Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), which causes coronavirus disease 2019 (COVID-19), has had a huge impact on global population health. According to the Johns Hopkins Coronavirus Resource Centerboard (https://coronavirus.jhu.edu/map.html), there have been more than 600,000,000 COVID-19 cases and 687,000 related deaths globally as of March 1, 2023. More COVID-19 cases are probably not diagnosed due to limited testing availability (1). With the rapid increase in the number of patients with COVID-19, clinical progress and prognosis have received more attention. Allergic disease is associated with complex immune responses (2), and persistent inflammation may affect the structure and abnormalities in their function (3). Allergic rhinitis (AR) is the most common nasal disorder, which contributes to the aggravation of respiratory virus-related disease (4) and affects 10%–40% of the population (5, 6). Interestingly, there was no statistically significant difference between the incidence of AR diagnosed during the pandemic compared with the period before the pandemic (7). The incidence of AR comorbid with COVID-19 was 1.8% in China (8). Whether AR is a risk factor for COVID-19 is controversial; nevertheless, accumulating evidence suggests that AR is a risk factor for COVID-19. In a nationwide Korean cohort study, AR conferred a greater risk of sensitivity to SARS-CoV-2 infection and severe clinical outcomes (9). In a Chinese cohort study, AR was also an independent risk factor [OR: 1.324 (95% CI: 1.049–1.671), P = 0.0183] for susceptibility to COVID-19 based on a propensity-score-matched nationwide cohort (10). However, a separate study in China showed that AR may not have a significant modifying effect on the development of COVID-19 (11). Moreover, AR patients had lower positive SARS-CoV-2 test rates in a cohort study in England (12). Even in a study in Iranian patients, AR disease status was inversely associated with the severity of COVID-19 (13). Based on clinical observations, AR patients have shown diverse clinical manifestations during the SARS-CoV-2 pandemic. Considering the current extent of different effects of AR disease status on COVID-19 and the complex pathological mechanisms of AR, we further investigated the risk factors for COVID-19 in AR patients.

China adjusted the national prevention and control strategy of 2019-nCoV infection and emerge an epidemic peak from early Dec.2022. We immediately and efficiently performed a nationwide survey with large sample size and short collection time (Dec. 28, 2022-Jan. 13, 2023), and the survey time coincided with this epidemic peak. To our knowledge, this is the first nationwide cohort study exploring the risk factors for COVID-19 in AR patients, with the goal of improving the management of AR and COVID-19.

In the present nationwide retrospective cohort study, we investigated the development of COVID-19 among 830 AR patients. Furthermore, we studied the association between the clinical outcomes of COVID-19 and the characteristics of AR. The results showed complex associations between age, BMI, comorbidity with allergic diseases, type of allergen, and frequency of vaccination and COVID-19 in patients with AR.

During the study period, China experienced the peak of the epidemic after the adjustment of the national prevention and control strategy of COVID-19 infection. The present study shows that during this period, the overall infection rate (75.54%) was much higher than before (1.8% in Wuhan and Zhuhai SARS-CoV-2 infection hospitalized patients (8) and 9.8% in Wuhan COVID-19-positive patients (11)). Of note, our infection rate (75.54%) was similar to the SARS-CoV-2 infection rate of 77.89% in Beijing city (n = 873) (Dec. 20∼23, 2023) in the same study period (14).

In a large cohort of patients with AR, we performed a category analysis based on BMI (<18.5 kg/m², 18.5–24.9 kg/m², and > 25.0 kg/m²). Similar to the studies in all patients (15), using normal BMI as the reference, overweight BMI was associated with a 2.038-fold higher risk of COVID-19 in the AR cohort. As other studies have reported, obesity (BMI ≥ 30 kg/m²) was associated with a significantly increased risk of critical COVID-19 and in-hospital mortality due to COVID-19 (16, 17). In addition, we found that underweight BMI was a protective factor against COVID-19 in AR patients. However, one study reported that underweight patients were more likely than normal-weight patients to develop secondary infections (18). However, the number of individuals in this study was only 11 patients and is not large enough to explain the relationship between underweight and COVID-19. Further research is warranted to clarify this interesting association. We also found a correlation between age and COVID-19. Under fully multivariable adjusted conditions, age under 60 years old was a protective factor against COVID-19 in AR patients. The result was similar to the advocation that age under 65 years old acts as a protective factor in asthma patients (12). Our study did not present old age as a significant risk factor for COVID-19. However, one study has already shown that older patients have a higher percentage of hospitalizations, ICU admissions, and deaths (19).

