Cumulative evidence for association of rhinitis and depression

Background Several primary studies evaluated the association between rhinitis and the incidence of depression and yielded inconsistent results. We conducted a meta-analysis of studies evaluating the association between rhinitis and depression. Methods We searched the EMBASE, PubMed and Cochrane Library databases for studies published in English before April 1, 2019. The studies were included if they reported any type of rhinitis in relation to depression. Two authors independently extracted the data. The odds ratios (ORs) were pooled using a random-effects model. Stratified analyses were conducted to evaluate the association. Results Among the 3472 initially identified studies, we included 14 studies involving a total of 19.36 ± 1.1 million participants according to predefined inclusion criteria. The associations between rhinitis (R), allergic rhinitis (AR), and nonallergic rhinitis (NAR) and depression were significant with ORs of 1.86 (95% CI 1.32 to 2.62, p < 0.05), 1.54 (95% CI 1.24 to 1.90, p < 0.05), and 2.15 (95% CI 1.49 to 3.09, p < 0.05), respectively. The results were consistent and statistically significant in all subgroup analyses. Conclusions Rhinitis was associated with an increased risk of depression. Further prospective studies involving large sample sizes are required to confirm the results by considering more confounders and clarify the mechanisms. Supplementary Information The online version contains supplementary material available at 10.1186/s13223-021-00615-5.

et al. [19] reviewed allergic disorders and the risk of depression and allergic disorders, including AR. Additionally, Sansone et al. [20] published a systematic review investigating the relationships between AR and mood syndromes, and 10 of 12 studies showed a positive relationship. Although previous systematic reviews/meta-analyses studied the association between AR and depression, this manuscript is original because this meta-analysis investigates the association between NAR and depression. Therefore, we conducted a metaanalysis to evaluate the association among rhinitis, AR, NAR and depression.

Retrieval of studies
The reporting of this meta-analysis of observational studies is consistent with the Meta-Analysis of Observational Studies in Epidemiology (MOOSE) guidelines (Additional file 1). The PubMed, EMBASE, and Cochrane Library databases were searched through April 1, 2019. The search consisted of the following two terms: rhinitis and depression. We used the following key words to search for the first term: "rhinitis" OR "rhinit*" OR "NARES" OR "NAR" OR "LAR" OR "NANIPER". We used the following key words to search for the second term: "depression" OR "depressive disorder" OR "depressive disorder, major" OR "dysthymic disorder" OR "depress*" OR "melancholia". In addition, we used "AND" to connect the two terms (for the search strategy, see https:// doi. org/ 10. 17632/ ccvm3 cvbtm.2). The retrieved studies were first screened by reading the titles and abstracts. Two authors (Jing Wang and Dongqiong Xiao) subsequently read the full texts of the remaining publications independently. A third author (Huayou Chen) resolved any disagreements (Additional file 3).

Definitions
AR is an IgE-mediated inflammatory disease of the nasal mucosa characterized by the presence of one or more nasal symptoms, including itching, sneezing, nasal discharge and nasal blockage [21,22]. NAR is not IgEmediated rhinitis and consists of at least the following 2 subtypes: a non-eosinophilic subtype and an eosinophilic subtype [23]. Rhinitis is a general term referring to various nose AR/NAR inflammation and infections (viral sinusitis). Depression is based on a highly variable set of symptoms rather than objective diagnostic tests. A diagnosis of major depression was made when a certain number of symptoms listed in the Diagnostic and Statistical Manual (DSM-5) were reported for longer than 2 weeks [24].

Study selection
The inclusion criteria were as follows: (1) studies involving participants investigated for any of the following outcomes: the incidence, prevalence, risk or odds ratio (OR) of depression among rhinitis, AR, NAR and control participants; (2) studies evaluating the association between rhinitis and depression and reporting the unadjusted and/or adjusted ORs and their corresponding 95% confidence intervals (CIs), unadjusted and/or adjusted OR estimates and 95% CIs, or the number of exposed and unexposed participants; and (3) studies published in English with a case-control, cohort, or cross-sectional design. The exclusion criteria were as follows: (1) studies reporting the results of only animal experiments; (2) unrelated studies or studies in which the data overlapped with those of another study; or (3) reviews, case reports, meta-analyses and letters.

