To the Editor
Since the end of February 2020 Italy, first non- Asian Country, has
reported an ever increasing number of COronaVIrus Disease 19 (COVID-19)
patients, which has reached over 200,000 confirmed Severe Acute
Respiratory Syndrome-Coronavirus-2 (SARS-CoV-2) infected subjects and
resulted in more than 34000 deaths (data updated to June 19th, 20201).
Patients with asthma are potentially more severely affected by by
SARS-CoV-2 infection 2 and it is well established that
respiratory viral infections are associated with severe adverse outcomes
in patients with asthma, including increased risk of asthma exacerbation
episodes 3. Nonetheless, according to the
epidemiological studies published so far, chronic pulmonary diseases are
not amongst the most common clinical conditions in COVID-19 patients4
About 5-10% of entire asthma population, are severe asthmatics5 and one would expect increased vulnerability to
SARS-CoV-2 infection, but no data is so fare available ti confirm this
hypothesis.
We investigated the incidence of COVID-19, describing its clinical
course, in the population of the Severe Asthma Network in Italy (SANI),
one of the largest registry for severe asthma worldwide6, and in an additional Center (Azienda Ospedaliero
Univeristaria di Ferrara, Ferrara, Italy). All centers, have been
contacted and inquired to report confirmed (i.e. patients with positive
test result for the virus SARS-CoV-2 from analysis of nasopharyngeal or
oropharyngeal swab specimens) or highly suspect cases of COVID-19 (i.e.
patients with symptoms, laboratory findings and lung imaging typical of
COVID-19 but without access to nasopharyngeal or oropharyngeal swab
specimens because of clinical contingencies/emergency) among their
cohorts of severe asthma. Demographic and clinical data of the entire
cohort of severe asthmatics enrolled in the study and all reported cases
of confirmed or suspect cases of COVID-19, have been obtained from the
registry platform and collected from the additional Center. Additional
data about COVID-19 symptoms, treatment and clinical course have been
collected for all cases reported.
Ethical issues and statistical analysis are reported in the online
supplementary material.
Twenty-six (1.73%) out of 1504 severe asthmatics had confirmed (11 out
of 26) or highly suspect COVID-19 (15 out 26); eighteen (69.2%) were
females and mean age was 56.2 ± 10 years. The geographical distribution
of COVID-19 cases is presented in Figure 1.
Nine (34.6%) infected patients experienced worsening of asthma during
the COVID-19 symptomatic period; four of them needed a short course of
oral corticosteroids for controlling asthma exacerbation symptoms.
The most frequent COVID-19 symptoms reported were fever (100% of
patients), malaise (84.6%), cough (80.8%), dyspnea (80.8%), headache
(42.3%) and loss of smell (42.3%). Four patients (15.3%) have been
hospitalized, one of which in intensive care unit; among hospitalized
patients, two (7.7%) died for COVID-19 interstitial pneumonia. No
deaths have been reported among the non-hospitalized patients.
Severe asthmatics affected by COVID-19, had a significantly higher
prevalence of non-insulin-dependent diabetes mellitus (NIDDM) compared
to non-infected severe asthma patients (15.4% vs 3.8%, p=0.002; odds
ratio: 4.7). No difference was found in other comorbidities (including
rhinitis, chronic rhinosinusitis with or without nasal polyps,
bronchiectasis, obesity, gastroesophageal reflux, arterial hypertension,
cardiovascular diseases).
Twenty-one patients with COVID-19 were on biological treatments: 15
(71%) were on anti-IL-5 or anti-IL5R agents (Mepolizumab n= 13;
Benralizumab n=2 - counting for the 2.9% of all severe asthmatics
treated with anti-IL5 in our study population) and 6 (29%) were on anti
IgE (Omalizumab - 1.3% of all severe asthmatics treated with omalizumab
in our study population).
Table I summarizes demographic and clinical characteristics of the 26
COVID-19 patients.
In conclusion, in our large cohort of severe asthmatics, COVID-19 was
infrequent, not supporting the concept of asthma as a particularly
susceptible condition to SARS-COV2 infection 2. This
is in line with the first published large epidemiological data on
COVID-19 patients, in which asthma is under-reported as comorbidity4. The COVID-19 related mortality rate in our cohort
of patients was 7.7%, lower than the COVID-19 mortality rate in the
general population (14.5% in Italy 1). These findings
suggest that severe asthmatics are not at high risk of the SARS-CoV-2
infection and of severe forms of COVID-19. There are potentially
different reasons for this. Self-containment is the first, because of
the awareness of virus infections acting as a trigger for exacerbations,
and therefore they could have acted with greater caution, scrupulously
respecting social distancing, lockdown and hygiene rules of prevention,
and being more careful in regularly taking asthma medications.
Another possible explanation stands in the intrinsic features of type-2
inflammation, that characterizes a great proportion of severe
asthmatics. Respiratory allergies and controlled allergen exposures are
associated with significant reduction in angiotensin-converting enzyme 2
(ACE2) expression 7, the cellular receptor for
SARS-CoV-2. Interestingly, ACE2 and Transmembrane Serine Protease 2
(TMPRSS2) (another protein mediating SARS-CoV-2 cell entry) have been
found highly expressed in asthmatics with concomitant NIDDM8, the only comorbidity that was more frequent
reported in our COVID-19 severe asthmatics.
The third possible explanation refers to the possibility that inhaled
corticosteroids (ICS) might prevent or mitigate the development of
Coronaviruses infections. By definition, patients with severe asthma are
treated with high doses of ICS 5 and this may have had
a protective effect for SARS-CoV-2 infection.
Noteworthy, among the patients of our case-series of severe asthmatics
with COVID-19, the proportion of those treated anti-IL5 biologics was
higher (71%) compared to the number of patients treated with anti-IgE
(29%). Although the number of cases is too small to draw any
conclusion, it is tempting to speculate that different biological
treatments can have specific and different impact on antiviral immune
response. In addition we may speculate of the consequence of blood
eosinophils reduction: eosinopenia has been reported in 52-90% of
COVID-19 patients worldwide and it has been suggested as a risk factor
for more severe COVID-19 9.
In conclusion, in our large cohort of severe asthmatics only a small
minority experienced symptoms consistent with COVID-19, and these
patients had peculiar clinical features including high prevalence of
NIDDM as comorbidity. Further real-life registry-based studies are
needed to confirm our findings and to extend the evidence that severe
asthmatics are at low risk of developing COVID-19.