroup analyses of atopy in children with LRTI in infancy and control without respiratory diseases.

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Metaregression analyses for the association of LRTI with subsequent atopy.

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Click here for additional data file.

P-value of Khi-2 and Fisher exact tests for qualitative confounding factors.

(PDF)

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Sensitivity analyses of the symmetrically distributed confounding factors.

(PDF)

Click here for additional data file.

Forest plot of the comparison of atopy in people with and without LRTI in infancy.

(PDF)

Click here for additional data file.

Funnel plot for publication for atopy diagnosed by skin prick tests.

(PDF)

Click here for additional data file.

Funnel plot for publication for atopy diagnosed by serum tests.

(PDF)

Click here for additional data file.

Funnel plot for publication for atopy diagnosis unknown/not reported.

(PDF)

Click here for additional data file.

Funnel plot for publication for allergic rhinoconjunctivitis.

(PDF)

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Funnel plot for publication for atopic dermatitis.

(PDF)

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Funnel plot for publication for pollens.

(PDF)

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Funnel plot for publication for food allergy.

(PDF)

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Funnel plot for publication for furred animals.

(PDF)

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Funnel plot for publication for house dust mite.

(PDF)

Click here for additional data file.

Funnel plot for publication for positive serum test for food.

(PDF)

Click here for additional data file.

Funnel plot for publication for positive serum test for inhalants.

(PDF)

Click here for additional data file.

9 Dec 2019

PONE-D-19-27663

Association of early viral lower respiratory infections and subsequent development of atopy, a systematic review and meta-analysis of cohort studies

PLOS ONE

Dear PhD Njouom,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

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PLOS ONE

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Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: No

Reviewer #2: Yes

Reviewer #3: Yes

**********

2. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: No

Reviewer #2: Yes

Reviewer #3: Yes

**********

3. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

**********

4. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: No

Reviewer #2: Yes

Reviewer #3: Yes

**********

5. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: The authors choose an interesting but very challenging topic, unfortunately their strategy has some serious flaws which make this paper requires intensive amendment.

1. Abstract: Conclusion “These results suggest that there is no association between viral LRTI at <5 years and the subsequent atopy”. but the results suggest there is an association?

2. It is not clear why the authors chose this research question. The authors may consider adding more background information about the potential linkage of viral LRTI in early childhood and atopy. To me, this association could be due to immature immune of children, so they are more likely to have both viral infections and allergies, which may not indicate the infections increase the chance of allergy. Also, why did they only include viral LRTI? We know bacterial LRTI are very common in children too. The age cut-off for LRTI is 5yrs, but why is atopy set to >2yrs? The more intuitive definition could be incidence of atopy after the first episode of LRTI.

3. Their search strategy should be moved into main text since it is critical for a systematic review. The authors declare “Limit #3 to humans”, how did they achieve it? by screening title and abstract? or include keywords related to human? The keyword combinations should be standardised, eg. “Atopy OR allergy OR hypersensitivity OR allerg* OR atop* OR asthma OR asthma* OR “immunoglobulin E” OR “Ig E”, why quotation marks are added to some of keywords? also atop* includes atopy, and IgE is a standard term instead of Ig E. The title is viral LRTI but there is no keywords specifically for viral infections. Influenza is one of most common causes of viral infections but apparently excluded by the authors for no reasons. Hence I really doubt this strategy could have missed a lot of related papers. It is surprising to see no keywords related to children <2 yrs or >5yrs and cohort study design.

4. They authors did not define viral LRTI clearly, and total rely on the terms adopted by individual studies. Was it based on symptoms, clinical records, or has to be confirmed by lab results? If the last one, it should be noted that few studies have tested every participant for viral infections, so these cases could be seriously under-reported.

5. Table 1. It is more conventional to summarise study by study. Also I am surprising to see none of the selected studies were from the US and none tested for flu (because influenza was not included in search keywords?)

6. L72. No need to add “human” to every virus, since the studies were conducted in children.

7. L96. “Children with 97 viral LRTI, reference cases, were compared to control children who had no history of LRTI in childhood”. add “as” before reference cases to avoid confusion.

8. Supplemental Table 3. This table does not provide useful information. NOS score of each selected study should be added to the summary table.

9. Supplemental table 4 is not necessary.

10. L145, 146. what are Khi-2 and Chi-2? Both are Chi-square tests?

Reviewer #2: This paper investigates the association between viral LRT1 in childhood and subsequent development of atopy through systematic review.

