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\begin{document}

\title{Angiotensin Converting Enzyme-2 (ACE2) Receptors, Asthma and Severe
COVID-19 Infection Risk}



\author[1]{Ayse Ozturk}%
\affil[1]{Koc University School of Medicine}%


\vspace{-1em}



  
  \date{May 26, 2024}


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\textbf{}To editor,

Asthma is one of the most common chronic respiratory diseases in the
world and it is possible that asthma-related factors may influence
susceptibility to coronavirus disease (COVID-19) or infection severity.
There is a great concern about the effect of asthma on COVID-19
morbidity: Centers for Disease Control and Prevention(CDC) stated that
people with moderate to severe asthma may have an increased risk for
COVID-19 and infection may lead to an asthma attack, pneumonia, or acute
respiratory disease. However, available data is limited and there is no
concrete evidence that asthma is a risk factor for COVID-19. In Zhang et
al. study including 140 community-infected COVID-19 patients, asthma or
other allergic diseases were not reported by any of the
patients\textsuperscript{1}. Although the prevalence of asthma in China
was 4.2\% and allergic rhinitis in Wuhan was \%9.7, allergy or asthma
was not detected as a risk factor for COVID-19 infection {[}1{]}. In
another article from Wuhan, Li et al. reported the prevalence of asthma
as 0.9\% in 548 patients with COVID-19 and the asthma rate did not
differ between severe and non-severe COVID-19 cases\textsuperscript{2}.

Angiotensin converting enzyme-2 (ACE2) receptors mediate the entry of
SARS-coronavirus 2 (SARS-CoV-2) into host cells and the virus uses the
transmembrane protease serine 2 (TMPRSS2) for S protein
priming\textsuperscript{3}. ACE2 receptors are expressed in the heart,
vessels, gut, lung, kidney, testis, and brain\textsuperscript{4} and
binding of SARS-CoV-2 to ACE2 receptors markedly down-regulates ACE2
receptors which have protective biological effects on human body. With
the loss of the protective effect of these receptors interstitial
fibrosis, endothelial dysfunction, enhanced inflammation, oxidative
stress and increased coagulation can be seen\textsuperscript{5}. It is
interesting to note that severity of the COVID-19 disease is associated
with several conditions which may have ACE2 deficiency such as older
age, male gender, hypertension, diabetes, or cardiovascular disease.

There may be a link between asthma and ACE2 deficiency and based on this
hypothesis Peters et al. investigated differences in ACE2 and TMPRSS2
gene expression in sputum cells of 330 asthma patients and 79 healthy
controls\textsuperscript{5}. Gene expression of ACE2 and TMPRSS2 was
similar in asthma and health. Among asthma patients, higher expressions
of ACE2 and TMPRSS2 were observed in males, African Americans, and
patients with diabetes mellitus. High expression of ACE2 in the lungs
facilitate the entry of corona virus into lungs and may result with
down-regulation of ACE2 receptors which make these subgroups more
susceptible to severe SARS-CoV-2 infection. Interestingly, use of
inhaled corticosteroids was associated with lower expression of ACE2 and
TMPRSS2 after adjustment for asthma severity.

This is an important study giving clues about possible factors
explaining the low prevalence of asthma among COVID-19 patients. Asthma
itself or the use of inhaled steroids may have protective effect against
SARS-CoV-2 infection. However, there are some limitations. ACE2
receptors are particularly expressed in type 2 pneumocytes which have an
effective role on triggering a cascade of inflammation in the lower
respiratory tract. Sputum may not reflect the amount of ACE2 receptors
in the lower respiratory tract including type 2 pneumocytes. Many of the
inhaler steroids have less peripheral airway deposition and so inhaler
steroids might not effect ACE2 expression of type 2 pneumocytes.
Although direct evidence regarding the role of ACE2 in chronic
obstructive pulmonary disease (COPD) and smokers is limited, studies
have shown that accumulation of inflammatory cells and the release of
proinflammatory cytokines in COPD were mediated by angiotensin II in
which ACE2 has an active role in degradation of angiotensin
II\textsuperscript{6}. There are also rat studies indicating that ACE2
deficiency may have a role in the pathogenesis and progression of COPD.
It is reasonable to infer that ACE2 deficiency in COPD may have a
negative effect on severity of SARS-CoV-2 infection like diabetes and
hypertension. Smoking status of the patients and asthma endotypes
(eosinophilic or neutrophilic, atopic, non-atopic) were not provided in
Peters et al study. ACE2 and TMPRSS2 expression in sputum may be
different in smokers, neutrophilic asthma, or asthma-COPD overlap (ACO)
subgroups and inhaled steroids may not influence ACE2 expression in
these subgroups.

