Inverse association between Helicobacter pylori infection and childhood asthma in a physical examination population: a cross-sectional study in Chongqing, China

Asthma is one of the most common chronic respiratory diseases worldwide and particularly affects children [1]. The latest data from the World Health Organization show that there are approximately 334 million patients with asthma worldwide [2], and approximately 250,000 deaths are attributable to asthma annually [3]. Several risk factors have been linked with asthma susceptibility, including host genetics, specific environmental exposures, and respiratory tract infections during early life. The classic risk factors include air pollution, smoking, infections, and personal allergy history, but the list is incomplete. Attention is turning to the role of the human microbiome in asthma pathogenesis and protection [4]. Identification of potential risk factors in cases of childhood asthma that are not explained by traditional risk factors might improve preventative strategies.

Helicobacter pylori is a spiral-shaped, Gram-negative, microaerophilic bacterium belonging to the genus Helicobacteraceae. It infects approximately 50% of the world population [5]. The prevalence of H. pylori infection varies widely between different parts of the world, with higher rates in developing countries. An up-to-date meta-analysis reported that the prevalence of H. pylori infection in China ranges from 35.4% to 66.4%, and varies according to socioeconomic status and the hygiene level [6]. In most instances, H. pylori colonizes the gastric stomach from early childhood [7]. H. pylori infection may lead to gastritis, peptic ulcer disease, gastric adenocarcinoma, and gastric mucosa-associated lymphoid tissue lymphoma; however, most infected subjects remain asymptomatic [8]. In addition, an increasing body of evidence indicates that there is a link between H. pylori infection and extra-gastric diseases [9].Recently, Sahin y et al. evaluated the association between neutrophil/lymphocyte ratio and mean platelet volume values with H. pylori infection, severity classification, and pre-and post-treatment status, however, no relationship was found [10].

As the incidence of asthma has increased, the prevalence of H. pylori infections has decreased. The hygiene hypothesis proposes that increased exposure to microorganisms in early life may confer a protective effect against asthma and allergic diseases [11]. Several epidemiological studies have reported an inverse association between H. pylori infection and allergic asthma, especially in children and adolescents [12, 13]. Nevertheless, There are still some conflicting views on whether there is an association between H. pylori infection and childhood asthma [14].

Our previous meta-analysis, which included 18 observational studies with 17,196 enrolled children, reported a significant negative association between H. pylori infection and the risk of childhood asthma, but lacked data about children from China [15]. Chongqing, a city in southwestern China, usually suffers from wet weather, and also most homes here have poor indoor ventilation, are usually plagued with dampness and mold, and prefer to use hygienic incense and mosquito coils, so that children in Chongqing have a significantly increased risk of childhood asthma [16]. Thus, we conducted a cross-sectional study to screen patients with childhood asthma and H. pylori-infected populations, to investigate the prevalence of childhood asthma and H. pylori infection in southwest China, and to explore the association between H. pylori infection and childhood asthma. Our findings can help to understand the different genetic and environmental contributors of asthma in order to better manage this disease.

This study of 2241 children who underwent urea breath testing in 2021 shows that H. pylori infection is an independent predictor for a positive diagnosis of pediatric asthma. To the best of our knowledge, this is the largest study documenting such an association for children in China and the first to use pediatric urea breath test results rather than serologies, which are considered less reliable in children from a healthy childhood population.

The Children’s Hospital of Chongqing Medical University is a medical center for children in southwest China and the only children’s hospital in Chongqing. All the participants lived in urban areas of Chongqing, meaning that the effect of living in an urban area, which is an independent risk factor for pediatric asthma [20], was eliminated. The average number of outpatient visits was higher than 20, and almost all disease information was recorded by electronic medical records and a big data system of the hospital. It was considered more reliable to use asthma diagnoses recorded by a respiratory physician with lung function results in the system rather than questionnaires completed by parents. In addition, we included two asthma-related laboratory tests, the percentage of eosinophils in routine blood examination and the serum vitamin D level, which were not included in previous studies. Moreover, there was no heterogeneity in the study population, including differences in sex, age, BMI, and other confounders. To eliminate the possible influence of other variables, propensity score matching (PSM) analysis was performed using a logistic regression model based on age, sex, and other confounders to assess the relationship between H. pylori infection and childhood asthma. PSM refers to screening of the experimental and control groups using certain statistical methods so that the screened study subjects are comparable in terms of clinical characteristics (adjusting for potential confounders). However, there was little difference between matched and unmatched data; therefore, we did not describe PSM in Section Methods. This homogeneity may improve the comparability of our study to a certain extent.

