Comorbid Asthma Increased the Risk for COVID-19 Mortality in Asia: A Meta-Analysis

We aimed to explore the influence of comorbid asthma on the risk for mortality among patients with coronavirus disease 2019 (COVID-19) in Asia by using a meta-analysis. Electronic databases were systematically searched for eligible studies. The pooled odds ratio (OR) with 95% confidence interval (CI) was estimated by using a random-effect model. An inconsistency index (I2) was utilized to assess the statistical heterogeneity. A total of 103 eligible studies with 198,078 COVID-19 patients were enrolled in the meta-analysis; our results demonstrated that comorbid asthma was significantly related to an increased risk for COVID-19 mortality in Asia (pooled OR = 1.42, 95% CI: 1.20–1.68; I2 = 70%, p < 0.01). Subgroup analyses by the proportion of males, setting, and sample sizes generated consistent findings. Meta-regression indicated that male proportion might be the possible sources of heterogeneity. A sensitivity analysis exhibited the reliability and stability of the overall results. Both Begg’s analysis (p = 0.835) and Egger’s analysis (p = 0.847) revealed that publication bias might not exist. In conclusion, COVID-19 patients with comorbid asthma might bear a higher risk for mortality in Asia, at least among non-elderly individuals.


Introduction
Coronavirus disease 2019 (COVID- 19), which is brought on by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has ravaged the world. As of 26 October 2022, 624 million patients have been confirmed with the COVID-19 diagnosis globally of which 6.5 million patients have died [1]. Vaccines have shown to be very effective against severe COVID-19 disease and mortality [2][3][4][5][6][7]; it is also important to understand risk factors (e.g., to decide whom to prioritize for vaccination). Until now, several variables (age, sex, and certain past medical history) have been identified as risk factors for COVID-19 mortality [8][9][10][11][12][13]. Although there have been several meta-analyses exploring the relationship of comorbid asthma with the risk for COVID-19 mortality in the full regions [14][15][16][17][18], the findings from previous meta-analyses were still inconclusive, which might suffer limitations from considerable variability in the prevalence of asthma across different regions [14,19,20]. Therefore, it is an urgent requirement to investigate the relationship of comorbid asthma with the risk for COVID-19 mortality based on specific regions.
To the best of our knowledge, three meta-analyses have explored this relationship in Asia [15,18,21]. However, the number of included studies (all are less than twelve) and the sample sizes are limited. Moreover, the conclusions drawn from these articles are inconsistent or even contradictory. Additionally, a substantial number of articles on this topic in Asia have emerged since then. Taken together, we conducted this updated metaanalysis to ascertain the relationship between comorbid asthma and COVID-19 mortality in Asia on the basis of the latest data.

Descriptive Characteristics
Summary characteristics of the enrolled studies are tabulated in Table 1. This metaanalysis was based on a total of 103 eligible studies with 198,078 COVID-19 patients. In terms of study design, there were eighty-five retrospective studies, ten prospective studies, six cross-sectional studies, one case series study, and one clinical trial study. From the point of view of geographical settings, we characterized the country's levels of social and economic development based on the 4-tier Human Development Index (HDI) from the United Nation's 2022 Human Development Report. Additionally, countries were categorized as very high HDI country (Korea, Singapore, Israel, Japan, Turkey, Kuwait, Saudi Arabia, and United Arab Emirates), high HDI country (China, Iran, and Indonesia), medium HDI country (India, Philippines, and Bangladesh), and low HDI country (Pakistan). Among these studies, ninety-eight studies reported the exact numbers of non-survivors

