Discussion
Global epidemiology of asthma among COVID-19 patients has been described by a number of contradictory reports. We aimed at investigating potential reasons underlying published discrepancies by joining forces with key academic institutions across three countries and three continents with varying local allergy and asthma epidemiology. Our study has contributed with important findings in the field: first, we showed that using the same inclusion criteria, a male gender bias characterized asthmatic populations, when they were overrepresented among hospitalized COVID-19 patients. Second, we tested the hypothesis whether COVID-19 patients with asthma have a more severe disease trajectory but found similar asthma prevalence among ICU and normal care patients. Third, we showed that the number of comorbidities is higher among COVID-19 patients in the Stanford cohort, which showed a higher prevalence of asthma as compared to the other centers (spectrum bias). The most frequent comorbidities among these asthma patients were other chronic inflammatory airway disorders such as COPD. The latter has been long recognized as a risk factor for COVID-19 hospitalization.
The prevalence of asthma among hospitalized COVID-19 patients in our German (2.85%) and Moscow (0.70%) centers is in accordance to previously published reports of up to 1-8-2.6% in Sweden and 1.8% in Russia . Our Stanford data (18.39%) show a similar trend but an even higher asthma prevalence as compared to previous reports of up to 14% . Clinical outcome was not adverse for asthmatics since there was no overrepresentation among ICU vs standard care patients. This finding is in accordance with prior studies looking into severe COVID-19 outcomes, including mortality, among asthma patients . Male sex bias is expected in childhood asthma and although the vast majority of participants were adults (Table 1), males were overrepresented among asthma patients in the Stanford cohort. Given the fact that male gender is also associated with more severe COVID-19 outcomes, this may somehow be associated with the higher prevalence of asthmatics among hospitalized patients in Stanford .
Patients with underlying comorbidities are at risk for developing severe COVID-19 and the association is closer with particular comorbidities such as diabetes and hypertension. The overrepresentation of asthmatics in the hospitalized COVID-19 cohort in Stanford may thus be due to the co-presence of a number of other comorbidities in this population, which shape their actual risk for hospitalization. Moreover, COPD stood out as a significantly more prevalent condition among asthmatics in Stanford. Indeed, COPD increases the risk for development of severe COVID-19 outcomes, including mortality. This may explain the epidemiological finding of high asthma prevalence in the Stanford cohort . Over 50% of asthma COVID-19 patients in Stanford (versus approx. 5% in Germany and 20% in Moscow) suffered from ≥3 additional comorbidities, which underlines the fact that this population significantly differed in terms of risk factors.
We have assessed basic hematological, biochemical, coagulation and inflammatory biomarkers of COVID-19 across patient groups and centers. The difference in terms of eosinophil counts at admission and trend during hospitalization between the Stanford and other centers could have several potential explanations. Peripheral blood eosinophil counts are associated with disease endotype and higher numbers could be indicative of a high T2 endotype among US asthmatics. In addition, SARS-CoV-2 is associated with peripheral blood eosinopenia and a difference in this regard could reflect different timing of admission since infection with the virus, differences in underlying pathomechanisms or differences in treatment regimens. Quite importantly, guidelines regarding reasons for hospital admission in individual countries differ. Therefore, asthma comorbidity as a potential risk factor for severe disease could potentially drive enhanced hospitalization in the US cohort as opposed to other included cohorts and this may be further reflected by the absence of eosinophil suppression in the former (collider bias).
Our study has several limitations. We could not address differences in COVID-19 severity as per WHO or NIH criteria across cohorts since the necessary information was not accessible by all centers. Moreover, one of of the participating centers (Moscow) delivered data in a case-control rather than cohort manner, while individual patients’ data were available for only the Moscow and the Stanford cohort thus excluding additional biostatistical analyses for the other centers. In order to determine overall risk for hospitalization we needed data on all patients being tested in participating centers, which was not possible for the index study. In addition, data on disease phenotype could not be collected for asthmatic patients included in the study. Precise data on the ethnicity of patients included in the German and Russian cohorts was not available and we therefore cannot test the hypothesis of an ethnicity bias with the Stanford cohort. Indeed, ethnicity may play an important role in susceptibility to-and severity of-COVID-19 . Finally, socioeconomic status and access to health care could also not be compared across study sites.
On the other hand, our study is characterized by a number of strengths including the intercontinental collection of both clinical and laboratory data, the stringent definition of comorbidities including asthma as well as the harmonized inclusion criterium in terms of hospitalization due to COVID-19 rather than SARS-CoV-2 testing positivity alone. Our findings suggest that pathogenetic mechanisms involving eosinophils and T2 disease endotype as protective factors for COVID-19 are less important compared to associated comorbidities, which seem to dictate hospitalization risk of asthmatics. Future research is required to address pending questions such as overall risk for hospitalization for people with asthma.