The prevalence of childhood asthma in our study was 6.78%, which is higher than reported by epidemiological surveys in 2013 in Chongqing (4.43%) [21] and a meta-analysis in 2020 in China (2.6%) [22]. This may be because the prevalence of childhood asthma has increased in recent years and the prevalence of asthma is high in Chongqing [21], and all participants of our study lived in urban areas. The H. pylori infection rate was 13.03% in the present study. This is lower than that reported by Ren et al. in a meta-analysis, which demonstrated that the pooled prevalence of H. pylori infection was 44.2% in mainland China, 46.6% in Southwest China, and 28.0% in children and adolescents [6]. This difference may be because the prevalence of H. pylori infection increases with age and varies across geographic areas [5, 6]. In addition, all our participants lived in urban areas and had better sanitary conditions, higher family incomes, and healthier lifestyles.

Our study showed an inverse association between H. pylori infection and asthma in children, consistent with our previous meta-analysis [15]. Furthermore, several other studies have suggested that H. pylori infection significantly protects children younger than 10 years against allergic asthma [23, 24]. Zevit et al. demonstrated that the prevalence of asthma was 7.3% in children with H. pylori infection and 9.1% in healthy children, meaning that the prevalence of asthma was reduced in patients with H. pylori infection [12]. Another case–control study performed in Greece, which included 27 pediatric patients with asthma and 54 controls, also reported an inverse association between H. pylori infection and asthma [25]. Moreover, a cohort study performed in 2020 found that 16.4% of children who were H. pylori-negative at 2 and 10 years of age had asthma at 16 years of age, whereas children who were H. pylori-positive at 12 years of age did not have asthma at 16 years of age, suggesting that early exposure to H. pylori can prevent asthma [26]. The results of these studies are consistent with ours.

The possible protective mechanisms of H.pylori against allergic asthma, including (1) according to the “hygiene hypothesis”, infectious agents can inhibit allergic T helper (Th) 2 cell response, thus eliciting a Th1-type immune response, (2) H.pylori neutrophil-activating protein(HP-NAP) is one of the major virulence factors of H. pylori, which can increase interferon-γ production and decrease the level of interleukin-4, thereby stimulating Th1 activation and attenuating Th2 response in allergy-related asthma, (3)Another possibility involves the inverse correlation between H. pylori infection and gastroesophageal reflux disease (GERD), because gastroesophageal reflux can induce or aggravate asthma, but H.pylori can reduce gastroesophageal reflux, (4) H. pylori can also inhibit dendritic cells to promote immune tolerance and enhance the protective effect against asthma, and this inhibition is highly dependent on the suppressed regulatory T cells, (5) The gut-lung axis theory suggests remote regulation of lung immune function by H. pylori, (6)H. pylori infection may also prevent allergic asthma by altering stomach hormones levels, affecting the autonomic nervous system, and reducing the expression of heat shock protein 70 [27, 28].

It is well known that family history of allergies and blood eosinophil counts are strongly associated with childhood asthma [29, 30]. Recently, the association between BMI and childhood asthma has received increasing attention. Several studies have shown that BMI is significantly associated with the prevalence and incidence of allergic asthma [31, 32]. However, our study did not show such relationship. A recent systematic review and meta-analysis of case–control studies of children by Azizpour et al. [31] reported that the risk of asthma was 1.64 times and 1.92 times higher in individuals who were overweight and obese than in individuals who were underweight/normal weight, respectively. However, by removing the confounding factors, the effect size was reduced from 1.64 and 1.92 to 1.30. This suggests that although obesity increases the risk of asthma, but the confounding factors might influence the relationship between BMI and asthma. Therefore, in future epidemiological studies, it is important to investigate the confounding factors that affect the relationship between BMI and asthma. In addition, we found that children with asthma had similar vitamin D leves to healthy children, consistent with the previous studies by Yang et al. and Reinehr et al. [33, 34]. However, in contrast to our study, a meta-analysis by Wang et al., which included 35 studies with 27,271 participants, reported that children with asthma had significantly lower vitamin D levels than children without asthma. Furthermore, children with asthma who received vitamin D supplements had significantly lower recurrence rates than those who received a placebo [35].

Our study has several limitations. First, it was a single-center study and the results may not reflect the general population. Second, the participants only underwent urea breath testing, not endoscopy with biopsy, and there was a lack of data about the cytotoxin-associated gene A status, which is an important factor in H. pylori infection and is negatively associated with asthma and allergies [36]. Third, other potential confounding factors that might interfere with asthma, such as passive smoking, birth mode, and early antibiotic use, were not collected. Finally, our study was cross-sectional and lacked a comparison intervention, and its results only reflected epidemiological links, but failed to draw a cause-effect inference. Larger studies with an appropriate epidemiological design are required to investigate the potential causal relationship between H. pylori infection and asthma in the future.