Comorbidities, including asthma, atopic dermatitis, allergic rhinitis, allergic conjunctivitis, chronic rhinosinusitis, and food allergy, represent a collection of disorders mediated by innate and adaptive immune responses. After evaluating 830 patients for AR comorbid with other types of allergic diseases and prevalence of COVID-19 positivity, our results showed that AR comorbid with AC was a major protective factor against COVID-19 and that AR comorbid with food allergy was a major risk factor for COVID-19 under the fully multivariable adjusted condition. In our cohort, 5.3% of patients with AR comorbid with AC were COVID-19 positive, which was lower than 10.8% in an Italian study (20). We consider the reason why AC has a protective effect. According to previous results, thirty-eight genes involved in the defense response to virus were overexpressed, while ACE II had low expression in conjunctivitis (21). In addition, the typical Th2 phenotype and eosinophilia may be important protective factors against COVID-19. Although there is no direct explanation for the protective effect of AR comorbid with AC against COVID-19, AR patients have a strengthened type 2 immune response to some extent. This may explain our results. The main clinical symptoms of food allergy are impaired skin barrier or gastrointestinal tract accompanied by basophil and mast cell activation. Seibold et al. found food allergies associated with lower risk of COVID-19 infection (22). In asthma cohort, there were more food allergy comorbid in COVID-19 infection than non-COVID-19 infection patients by Francisco's study (23). This study was similar to our study, food allergy comorbid with AR was a risk factor for COVID-19 infection. We consider that both food allergy and AR are IgE-mediated immune responses. Patients with AR comorbid with food allergy are in a state of prolonged B-cell activation. In addition, SARS-CoV-2 infection elicits an IgE response, and the serum levels positively correlate with the severity of COVID-19 (24). Therefore, we suggest that the immune responses resulting from B cell activation could explain why AR comorbid with food allergy is a risk factor for COVID-19.

During the period of our study, the predominant variant of SARS-CoV-2 was omicron. According to previous study, two doses of vaccine only offered limited protection against the omicron variant, and the third dose could be effective in preventing patients' symptoms and severe disease (25). More importantly, a fourth dose is more effective in preventing COVID-19 compared with three standard doses of vaccine (26). In our study, it was also clear that receiving four doses of the vaccine had a significant protective effect in patients with AR, while three doses did not show protection against COVID-19 in AR patients (cohort with large sample size verification is required). In addition, even after full multivariable adjustment, four doses showed a protective factor.

House dust mite (HDM)-specific AR is prevalent due to the ubiquitous and perennial presence of HDMs in indoor environments worldwide (27). From an immune characteristic perspective, HDM-allergic AR patients show increased group 2 innate lymphoid cells (ILC-2s) and high levels of secretion of IL-5 and IL-13 (28). In COVID-19 immunopathology, the interferon (IFN) response results in exacerbated proinflammatory cytokine production in the respiratory tract and lung pathology (29). In the nasal tissue and epithelial cells of COVID-19 patients, type 2 cytokines are downregulated, while IFNs are unregulated. In addition, allergen stimulation of lower airways induces a reduction in ACE II expression, suggesting that allergic inflammation may play a significant role in lowering the risk of COVID-19. In addition, patients with HDM-specific AR are permanently exposed to an immune environment mediated by type 2 inflammation response (30). This may explain why HDM-specific AR was found to be a protective factor in COVID-19 patients.

There existed some limitations in our study. First, our study was not a clinical study, and all patients included in the study provided information by filling in online questionnaires using mobile phones. Second, some history of comorbidity data in our study was taken from the patient's self-report only. Third, we only recorded the frequency of vaccinations given to participants, without carefully distinguishing the type of vaccines. Fourth, the subjects of our study were all Chinese, and there was a lack of inclusion of other ethnic groups. Although this is a nationwide survey, the sample size is not big. Study with large sample size verification is required. Other limitations including most of the participants who were able to successfully complete the online survey were young people, with a median age of 34, which may be subject to confounding bias, etc. Despite these limitations, to our knowledge, this is the first time that a questionnaire has been used to explore risk factors in AR patients during the COVID-19 peak in China. The advantages of our cohort study are that the collection time was short, and the survey time coincided with the epidemic peak.

Of note, the SARS-CoV-2 variants at the peak of the Chinese epidemic in 2022–2023 are quite different from the main prevalent variants now. Moreover, the prevalence of SARS-CoV-2 variants varies globally, which may be one of the reasons for the conflicting results of several previous studies. Cohort study involved different countries with large sample size verification are required.

In summary, the different clinical manifestations of AR patients are closely associated with COVID-19. We analyzed the demographic characteristics of the patients, and BMI and age had a significant impact on COVID-19. Underweight BMI and age lower than 60 years were protective factors, and overweight BMI was a risk factor for COVID-19 after full multivariable adjustment. We present for the first time the effect of different allergic disease comorbidities on COVID-19 in AR patients. AR comorbid with AC and AR comorbid with food allergy have the opposite effect on COVID-19. HDM-specific AR patients, compared to other AR patients, are better protected against COVID-19.