Main text:
“Misfortune might be a blessing in disguise.”
~ Tao-Te-Ching (Book of the Way) by Lao-Tzu, 350 B.C.E
Since its first report in Wuhan, China, in December 2019, the novel
pandemic COVID-19 caused by the severe acute respiratory syndrome
coronavirus 2 (SARS-CoV2 virus), has rampaged throughout the world.
Approximately 80% of the COVID-19 patients manifest with only mild
upper respiratory symptoms, 10-15% develop bilateral infiltrated
pneumonia, and 5 to 10% of the severe cases progress to develop Acute
Respiratory Disease Syndrome (ARDS) and multiple organs failure by the
‘cytokine releasing storm’ (CRS).1 Older age, male
gender, chronic cardiovascular diseases and metabolic syndrome, such as
obesity, hyperlipidemia, and diabetes are among the risk factors
associated with severe COVID-19.2 Asthmatics are known
to be more frequently infected and at a greater risk of developing more
severe outcomes with respiratory/common cold viral infections,
particularly in those with poorly controlled asthma.3Moreover, there is a deficiency and delay of the production of type I
and type III interferons in the lung cells of asthmatic patients,
potentially more favorable for SARS-CoV2 infection that depends on a
hampered innate anti-virus immune response in the respiratory
tract.3 However, recent reports have accumulated
evidences that the prevalence of allergic diseases and asthma in
patients with COVID-19 is lower than expected and underrepresented among
other comorbidities and risk factors of the severe form of
COVID-19.4-6 Li et al.5 reported
that the prevalence of asthma in patients with severe COVID-19 (n= 269,
49.1% of total 548 patients) was 0.9%, markedly lower than that in the
adult population of Wuhan. Moreover, none of the children (below 12
years of age) infected with SARS-CoV2 at the Wuhan Children’s Hospital
had underlying asthma.6 These findings on the low
prevalence of asthma may be confounded by a sampling bias (all
hospitalized patients) in the reported cases, underdiagnoses, or lack of
recognition of asthma in those with COVID-19. In fact, lack of surveys
of the confirmed COVID-19 cases in the general population is a major
limiting factor in answering the question whether chronic respiratory
diseases, such as asthma, are key risk factors of SARS-CoV2
infection.4
However, the interesting question to ask is why asthmatic patients did
not have an increased exacerbation of asthma or became more prone to the
severe form of COVID-19 after being infected with SARS-CoV2? We,
therefore, propose the following plausible mechanisms in asthmatic
patients that may have effects in the determination of the
susceptibility and severity regarding SARS-CoV2 infection. Firstly,
coronavirus recognition and infection is dependent on the cellular
receptors, the angiotensin converting enzyme 2 (ACE2) for ducking spike
protein of SARS-Cov2, and transmembrane protease serine 2 (TMPRSS2) to
cleave the ducked spike protein for virus entry by membrane
fusion.7 Lung cells that co-express these two
molecules include nasal goblet secretory cells, bronchial transient
secretory cells, and alveolar type II pneumocytes.8The gene expression levels of ACE2 and TMPRSS2 are influenced by the
genetic variants of the host, microbial infections, and induced by
innate immune response, such as the production of interferons and
mucins.8 It has been found that SARS-COv2 virus can
hijack and enhance this innate anti-virus defense interferon production
to induce ACE2, a human interferon stimulated gene (ISG), expression in
the other uninfected cells, and promote its potential transmission and
spread.8 While in asthma patients, the expression of
these two molecules in the respiratory epithelial cells for SARS-CoV2
infection are determined by the age, gender, comorbidity and type 2
allergic inflammation. Jackson et al. found asthma and respiratory
allergy are associated with reduced ACE2 expression in airway cells
based on their patient cohorts.9 Moreover, ACE2
expression in the lower airway epithelium was lower in the
post–allergen challenge samples, and its levels of expression was also
significantly inversely associated with type 2 immune inflammation
biomarkers. 9 In contrast, in an analysis of the nasal
airway epithelial transcriptome in 695 children, Sajuthi et
al.10 demonstrated that TMPRSS2 is part of a mucus
secretory network, highly upregulated by type 2 allergic inflammation
mainly by interleukin-13. Peters et al.11 from the
same group, found the gene expression for ACE2 and TMPRSS2 in the cells
obtained from induced sputum did not differ between healthy and
asthmatics. Instead, a higher expression of ACE2 and TMPRSS2 in males,
African Americans, and patients with diabetes mellitus provides
rationale for monitoring these asthmatic subgroups for poor COVID19
outcomes.11 Therefore, these reports did not describe
convincing information as to whether the asthmatic patients had a lower
expression of ACE2 and serine protease TMPRSS2 for SARS-CoV2 based on
their allergic status and/or chronic lung inflammation. Particularly,
these studies lacked information on the effect of SARS- CoV-2- specific
analysis and observations in asthmatic patients to be able to reach a
conclusion in the real world.