Comments:

There should be a discussion about the possible reason for the different results obtained by SPT and serum test.

Page 4, line 77-78, why opposite meaning to the previous one “conversely”?

Page 7, line 145 “Khi-2” – Chi-sq?

Reviewer #3: The present is an interesting meta-analysis aiming to evaluate relationship between LRTI and atopy in 5 years

The paper is well written and was recorded on PROSPERO.

Abstract,

It should be added if relationship was evalauted with multivariate model or not

Methods.

Random effect was correctly choosen. It should be added if data derived came from multivariate analysis or not.

Meta regression for age and lenght of follow up should be added

**********

6. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

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Reviewer #1: No

Reviewer #2: No

Reviewer #3: Yes: Fabrizio D'Ascenzo

[NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files to be viewed.]

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18 Jan 2020

Reviewer #1: The authors choose an interesting but very challenging topic, unfortunately their strategy has some serious flaws which make this paper requires intensive amendment.

1. Abstract: Conclusion “These results suggest that there is no association between viral LRTI at <5 years and the subsequent atopy”. but the results suggest there is an association?

Authors: We thank the reviewer for this relevant comment. The conclusion has been modified and can now be read in the revised version as: "These results suggest that there is no association between LRTI at <5 years and the majority of categories of atopy studied in this work. This result, however, is not confirmed for the remaining categories of atopy and more particularly those diagnosed by serum tests. There is a real need to develop more accurate atopy diagnostic tools."

2. It is not clear why the authors chose this research question. The authors may consider adding more background information about the potential linkage of viral LRTI in early childhood and atopy. To me, this association could be due to immature immune of children, so they are more likely to have both viral infections and allergies, which may not indicate the infections increase the chance of allergy.

Authors: We thank the reviewer for these thoughtful comments. A paragraph that clarifies the association between viral infections in childhood, primarily HRSV and RV, and the development of wheezing/asthma later was added in background. Data on the association between these viral LRTIs in childhood and the development of atopy later on contrary have remained conflictual to date. This is why we started the present work to determine the link between viral LRTI in childhood and the development of atopy later.

Also, why did they only include viral LRTI? We know bacterial LRTI are very common in children too.

Authors: Dear reviewer, thank you for this important comment. A first systematic review and meta-analysis has already been conducted on the long-term sequelae of pneumonia, including bacteria pneumonia (3 studies with Mycoplasma pneumoniae, 1 with Staphlococcus aureus, and 1 with Chlamydia pneumoniae) (Edmond et al., 2012, 10.1371 / journal.pone.0031239). The subgroup analyses in this meta-analysis had shown that the 3 included studies with Mycoplasma pneumoniae pneumonia were not associated with long-term sequelae.

The authors agree with the reviewer that bacteria are also responsible for childhood LRTI and could therefore be associated with the development of atopy later. However, this was not the aim of the present study. We aimed at investigating the association between childhood LRTIs with laboratory confirmed viral infection and the subsequent atopy development. This objective still does not exclude the possibility of viral and bacterial co-infections in the studies that have been included. However, the majority of the authors of the included studies did not report the coinfections, so it is difficult for us to be able to discuss the contribution of bacteria in the effect reported in the present study.

The age cut-off for LRTI is 5yrs, but why is atopy set to >2yrs? The more intuitive definition could be incidence of atopy after the first episode of LRTI.

Authors: We thank the reviewer for this comment. We chose LRTI at <5 years since this is the most at risk age group for LRTI infections. Also, atopy at> 2 years is not link to any issue, since we only consider studies with the episode of atopy occurring after that of LRTI. We also have only 6 out of the 24 included studies that confirmed that participants were presenting the first episode of LRTI. We conducted sensitivity analyses with studies with participants having the first episode of LRTI and no difference in effect was observed compared to the overall results. These are all reasons why we keep our inclusion criteria without change.

3. Their search strategy should be moved into main text since it is critical for a systematic review.

Authors: The search strategy is now presented in Table 1 of the main manuscript as suggested by the reviewer. Thanks for the comment.

The authors declare “Limit #3 to humans”, how did they achieve it? by screening title and abstract? or include keywords related to human?

