Challenges in asthma management during COVID-19 pandemics
The recent outbreak of severe acute respiratory syndrome coronavirus 2
(SARS-CoV-2) causing Coronavirus Disease 2019 (COVID-19) pandemics led
to the worldwide emergency affecting the life of more than 21 million
people (status for 14.08.2020). It also raised a vigorous discussion in
the research community, whether or not asthma should be classified as a
COVID-19 risk factor. Reports regarding asthma prevalence among COVID-19
patients are inconsistent, varying from 0.9% in Wuhan to 17% in the
US. 185 Wang et al. exclude asthma as a factor
influencing COVID-19. Their statement is supported by the data from
Avdeev et al. and Zhang et al. 186,187 Both groups did
not observe the increase in the prevalence of bronchial asthma or COPD
among patients with COVID-19. 186,187 Additionally,
experts from 43 countries around the world in ARIA-EAACI statement185, as well as a recent publication from Carli et
al.188 rule out asthma as a risk factor for COVID-19,
while another group advocates asthma as a COVID-19 risk factor based on
the impaired antiviral responses that may predispose asthmatic patients
to severe COVID-19 manifestations. 189 Indeed, the
United Kingdom reported increased asthma-related deaths in non-COVID-19
patients.190 The US Center for Disease Control and
Prevention proposed that moderate to severe asthma should be considered
a risk for severe COVID-19 manifestations.185Additionally, a recent study from Zhu et al. (n=492 768) demonstrated
inflammatory phenotype of underlying asthma as a crucial factor for
COVID-19 risk assessment. They showed, that nonallergic, but not
allergic asthma predisposes patients to COVID-19. Due to the reported
discrepancies, available data should be interpreted with
caution.191
Data are still unclear as the COVID-19 population included in the
studies is skewed towards older and hospitalized patients with
predisposing comorbidities (such as hypertension, obesity, or diabetes)
which are strong confounders.185,186 As gender,
smoking status, ethnicity, lifestyle and genetic background can
influence COVID-19 outcomes, these factors should be carefully
investigated. 185,192 Age seems especially
significant, as childhood and adolescent asthma does not seem to be a
hazard for COVID-19. 192 This may be related to
reduced prevalence of comorbidities, lack of smoking, or boosted immune
system due to recent vaccinations.192
Allergic responses accompanying asthma are hypothesized to play a
protective role in the course of COVID-19. Eosinopenia (decreased
frequencies of eosinophils in the blood) is a biomarker of severity and
poor prognosis for COVID-19 patients.192 Eosinophils
respond to viral infections by releasing cytotoxic proteins, reactive
oxygen species, and type 1 cytokines.192 Therefore,
they play a supportive role in fighting the infection. Allergic patients
present eosinophilia (increased frequencies of eosinophils in the blood)
and could have an advantage for the eosinophil-dependent antiviral
responses.192 Notably, in the cohort from Licari et
al. allergic children had significantly higher frequencies of
eosinophils in the blood, when compared to COVID-19 pediatric
patients.192
Receptor ACE2 and serine protease TMPRSS2 mediates SARS-CoV-2 entry into
host cells.193-195 CD147, CD26, ANPEP, ENPEP, or
DC-SIGN are other receptors, proven or potentially involved in COVID-19
pathogenesis.193 Radzikowska, Ding et al. demonstrated
that ACE2 and TMPRSS2 are expressed only in the epithelial tissues,
whereas CD147 and its interaction partners are present in both –
epithelial tissues and immune cells. 196 The
expression of several SARS-CoV-2 receptors seems to be different in
asthma patients (increased: TMPRSS2 , CD44 , ITGA6 ,NFATC2 , NME1 , APOD ; decreased: ACE2 ,ACE , MCT4 , APH1A , S100A9 , NOD2 ).
