4 Discussion
This is the first comprehensive bidirectional and multivariable MR
analysis to investigate the potential causal link between allergic
disease and COVID-19. Our results revealed that allergic diseases have a
protective causal association with severe COVID-19, including
self-reported asthma and/or hay fever (or AR) and/or eczema (or AD).
Though the heterogeneity test indicated a minor problem, heterogeneity
is pervasive across MR analyses25 and the existence of
heterogeneity does not render an MR study inadmissible when horizontal
pleiotropy is absent21. The expression level of
angiotensin-converting enzyme 2
(ACE2), the receptor for SARS-CoV-2,
decreases with the increase of environmental allergens, which may be one
of the reasons for protecting allergic patients from severe
COVID-1926.
However, SARS-CoV-2 infection was
not found to be causally associated with allergic diseases, and severe
COVID-19 did not in turn lead to an increase or decrease in the risk of
the allergic disease. The Korea National Health and Nutrition
Examination Survey also did not show a significant reduction in the
incidence of each allergic disease
(asthma, AD, AR), whether self-reported or physician-diagnosed, in 2020
compared with 201927. Although COVID-19 does not cause
allergic diseases, viral infections (not just
SARS-CoV-2) may exacerbate the
symptoms of allergic diseases, so
telemedicine is still advised during the COVID-19
pandemic28.
Further analysis of various types of allergic diseases and asthma showed
that AD and asthma (especially mixed asthma and childhood asthma) were
causal protective factors for severe COVID-19. AD, a form of eczema, is
an allergic skin disease often related to asthma, food allergy, allergic
conjunctivitis, and AR29. In observational studies,
the relationship between AD and COVID-19 remained
murkier: some
studies30-32 suggested that AD was associated with
increased risk for COVID-19, while others suggested that it was
associated with reduced risk33-35 or had no
effect36. Cohort studies have shown a reduced risk of
SARS-CoV-2 infection in patients
with AD treated with Dupilumab35.
This may be attributable to the fact
that Dupilumab lowered the incidence of severe infections, such as
herpes simplex and skin infections37, and thus
SARS-CoV-2. In addition, Dupilumab was also found to reduce the risk of
SARS-CoV-2 infection in patients
with asthma38.
A meta-analysis concluded that asthma was not associated with higher
SARS-CoV-2 infection or a worse prognosis and that patients with asthma
had lower mortality than those without asthma39.
Previous MR analysis studies have also suggested that asthma was a
protective factor for SARS-CoV-2
infection and severe COVID-197,8. Although similar
results were obtained only in the multivariate MR analysis with AR and
AD as references, the two-sample MR analysis of asthma-severe COVID-19
in this study was negative. After comparing the differences between this
study and these two previous studies, three possible reasons for the
different results were found. First, limited by research time, the study
that suggested asthma was a protective factor for
SARS-CoV-2
infection8 used a relatively old COVID-19 database
(the COVID-19 Host Genetic Initiative GWAS meta-analyses round 4,
released on October 20, 2020), when the COVID-19 pandemic was just
beginning, and the amount of GWAS data for COVID-19 patients was far
from enough. Second, ”COVID-19 infection” and ” COVID-19
hospitalization” were chosen as the outcomes in these two MR studies,
instead of ”very severe respiratory confirmed COVID-19” as in our study.
Differences in the selection of outcomes may have contributed to the
differences in results. Thirdly, the choices of LD value in these two
studies were more liberal than that in our study, and both of them chose
r2<0.01. Our choice
(r2<0.001) was 10 times more
stringent. These factors are all
optional and acceptable. Given the positive result of multivariate MR
analysis after adjusting for AD and AR and the further analysis of
asthma subtypes, we still consider asthma a protective factor for severe
COVID-19.
Both mixed asthma and childhood asthma have causal protective effects
against severe COVID-19, with childhood asthma playing a major role. To
our knowledge, this study is the first to suggest that mixed asthma is a
protective factor against severe COVID-19. Mixed asthma was described in
the FinnGen database as the “combination of conditions listed in
predominantly allergic asthma and nonallergic asthma”. Conditions
listed in “predominantly allergic asthma” included allergic
(bronchitis, rhinitis with asthma), atopic asthma, extrinsic allergic
asthma, and hay fever with asthma. Symptoms of “nonallergic asthma”
included idiosyncratic asthma and intrinsic nonallergic asthma. We
hypothesized that the development of mixed asthma is involved in the
interaction of exogenous anaphylaxis and endogenous infection, leading
to a more active asthma-related immune response. However, the specific
pathophysiological reasons still need to be further explored.
Childhood asthma was considered a major protective factor against severe
COVID-19 in our study, and there have been many reports on childhood
asthma and severe COVID-19. In Spain, children were thought to usually
develop mild COVID-1940.
Clinical observations indicated that
allergies or asthma were not hazardous conditions in
pediatric patients with
COVID-1941. A meta-analysis of COVID-19 patients in
children and young people found that patients with asthma were less
likely to be admitted to critical care and less likely to
die42. Data from a pediatric referral hospital
indicated that the prevalence of asthma in pediatric patients with
COVID-19 was low, with varied clinical manifestations and laboratory
findings40. New confirmed cases of childhood asthma in
Japan dropped significantly after the COVID-19 pandemic began, and 15
months later they have not recovered43. The impact was
particularly strong for younger children. New diagnoses of atopic
dermatitis also fell slightly43. As mentioned above,
no significant decrease was shown in the incidence rates of allergic
diseases (asthma, AD, AR) in Korea27. However, data
from the nationally representative Korean Adolescent Risk Behavior
Survey presented that the prevalence of allergy among Korean adolescents
increased before 2019, but decreased significantly in
202044. Regardless of prior trends, the prevalence of
three allergic diseases, asthma, AD, and AR, all decreased in
adolescents in 202044. All of these studies showed an
association between COVID-19 and asthma in children.
Our study has several strengths. Firstly, large datasets covering
multidimensional phenotypes were used,
and the F-statistics were also large
enough to prevent any weak instrumental bias. Second, compared with
traditional observational studies, MR analysis is usually less affected
by confounding factors and reverse causality, leading to a higher level
of evidence. Third, the sample used was largely derived from populations
of European ancestry, which minimized stratification bias. In addition,
the pleiotropy that IVs do not have also illustrates the robustness of
this study. Our study also has certain limitations, such as uneven
weighting among phenotypes and a
relatively small number of cases in some phenotypes. Moreover, most of
the included populations were of European ancestry, which does not
represent the general population,
and verification of the results in
populations with different ancestries is required.
In summary, this study, based on the
population genetic variation model, pointed out the protective effect of
allergic diseases against severe COVID-19. More specifically, AD and
asthma (both mixed and childhood asthma) were protective, but childhood
asthma played a major role. This protective effect may come from the
persistent inflammatory response and ACE2. More research is still needed
to figure out why the protective effect is stronger in children than in
adults.