Descriptive Characteristics
Summary characteristics of the enrolled studies are tabulated in Table 1. This metaanalysis was based on a total of 103 eligible studies with 198,078 COVID-19 patients. In terms of study design, there were eighty-five retrospective studies, ten prospective studies, six cross-sectional studies, one case series study, and one clinical trial study. From the point of view of geographical settings, we characterized the country's levels of social and economic development based on the 4-tier Human Development Index (HDI) from the United Nation's 2022 Human Development Report. Additionally, countries were categorized as very high HDI country (Korea, Singapore, Israel, Japan, Turkey, Kuwait, Saudi Arabia, and United Arab Emirates), high HDI country (China, Iran, and Indonesia), medium HDI country (India, Philippines, and Bangladesh), and low HDI country (Pakistan). Among these studies, ninety-eight studies reported the exact numbers of non-survivors and survivors of COVID-19 patients with asthma, while five studies reported OR with 95% CI to reflect the effect of comorbid asthma on Asian COVID-19 mortality.
Considering comorbidities could lead to additional "noise" and measurement error, we subsequently calculated the pooled OR on the basis of adjusted effect estimates. The results indicated asthma was significantly associated with the increased risk of mortality among Asian COVID-19 patients on the basis of 19 studies (adjusted OR = 1.22, 95% CI: 1.05-1.42), which supported the findings based on crude effects.

Sensitivity Analysis and Publication Bias
The sensitivity analysis showed the effect estimate was not unduly impacted by any single study, indicating the stability and robustness of our results. Begg's analysis (p = 0.835, Figure 3A) and Egger's analysis (p = 0.847, Figure 3B) demonstrated publication bias might not exist in this study. Considering comorbidities could lead to additional "noise" and measurement error, we subsequently calculated the pooled OR on the basis of adjusted effect estimates. The results indicated asthma was significantly associated with the increased risk of mortality among Asian COVID-19 patients on the basis of 19 studies (adjusted OR = 1.22, 95% CI: 1.05-1.42), which supported the findings based on crude effects.

Discussion
Our findings based on 103 eligible studies indicated comorbid asthma was significantly associated with an increased risk for mortality in COVID-19 patients compared with those without in Asia. The subgroup analyses by male proportion, sample sizes, and setting yielded consistent results, but the subgroup analysis by age indicated comorbid asthma was significantly associated with higher risk for COVID-19 mortality in Asia among studies with mean/median age <60 years old and not among studies with mean/median age ≥60 years old. Previous studies have shown advanced age and asthmatic patients are prone to other comorbidities, such as hypertension and diabetes mellitus, which are closely related to the severity and mortality of COVID-19 patients [128]. We also investigated the proportion of hypertension and diabetes mellitus in enrolled studies among age <60 years old and ≥60 years old and found the proportions of hypertension and diabetes mellitus were relatively higher in groups ≥60 (44.39% and 30.64%, respectively) than in groups <60 years old (32.03% and 25.8%, respectively). Thus, we speculated the existence of other comorbidities (such as hypertension and diabetes mellitus) might mask the relationship between asthma and COVID-19 mortality.
Asthma is a heterogeneous disease, and some phenotypes are related to obesity, which has continued to attract respiratory experts' attention since the pandemic of COVID-19 [129]. Furthermore, high body mass index has been identified as a risk factor for COVID-19 mortality. In our subgroup analyses stratified according to the proportion of males, the odds ratio increased to 2.08 in the group with males being less than 50% and was reduced to 1.24 in the subgroup where males dominated, while Wenzel et al. showed females usually dominate in obesity-related asthma [129]. This suggested part of the conflicting results on asthma and COVID-19 mortality could be due to the differences in handling of obesity in different studies. Our further analysis stratified by obesity prevalence supported this opinion. The subgroup results regarding ICU versus non-ICU deaths may be explained by the facts that ICU patients may rely either on a better economic status (theirs or for their countries) than non-ICU patients (whose access to intensive care may be impaired by economic status).
At present, research has explored the potential mechanism of the association between COVID-19 and asthma from the standpoints of pathophysiology. Viral infections, including SARS-CoV-2 and Middle East respiratory syndrome coronavirus (MERS) could directly result in the exacerbation of asthma and thus lead to serious airway inflammation, which might be linked to critical unfavorable outcomes [130,131]. Additionally, several researchers proposed host antiviral immunity was decreased due to asthma associated type II inflammatory response [132,133]. In addition, interferon responses as a crucial step