Authors: Thanks to the reviewer for these comments. Unfortunately, we inadvertently submitted the article with an old version of the search strategy that we developed. We have included the final search strategy that does not contain this filter in the current version of the manuscript. This is actually a filter that is available by default in the Pubmed database that we used during the testing phase of our search strategies.

The keyword combinations should be standardised, eg. “Atopy OR allergy OR hypersensitivity OR allerg* OR atop* OR asthma OR asthma* OR “immunoglobulin E” OR “Ig E”, why quotation marks are added to some of keywords? also atop* includes atopy, and IgE is a standard term instead of Ig E.

Author: The final search strategy has been standardized as recommended by the reviewer, thanks for the comment.

The title is viral LRTI but there is no keywords specifically for viral infections. Influenza is one of most common causes of viral infections but apparently excluded by the authors for no reasons. Hence I really doubt this strategy could have missed a lot of related papers. It is surprising to see no keywords related to children <2 yrs or >5yrs and cohort study design.

Authors: The final research strategy that included the specific keywords of the study's major areas of interest is now clarified in the manuscript (LRTI, virus and atopy). We opted for a very sensitive search strategy to increase our chances of not missing relevant articles. The included studies were longitudinal and some followed patients even until the age of 30. We therefore considered appropriate to not restrict the age of the participants according to our inclusion criteria (<2 years or <5 years). Similarly, the study design specific keywords are not always reported by some authors reason why we did not associate restriction according to this criterion in our search strategy.

4. They authors did not define viral LRTI clearly, and total rely on the terms adopted by individual studies. Was it based on symptoms, clinical records, or has to be confirmed by lab results? If the last one, it should be noted that few studies have tested every participant for viral infections, so these cases could be seriously under-reported.

Authors: We thank reviewer for the comment. The 24 included studies in the present systematic review confirmed laboratory viral infection in all participants. This was the main eligibility criterion. We have now added individual LRTI case definitions for each study included in the supplementary table 4 of individual data of included studies. Case definitions were based on clinical symptoms recorded in hospitals prospectively or in secure databases or radiographic exams.

5. Table 1. It is more conventional to summarise study by study.

Authors: We thank reviewer for the comment. We have now removed Table 1. The supplementary table 4 of individual data of included studies is now to be considered for the description of included studies.

Also I am surprising to see none of the selected studies were from the US and none tested for flu (because influenza was not included in search keywords?)

Authors: Only two included studies had performed the detection of common respiratory viruses including Influenza virus (Nicolai, 2017 et al., doi: 10.1097/INF.0000000000001385 and Ruotsalainen et al., 2013, doi: 10.1002/ppul.22692). Indeed, to date most studies on the long-term sequelae of LRTI in childhood have focused mainly on the involvement of HRSV bronchiolitis in the development of subsequent wheezing or asthma. Authors agree with the reviewer that many of the eligible studies examined were conducted in the US but none of these studies met the inclusion criteria of the present article.

6. L72. No need to add “human” to every virus, since the studies were conducted in children.

Authors: We thank reviewer for this comment, the text is now modified accordingly.

7. L96. “Children with 97 viral LRTI, reference cases, were compared to control children who had no history of LRTI in childhood”. add “as” before reference cases to avoid confusion.

Authors: We thank reviewer for this comment, the text is now modified accordingly.

8. Supplemental Table 3. This table does not provide useful information. NOS score of each selected study should be added to the summary table.

Authors: A supplementary table 3 that specifying the NOS scale ratings has been added to the appendix.

9. Supplemental table 4 is not necessary.

Authors: Thank you for the comment, the supplementary table 4 has been removed.

10. L145, 146. what are Khi-2 and Chi-2? Both are Chi-square tests?

Authors: Yes both are Chi-square tests, the manuscript is now corrected accordingly.

Reviewer #2: This paper investigates the association between viral LRT1 in childhood and subsequent development of atopy through systematic review.

Comments:

There should be a discussion about the possible reason for the different results obtained by SPT and serum test.

Authors: We really appreciate the suggestion. The following paragraph has been added in discussion section. "Similar to the findings of the present work, several studies have also shown divergent results between serum and skin tests [1-4]. There are many hypothetical reasons that may explain these observed differences between serum and skin test results. First, differences in the composition and/or concentration of skin and serum tests targets may lead to differences in the results of both tests [1]. In a context of immune immaturity, for example, insufficient migration of mast cells to the epidermis could lead to positive results for serum tests and false negative for skin tests. Serum tests also involve false positive results due to nonspecific binding with the antibodies used [5]. Technical differences in the handling of skin and serum tests may also be involved in the differences observed between the two methods [6]."