Data extraction
The data were independently extracted from the studies by two reviewers (Jing Wang and Dongqiong Xiao) and aggregated using a standardized form; the collected data included the study author, publication year, study design, study location, sample size, age, ascertainment of rhinitis, type of rhinitis, ascertainment of depression, depression diagnostic criteria, primary outcomes, confounding factors, data source, and Newcastle-Ottawa Scale (NOS) score.

Quality evaluation
The methodological quality of all included studies (Additional file 2: Table S1) was examined using the NOS [25] by two reviewers (Jing Wang and Dongqiong Xiao) independently, and a third author resolved any disagreements. The reviewers assessed the quality scores (varying from 0 to 9) in the following three domains: selection of the study population, comparability, and evaluation of exposure and outcomes.

Statistical analysis
The ORs and 95% CIs were used as measures of the association between rhinitis and depression across the studies. In the case of original studies comparing the number of participants who developed depression following exposure to rhinitis compared with control groups, we calculated the ORs and 95% CIs of each study. All data from the included studies were converted into log(ORs) and standard errors (SEs) [26]. We pooled the log(ORs) and SEs of each study separately using the DerSimonian-Laird formula (random effects model)  [27]. The statistical heterogeneity [28] among the studies was assessed using the I 2 statistic [29]. Values of I 2 > 50% and p < 0.1 indicated high heterogeneity [30]. We conducted stratified analyses based on the study location (Asia, the United States, Europe, or other countries), study design (cohort or cross-sectional), sample size (≥ 10,000 or ˂10,000), sample population (< 18 years or ≥ 18 years), ascertainment of depression (self-reported or diagnosed), ascertainment of rhinitis (self-reported or diagnosed), study quality (NOS score > 5 or NOS score ≤ 5), adjustment for confounding factors (≥ 8 factors or ≤ 7 factors), adjustment for age (yes or no), adjustment for sex (yes or no), adjustment for asthma (yes or no), adjustment for atopic dermatitis (yes or no), adjustment for household income (yes or no), and adjustment for comorbidities (yes or no).
We used funnel plots [31], Egger's tests and Begg's tests in the meta-analysis to assess publication bias. We used Stata software version 12.0 (StataCorp, College Station, TX) to perform the statistical analyses.

Literature search
We identified 3472 potential studies, including 331 studies from PubMed, 146 studies from the Cochrane Library, and 2995 studies from EMBASE (https:// doi. org/ 10. 17632/ ccvm3 cvbtm.2). After careful screening, 3458 studies were excluded for the reasons listed in Fig. 1, and 14 studies reporting the association between rhinitis and depression met the final inclusion criteria (see Fig. 1).
The characteristics of these 14 included studies (study author, publication year, study location, study design, sample size, participants, ascertainment of rhinitis, type of rhinitis, diagnosis of rhinitis, ascertainment of depression, depression diagnostic criteria, outcomes, confounding factors, and data source) are summarized in Table 1.

Characteristics and quality of the included studies
The characteristics of the fourteen included studies are shown in Table 1. Among the included studies, four studies [1,17,32,33] were cohort studies, and ten studies [5-7, 13, 14, 34-38] were cross-sectional studies. The association between rhinitis and depression was the primary outcome of interest in six studies [7, 32-34, 37, 38], the association between AR and depression was the primary outcome in nine studies [1, 5-7, 13, 17, 35, 36, 39], and the association between NAR and depression was the primary outcome in two studies [7,35].
The included studies were published between 2008 and 2019, and the number of participants ranged from 175 to 19.1 ± 1.1 million, yielding a total of 19.36 ± 1.1 million participants across the studies.