Discussion
Our findings based on 103 eligible studies indicated comorbid asthma was significantly associated with an increased risk for mortality in COVID-19 patients compared with those without in Asia. The subgroup analyses by male proportion, sample sizes, and setting yielded consistent results, but the subgroup analysis by age indicated comorbid asthma was significantly associated with higher risk for COVID-19 mortality in Asia among studies with mean/median age <60 years old and not among studies with mean/median age ≥60 years old. Previous studies have shown advanced age and asthmatic patients are prone to other comorbidities, such as hypertension and diabetes mellitus, which are closely related to the severity and mortality of COVID-19 patients [128]. We also investigated the proportion of hypertension and diabetes mellitus in enrolled studies among age <60 years old and ≥60 years old and found the proportions of hypertension and diabetes mellitus were relatively higher in groups ≥60 (44.39% and 30.64%, respectively) than in groups <60 years old (32.03% and 25.8%, respectively). Thus, we speculated the existence of other comorbidities (such as hypertension and diabetes mellitus) might mask the relationship between asthma and COVID-19 mortality.
Asthma is a heterogeneous disease, and some phenotypes are related to obesity, which has continued to attract respiratory experts' attention since the pandemic of COVID-19 [129]. Furthermore, high body mass index has been identified as a risk factor for COVID-19 mortality. In our subgroup analyses stratified according to the proportion of males, the odds ratio increased to 2.08 in the group with males being less than 50% and was reduced to 1.24 in the subgroup where males dominated, while Wenzel et al. showed females usually dominate in obesity-related asthma [129]. This suggested part of the conflicting results on asthma and COVID-19 mortality could be due to the differences in handling of obesity in different studies. Our further analysis stratified by obesity prevalence supported this opinion. The subgroup results regarding ICU versus non-ICU deaths may be explained by the facts that ICU patients may rely either on a better economic status (theirs or for their countries) than non-ICU patients (whose access to intensive care may be impaired by economic status).
At present, research has explored the potential mechanism of the association between COVID-19 and asthma from the standpoints of pathophysiology. Viral infections, including SARS-CoV-2 and Middle East respiratory syndrome coronavirus (MERS) could directly result in the exacerbation of asthma and thus lead to serious airway inflammation, which might be linked to critical unfavorable outcomes [130,131]. Additionally, several researchers proposed host antiviral immunity was decreased due to asthma associated type II inflammatory response [132,133]. In addition, interferon responses as a crucial step of antiviral immune reaction were shown to be lacking in asthmatic patients attributed to decreased production [134,135]. Additionally, asthma resulted in mucus plugging in the lower respiratory tract, limiting the airflow and worsening the hypoxemia from diffuse alveolar damage by SARS-CoV-2 infection [136]. However, these theoretical relationships remain to be observed. Further studies focusing on the molecular mechanisms underlying the association between comorbid asthma and the increased risk for COVID-19 mortality are warranted to verify our results.
The strengths of this study were the number of eligible studies included (103 eligible studies), and the sample sizes (198,078 cases) were large, and subgroup analyses were conducted. However, several limitations need to be acknowledged in this study. First, although the investigators tried to avoid duplicates in the process of article selection, several studies collected clinical records of COVID-19 patients retrospectively from large national public databases. This inevitably led to repeated populations and selective bias. Second, most of the included articles were observational retrospective studies, which resulted in lack of proof for casual links between asthma and mortality risk of COVID-19. Third, the medical history of enrolled patients could not be clearly analyzed, especially for the use of theophylline, inhaled corticosteroids, leukotriene receptor antagonists, and other drugs. Length of in-hospital treatment, the severity of asthma, types of asthma, and other comorbidities could not be extracted either, which should be a focus in the future study. Fourth, the existence or history of other comorbidities, such as coronary artery disease, chronic obstructive pulmonary disease, and so on was not addressed presently, which still restricted the generalization of our findings.

Conclusions
Our findings demonstrated comorbid asthma significantly increased the risk for mortality among patients with COVID-19 in Asia, at least among non-elderly individuals. Funding: This study was supported by a grant from Henan Young and Middle-aged Health Science and Technology Innovation Talent Project (No. YXKC2021021). The funder has no role in the data collection, data analysis, preparation of manuscript and decision to submission.

Institutional Review Board Statement: Not applicable.
Informed Consent Statement: Not applicable.

Data Availability Statement:
The data that support the findings of this study are included in this article and are available from the corresponding authors upon reasonable requests.

Conflicts of Interest:
The authors declare they have no potential conflicts of interest regarding this submitted manuscript.