These finding were partially confirmed by
others.185,197 There is growing evidence that allergic
type 2 inflammation (mainly IL-13) decreases ACE2 and increase TMPRSS2
expression.185,197 Additionally, ACE2 is an
interferon-induced gene.197 Impaired/delayed
interferon responses observed in asthma patients, usually a foe, may
play a protective role during SARS-CoV-2 infection and result in a
subsequent decrease of an ACE2. 197 Carli et al.
suggested that the altered interferon responses and the type 2 immunity
signature in asthmatic patients downregulates the late phase hyper
inflammation and consequently decrease tissue damage in the lungs which
might be beneficial in allergic asthma during
COVID-19.188
Asthma management in the times of COVID-19 pandemics presented a
challenge due to the overlap of the respiratory symptoms induced by
asthma or by SARS-CoV-2 and by reduced face-to-face appointments and
risky pulmonary function testing generating aerosols (Figure
4).185,190,198-202 If possible, a video examination
and attentive observation of the patient may help in proper
diagnosis.190,203 Fever, persistent dry cough,
flu-like symptoms, and lack of wheeze can indicate COVID-19 over asthma
exacerbation.190 Severe asthma exacerbation leads to
the hospitalization, which exposes asthmatics to unnecessary risk of
being infected with SARS-CoV-2. 192 Steroid therapy in
asthmatic patients in times of COVID-19 pandemics should be continued as
clinically indicated.186,189,190,197,200 Additionally,
ICS use can be beneficial during COVID-19 as it restores the impaired
antiviral responses in asthma, subsequently leading to less severe
manifestations.189 ICS suppresses coronavirus
replication and decreases the ACE2/TMPRSS2
expression.197 However, ICS treatment can cause
SARS-CoV-2 nebulization and its spread to the lower airways and
surrounding surfaces.192 Therefore the use of a spacer
is encouraged.192 On the other hand, the use of OCS
was linked with a risk of severe COVID-19 manifestations (including
death).185 If good asthma control in patients cannot
be maintained, the introduction of azithromycin prophylaxis can be
considered. 189 Azithromycin reduces asthma
exacerbations in patients, probably by augmenting IFN-β and IFN-λ
responses, a subsequent decrease in viral replication, and reduced
inflammatory response. 189,197 Azithromycin interferes
with the CD147 receptor and decrease its downstream signals after viral
(rhinovirus) infections.197 COVID-19 in high endemic
HDM environment may affect antiviral immune responses. In a study by
Akbarshahi et al. the authors hypothesized that HDM may adversely affect
viral stimulus-induced antiviral interferon response. To test the
hypothesis, they investigated the effects of HDM exposure in both human
bronchial epithelial cells and a mouse model of asthma exacerbation.
They observed that toll-like receptor-3 is the main target involved in
reducing the antiviral response by HDM.204
Lommatzsch et al. reported the safety of Omalizumab in an 52-year-old
severe allergic asthmatic patient with SARS-CoV-2
infection.205 During the SARS-CoV-2 infection, the
patient did not report any asthma exacerbation and maintained proper
asthma control. A mild manifestation of COVID-19 observed in this study,
was related to either i) allergic endotype of underlying asthma, ii)
ongoing omalizumab treatment, or iii) both.205However, this observation needs further confirmation in the bigger
patients’ population. Furthermore, Omalizumab decreases the duration of
rhinovirus infections and virus-related
exacerbations.189,197 It can be hypothesized that
anti-IgE therapy protects also during SARS-CoV-2 infection. Experts
suggest that immunomodulatory biological treatment strategies should
continue in SARS-CoV-2-negative asthmatic individuals in times of
pandemics.185,192,197 However, due to possible
immunosuppressive effects, they should be suspended in patients which
developed COVID-19, until disease resolution.185,192
In summary, available data suggest, asthma is not a risk factor for the
development of severe forms of COVID-19. Yet, COVID-19 can be a severe
disease in already damaged lungs of chronic asthma, particularly, ACOS
and COPD patients. More evidence is needed to fully understand the
impact of asthma and asthma therapies on the prevalence and the course
of COVID-19. More data are required from controlled clinical trials.
Meanwhile, considering the current emergency, asthmatic patients should
avoid SARS-CoV-2 infection and should receive the SARS-CoV-2 vaccine
with priority, as recommended for the influenza and the pneumococcal
vaccine. In the present situation, prevention and proper asthma control,
including continuation of the background controller treatment, is the
most efficacious way to assure the safety of asthma
patients.206