Quantitative results (meta-analysis)
Among the 14 selected studies, one study [7] found a nonsignificant association between AR and depression, while the other studies revealed an association between rhinitis, AR, or NAR and a significantly increased risk of depression. Two studies [34,36] reported unadjusted ORs, eight studies reported adjusted ORs, and four studies [5,33,37,38] reported the number of participants with and without rhinitis who developed depression.
All 14 studies reported the risks as ORs, ranging from 0.9 to 4.25. Any type of rhinitis was associated with an increased risk of depression compared with the control with a pooled OR of 1.67 (95% CI 1.46, 1.91). High heterogeneity was found in these studies (I 2 = 89.5%, p < 0.001) (Fig. 2).

Stratified analyses Allergic rhinitis and the risk of depression
Among the fourteen studies included in our analysis, nine articles reported an association between AR and depression. Stratified analyses of several key study characteristics and clinical factors were performed to evaluate the possible sources of heterogeneity in the  included studies ( Table 2). The association between AR and depression was significant (OR: 1.54, 95% CI 1.24-1.90), and this association was consistent in all stratified analyses (Table 2). Stronger associations between AR and depression were found in the cohort studies (OR: 2.15, 95% CI 1.09-4.25) compared with the cross-sectional studies (OR: 1.42, 95% CI 1.14-1.75), in the studies with small sample sizes (< 10,000) (OR: 1.86, 95% CI 1.08-3.18) compared to the studies with large sample sizes (≥ 10,000) (OR: 1.41, 95% CI 1.12-1.78), and in the studies conducted in Europe and other countries compared with the studies conducted in the United States and Asia ( Table 2). The diagnosis modality included in the primary studies also seemed to be related to the results. For example, studies ascertaining AR and depression by diagnosis demonstrated a stronger association between AR and depression incidence (OR: 2.20, 95% CI 1.56-3.08 and OR: 2.19, 95% CI 1.42-3.38, respectively) than the studies using self-reporting (OR: 1.29, 95% CI 1.05-1.57 and OR: 1.34, 95% CI 1.09-1.65, respectively).
The association between AR and depression was strong when the studies were not adjusted for age or adjusted for the presence of atopic dermatitis (Table 2).

Rhinitis and the risk of depression
Among the fourteen studies included in our analysis, six articles reported an association between rhinitis and depression. Stratified analyses across several key study characteristics and clinical factors were performed to evaluate the possible sources of heterogeneity in the included studies ( Table 2). The association between rhinitis and depression was significant (OR: 1.86, 95% CI 1.32-2.62), and this association was consistent in all stratified analyses ( Table 2). The study location, study quality, and sample size seemed to be related to the results. For example, stronger associations between rhinitis and depression were found in studies conducted in Europe (OR: 2.61, 95% CI 1.07-6.37) compared to studies conducted in the United States  Table 2).
The association between rhinitis and depression was stronger in the studies unadjusted for age, asthma, and comorbidities or adjusted for fewer confounding factors (< 8) ( Table 2).