Asymptomatic nasal carriage of COVID-19 is more common in children,
asthmatic children seems to have most likely asymptomatic COVID-19
infection .Therefore to understand the basic underlying mechanisms
related with chilhood asthma and mild COVID-19 infection may help to
understand the possible mechanistic links for adult asthma and severe
COVID-19 infection. Sajuthi et al. used nasal airway transcriptome and
network co-expression analysis to identify the cellular and
transcriptional factors in COVID-19 infectivity\textsuperscript{7}. They
used a children cohort including 695 subjects with asthma and healthy
controls between the ages of 8 and 21. They mainly focused on ACE2 and
TMPRSS2 expression. Intrestingly, 43\% of non-asthmatics in this study
were scored as T2-high like asthmatics based on their expression
profile. They found that interleukin (IL)-13 mediated T2 high
inflammation had a major role in ACE2 downregulation and TMPRSS2
upregulation. The results of this study can be interpreted as T2 rich
inflammation may have protective role against COVID-19 by causing ACE2
downregulation or exacerbates COVID-19 infection by causing TMPRSS2 over
expression. They showed that ACE2 was expressed in secretory cells and
ciliated cells while TMPRSS2 was expressed by all epithelial cell
types\textsuperscript{7}. Virus behavior may be different depending on
ACE2 and TMPRSS2 expression variations in different part of the airways
such as nasal and peripheral airways and TMPRSS2 may have more effective
role in peripheral airways compared to ACE2.

In conclusion, it is yet to be proved that asthma is a risk factor for
COVID-19 infection. Whether there is a link between asthma and COVID-19
infection remains to be determined. The heterogeneous nature of asthma
may cause interindividual variation in COVID-19 infection immunology.
More clinical studies focusing ACE2 and TMPRSS2 expression in central
and peripheral airways are warranted to understand the role of
individual factors such as atopy, obesity and smoking habit and
treatment related factors such as inhaled/systemic steroid use in
different asthma groups (mild/severe, T2-high and T2- low asthma) for
the risk of COVID-19 morbidity.

\textbf{References:}

\begin{enumerate}
\tightlist
\item
  Zhang JJ, Dong X, Cao YY, et al. Clinical characteristics of 140
  patients infected with SARS-CoV-2 in Wuhan, China {[}published online
  ahead of print, 2020 Feb 19{]}. Allergy. 2020;10.1111/all.14238.
  doi:10.1111/all.14238.
\item
  Li X, Xu S, Yu M, et al. Risk factors for severity and mortality in
  adult COVID-19 inpatients in Wuhan {[}published online ahead of print,
  2020 Apr 12{]}. J Allergy Clin Immunol. 2020;S0091-6749(20)30495-4.
  doi:10.1016/j.jaci.2020.04.006
\item
  Hoffmann M, Kleine-Weber H, Schroeder S, et al. SARS-CoV-2 Cell Entry
  Depends on ACE2 and TMPRSS2 and Is Blocked by a Clinically Proven
  Protease Inhibitor. Cell. 2020;181(2):271-280.e8.
  doi:10.1016/j.cell.2020.02.052.
\item
  Verdecchia P, Cavallini C, Spanevello A, Angeli F. The pivotal link
  between ACE2 deficiency and SARS-CoV-2 infection {[}published online
  ahead of print, 2020 Apr 20{]}. Eur J Intern Med.
  2020;S0953-6205(20)30151-5. doi:10.1016/j.ejim.2020.04.037.
\item
  Peters MC, Sajuthi S, Deford P, et al. COVID-19 Related Genes in
  Sputum Cells in Asthma: Relationship to Demographic Features and
  Corticosteroids {[}published online ahead of print, 2020 Apr 29{]}. Am
  J Respir Crit Care Med. 2020;10.1164/rccm.202003-0821OC.
  doi:10.1164/rccm.202003-0821OC.
\item
  Jia H. Pulmonary Angiotensin-Converting Enzyme 2 (ACE2) and
  Inflammatory Lung Disease. Shock. 2016;46(3):239-248.
  doi:10.1097/SHK.0000000000000633.
\item
  Sajuthi SP, DeFord P, Jackson ND, et al. Type 2 and interferon
  inflammation strongly regulate SARS-CoV-2 related gene expression in
  the airway epithelium. bioRxiv. 2020 doi: 10.1101/2020.04.09.034454
\end{enumerate}

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