Secondly, viral load and immune response of the host determines the
final outcome and/or the severity of ARDS and multiple organ failures in
COVID-19 patients. At the initial phase, antivirus innate immune
response determine the clearance of virus by the production of Type
I/III interferons of infected cells. Lack of or lowered production of
IFNα2 and IFNλ, and high viral loads are frequently found in the severe
cases that deteriorated into needing ICU care.12 At
the second phase of COVID-19 infection, aberrant host immune response by
infected macrophages that lead to cytokines releasing storm, and T
lymphocytes depletion due to the prolonged viral infection are the two
major determining factors for a final clinical
outcome.12 For asthmatic patients, the innate immune
response to COVID-19 infection may be impaired due to lower levels of
IFNγ in their bronchial epithelial cells, but it may also turn into
favor for reducing ACE2 expression, which is depended on IFNγ
production.8 In addition to IFNs, there are other
molecules of innate immunity in the respiratory tract that may also have
anti-viral functions, such as mannose binding lectin (MBL), and
surfactant protein A (SP-A) and D (SP-D) that are produced by alveolar
type 2 cells in the lung, which are also the largely infected by SARS
coronavirus. These molecules, MBL and SP-D, found in higher
concentrations in the Broncho-alveolar lavage fluids (BALF) of patients
with asthma and respiratory allergy and are increased due to chronic
inflammation, have been identified to bind spike protein of SARS
coronavirus, and inhibit its binding to ACE2 cellular receptor, and
thereby able to protect the alveolar macrophages from virus-induced
activation.13, 14
Recently, it is found that long-term boosting of the innate immune
responses, also termed ‘trained immunity’, by prior microbial infection
or certain live vaccines, induces heterologous protection against
infections, through epigenetic, transcriptional and functional
reprogramming of innate immune cells.15 Experimental
studies have demonstrated that alveolar or lung macrophages can also
undergo long-term reprogramming after infections. For example, gamma
herpes virus infection can protect against an allergic response in
experimental asthma,16 while adenovirus
infection-induced remodeling in alveolar macrophages and subsequently
induced more pronounced anti-bacterial immunity.17This trained immunity in the myeloid cells and alveolar macrophages of
asthmatics may provide anti-viral immunity in specific organs such as
the lungs. Although this hypothesis has not been validated in patients
with COVID-19, clinical trials to booster trained innate immunity by BCG
vaccination to protect against COVID-19 have been initiated in several
countries.18
Finally, we highlight that therapeutic medications and biologics used
for asthma control may have some beneficial pharmacological effects in
COVID-19 infections. From in-vitro models, inhaled
corticosteroids alone or in combination with bronchodilators have been
shown to suppress coronavirus replication and cytokine
production.19 Asthmatic patients using inhaled
corticosteroids (ICS) demonstrated lower expression of ACE2 and TMPRSS2
in their bronchial epithelial cells.11 There is a
clinical report of the improvement in three COVID-19 patients after
using inhaled ciclesonide, although this study did not have proper
controls.20 Before the outbreak of COVID-19, clinical
observation in children with severe asthma who received anti-IgE
monoclonal antibody (omalizumab) have shown decreased duration of human
rhinovirus (HRV) infections, viral shedding, and risk of HRV-related
illnesses compared with guideline-driven care alone.21In vitro, omalizumab attenuated plasmacytoid dendritic cell (pDC) FcεRIα
protein expression while simultaneously augmenting pDC IFN-α responses
to HRV and influenza virus.22 Together, these findings
provide direct evidence that blocking IgE decreases susceptibility to
respiratory viral illnesses through enhanced IFN-α responses in pDCs.
Whether this anti-virus effect by anti-IgE treatment also includes
infection with coronavirus and SARS-CoV2 is an open question that
remains to be verified. More interestingly, azithromycin combined with
hydroxychloroquine in an open-label non-randomized clinical trial for
COVID-19 patients, has significant decreased the viral load after six
days of treatment compared to untreated controls.23Azithromycin has been demonstrated to reduce the frequency of asthma
exacerbation and improve the quality of life of asthmatic adults and
preschool children with asthma that was not adequately controlled on
standard inhaler therapy.24 Although the mechanisms of
this anti-inflammatory effect in asthma is still not well defined, some
studies presented a reduction of IL-6 levels after azithromycin
treatment.25 Moreover, a relevant study from Gielen
and co-workers demonstrated that azithromycin augments IFN-β and IFN-λ
production and decreasing rhinovirus replication and release from
rhinovirus-infected human bronchial epithelial cells in
vitro.26 Hence, it is suggested that azithromycin may
have protective effects in reducing SARS-CoV-2 invasion by interfering
with ligand/CD147 receptor interactions, a novel SARS-CoV2 cellular
receptors beside ACE2, and decreasing the expression of some
metalloproteinase (downstream to CD147) in primary human bronchial
epithelial infected with rhinovirus.27 However,
controlled clinical trials using azithromycin to treat patients with
COVID-19 (not involving asthmatic subjects) are now registered in
several countries with results still pending.
In summary, we have seen a new zoonotic coronavirus, SARS-CoV2,
infection that has had a devastating effect on the host immunity via the
inhibition of interferons leading to aberrant innate immune response,
macrophages inflammation in cytokine releasing storm, and exhaustion of
the cellular immunity of T lymphocytes.28 In contrast,
due to chronic and sustained type 2 immune inflammation in the lungs of
asthmatic patients, or fortunately by the medications they use for
asthma control, it seems asthma may not be a major confounding disease
in COVID-19 infection, and this unexpected phenomenon may throw a new
light in finding therapies or preventative strategies for SARS-CoV2
(Figure 1 ). We still need a more comprehensive and in-depth
immune analysis of SARS-CoV2 infection in the coming days to explore
this hypothesis. However, all standard asthma therapies, whether inhaled
steroids, combination of inhaled steroid plus long acting bronchodilator
therapies, or monoclonal antibodies like omalizumab and azithromycin,
should be continued to be used to optimize asthma control as recommended
by all medical societies, for they can not only substantially reduce the
risk of asthma exacerbation, but also will reduce risks and severe
outcomes of COVID-19.