Discussion
To the best of our knowledge, this study presents the first meta-analysis to evaluate the association between rhinitis, including AR and NAR, and the incidence of depression. The results of this meta-analysis, which included 14 studies, revealed that any type of rhinitis was associated with a 67% increased risk of depression. Furthermore, our analysis revealed that AR was associated with a 54% increased risk of depression and that NAR was associated with a 115% increased risk of depression. The association persisted and remained statistically significant in all stratified analyses.
The results of this meta-analysis reveal that the patients with NAR were more likely to experience depression than the patients with AR. There are several reasons for this result. First, only two studies [7,35] with relatively small numbers of participants evaluated the association between NAR and depression; therefore, the association may be overestimated. The sample size may affect the results of the meta-analysis in the stratified analyses (Table 2). Second, depression occurs at an increased frequency in individuals with diseases with prolonged progression, such as chronic respiratory diseases, asthma, chronic atopic dermatitis, cardiovascular diseases and other systemic comorbidities [40,41]. The patients with NAR had an increased likelihood of a generally poor health status, and these confounding factors were not adjusted in the study by Bedolla-Barajas et al. [35]. Third, the patients with NAR had an increased likelihood of developing nasal obstruction and rhinorrhoea, and these specific presenting symptoms may lead to depression in NAR patients [7]. Fourth, the chronicity of NAR may increase the rate of depression. For example, patients with AR may present with seasonal symptoms, while patients with NAR constantly experience symptoms [7]. Collectively, future prospective cohort studies with large sample sizes are needed to clarify the results by considering additional confounding factors.
The association among AR, rhinitis and depression was significant (Table 2). Patients with AR are prone to allergic disorders with a predominance for the differentiation of CD4-positive T helper 2 (Th2) cells. AR with neuroinflammatory markers may trigger allergies caused by IL-4, IL-5 and IL-6 and, thus, affect psychopathology [5,42,43], such as depression, that may be associated with increased inflammatory markers [44]. The association between AR and depression was stronger in the participants in Europe [5] and other countries [35] than in those in Asia [1,6,14,36] and the United States [7,13,17] in the stratified analysis (Table 2). Genetic and environmental factors may affect mood [5]. The study location may have affected the results via other confounding factors, such as genes, subjective health status, residential area, and occurrence of allergic disease. The association among AR, rhinitis and depression was slightly stronger in the studies with small sample sizes (˂10,000) than in those with large sample sizes (≥ 10,000). Thus, studies with small numbers of participants may have overestimated the association among AR, rhinitis and depression. The different methods of ascertaining depression and AR seemed to be related to the results. The studies in which depression and AR were diagnosed by physicians reported a slightly stronger association than those in which depression and AR were self-reported, and the studies with self-reporting may have been subject to recall bias [5].
Furthermore, many confounding factors are related to the results. Patients with AR often also suffer from asthma and atopic dermatitis [5,19]. Age, asthma, atopic dermatitis, and sex were found to be related to an increased risk of depression in the stratified analysis. The studies considering fewer than 8 confounding factors may have overestimated the association between AR and depression. Future studies are needed to clarify these associations by considering additional confounding factors.
Our meta-analysis has the following limitations. First, the studies included a wide range of participants, including children and adults, in different age groups, which could result in biases. Second, some included studies reported the association between any type of rhinitis and depression without adjusting for confounding factors, such as the crude ORs or number of participants, which may have led to an overestimation of the results of the meta-analysis. Third, the treatment options for rhinitis, AR and NAR may impact their risk of expressing depressive symptoms, but the original included studies did not discuss this issue. Fourth, potential publication bias exists because we included only studies published in English. Fifth, studies reporting outcomes in alternative manners were not included in our meta-analysis, which may contribute to publication bias. For example, studies that did not evaluate the association between rhinitis and depression by ORs or conversion of ORs were excluded. Sixth, there was no analysis of the association between different types of rhinitis and different degrees of depression based on the original studies. Furthermore, bias inherent to observational studies was not eliminated in the quantitative synthesis.
The merits of this meta-analysis are as follows. First, this study evaluated the association between rhinitis and depression in a large global sample. Considering the consistent finding of an increased depression incidence associated with rhinitis, we recommend that further prospective cohort studies considering additional adjusted confounding factors should be performed to test this hypothesis. Second, this study demonstrated that the study location, study design, sample size, ascertainment of depression and rhinitis, and adjustment for confounding factors were all sources of heterogeneity.

Conclusions
In conclusion, our pooled analyses provide evidence that participants with rhinitis, including AR and NAR, had an increased risk of depression. Future studies may focus on treatment options for rhinitis and explore how AR and NAR impact the risk of expressing depressive symptoms.