Page 4, line 77-78, why opposite meaning to the previous one “conversely”?

Authors: "conversely" has been removed, thank for the comment.

Page 7, line 145 “Khi-2” – Chi-sq?

Authors: Both are Chi-square tests; the manuscript is now corrected accordingly.

Reviewer #3: The present is an interesting meta-analysis aiming to evaluate relationship between LRTI and atopy in 5 years

The paper is well written and was recorded on PROSPERO.

Abstract,

It should be added if relationship was evalauted with multivariate model or not

Authors: Thank you to the reviewer for this suggestion. We have now specified in the abstract that we have performed multivariate metaregresssion.

Methods.

Random effect was correctly choosen. It should be added if data derived came from multivariate analysis or not.

Authors: We performed multivariate analyzes only in metaregression. However, we have not obtained any multivariate metaregression model including two or more factors associated with the development of atopy following LRTI.

Meta regression for age and lenght of follow up should be added

Authors: Thanks to the reviewers for this suggestion, we have now done a metaregression to find the factors linked to the development of atopy following childhood LRTI. We have added the corresponding methodology and the results obtained (Supplementary Table 6). We only considered the length of follow-up of the children in the model since it represents the difference between the age at the end and at the start of follow-up.

Submitted filename: Response to Reviewers PONE-D-19-27663.docx

Click here for additional data file.

9 Mar 2020

PONE-D-19-27663R1

Association of early viral lower respiratory infections and subsequent development of atopy, a systematic review and meta-analysis of cohort studies

PLOS ONE

Dear PhD Njouom,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

Please address the concern raised by Reviewer 3.

We would appreciate receiving your revised manuscript by Apr 23 2020 11:59PM. When you are ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

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To enhance the reproducibility of your results, we recommend that if applicable you deposit your laboratory protocols in protocols.io, where a protocol can be assigned its own identifier (DOI) such that it can be cited independently in the future. For instructions see: http://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols

Please include the following items when submitting your revised manuscript:

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Kind regards,

Renee W.Y. Chan, Ph.D.

Academic Editor

PLOS ONE

[Note: HTML markup is below. Please do not edit.]

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #1: All comments have been addressed

Reviewer #2: All comments have been addressed

Reviewer #3: (No Response)

**********

2. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

**********

3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: No

**********

4. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

**********

6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: (No Response)

Reviewer #2: The manuscript is much improved after the revision. The authors have addressed all my questions. I have no further comments.

Reviewer #3: The most relevant problem there is the level of evidence. That is the measure of association do not derive from multivariate analysis of original studies but from multivariate metaregression which is totally different. This should be' clearly stated.

**********

7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

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Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #1: No

Reviewer #2: No

Reviewer #3: Yes: Fabrizio D'Ascenzo

[NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files to be viewed.]

While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email us at figures@plos.org. Please note that Supporting Information files do not need this step.

9 Mar 2020

Reviewer #1: (No Response)

We thank the reviewers for their relevant comments.

Reviewer #2: The manuscript is much improved after the revision. The authors have addressed all my questions. I have no further comments.

We thank the reviewers for their relevant comments.

Reviewer #3: The most relevant problem there is the level of evidence. That is the measure of association do not derive from multivariate analysis of original studies but from multivariate metaregression which is totally different. This should be' clearly stated.

We thank to the reviewer for this suggestion. We had previously specified in the abstract that we had conducted multivariate metaregression (Page 2, Line 30). We have now precise also in Methods section that we have performed multivariate metaregression (Page 8, Line 157).

Submitted filename: Response to Reviewers PONE-D-19-27663.docx

Click here for additional data file.

2 Apr 2020

Association of early viral lower respiratory infections and subsequent development of atopy, a systematic review and meta-analysis of cohort studies

PONE-D-19-27663R2

Dear Dr. Njouom,

We are pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it complies with all outstanding technical requirements.

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Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Reviewers' comments:

8 Apr 2020

PONE-D-19-27663R2

Association of early viral lower respiratory infections and subsequent development of atopy, a systematic review and meta-analysis of cohort studies

Dear Dr. Njouom:

I am pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now with our production department.

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