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.