Running title: “Effect of severe asthma on COVID-19 disease
outcomes”
Keywords: asthma, biologics, virus, infections, asthma
treatment.
To the Editor,
Severe asthma (SA) is a chronic disease affecting around 3-8% of adult
asthma population in Europe, with the refractory form estimated to occur
in 0.1% of the general population (1,2). SA is characterized by
increased use of healthcare resources (i.e. emergency room/hospital
admissions, access to intensive care units (ICU), use of biologics) due
to exacerbations compared to the less severe form. In the current
SARS-CoV-2 pandemic, there is an ongoing debate on the role of asthma
and use of immunomodulating drugs, like corticosteroids and biologics,
on COVID-19 outcomes. According to available data on COVID-19
hospitalizations, asthma seems to play little role on the clinical
severity or access to health resources, unlike other chronic conditions
such as hypertension, obesity and chronic obstructive pulmonary disease
(3). However, to date, no information is available on the burden of SA
on COVID-19 severity and hospitalization rates.
A questionnaire was submitted to the Italian Registry of Severe Asthma
(IRSA) network (4), assessing the prevalence and clinical
characteristics of patients with SA who contracted COVID-19 during the
outbreak in Italy (February 24th - May
18th 2020), and 41 out of 78 centers distributed
evenly among different Italian regions participated to the survey
(Figure 1a).
Among the 558 subjects surveyed, 7 subjects contracted COVID-19 (1.25%
of the national sample), with an average age of 54.5 years: 5 isolated
at home/received home care (71.5%), while 2 subjects were admitted to
the hospital (28.5%), none required accessed to ICU and no deaths were
reported. All COVID-19 subjects with SA came from 2 regions of Northern
Italy (6 Lombardy, 1 Emilia-Romagna, 3.7% of the regional population),
all showing one or more comorbidities, and were treated with high-dose
inhaled corticosteroids plus long-acting beta-2 agonists (ICS-LABA) and
biologics (see Table 1).
We then compared our results with data provided by the Italian
Department for Civil Protection in the same time period from the
affected geographic areas (5), and we observed that the frequency of
COVID-19 among subjects referred to IRSA centers strongly correlated
with the prevalence of SARS-CoV-2 infection in the corresponding
province (Figure 1b). Furthermore, the hospitalization rate in
COVID-19-SA subjects was not significantly different from the general
population (24.1%, 23.6-24.6 95% C.I.; p=0.25, Chi-squared test).
Lastly, we could not observe a significantly increased COVID-19
frequency in subjects undergoing high-dose ICS-LABA and biologics
compared to SA treated with ICS-LABA alone (p=0.09, Fisher exact test).
These findings from the IRSA registry offer some insights on the
susceptibility to SARS-CoV-2 infection, access to healthcare resources
and mortality by SA patients.
Given the low prevalence of SA in Italy (2), we expected less
COVID-19-SA cases per region than what reported by the IRSA survey.
However, we observed that the geographic location of COVID-19-SA
patients mostly reflected the bimodal distribution of the COVID-19
outbreak in Italy, mainly clustered in Lombardy and neighboring regions,
where the highest cumulative COVID-19 cases were recorded
(>500/100000 cases per inhabitants) (5). In these areas,
the prevalence of positive cases by province also strongly correlated
with the frequency of COVID-19-SA patients observed in each IRSA center
(Figure 1b), suggesting that patients with SA most likely contract the
infection when high circulation of the virus within the area of
residence is present. The lack of positive cases reported in Southern
regions further proves this hypothesis, and demonstrates the efficacy of
the lockdown measures adopted to contain the further spread of the
virus.
Our results also suggest no increased risk of contracting COVID-19 in SA
treated with biologics compared to ICS-LABA alone. Although there is
currently no strong evidence that biologics used in asthma might affect
the risk of contracting COVID-19, new evidence suggests a protective
effect of inhaled corticosteroids against viral entry by ACE2 receptor
downregulation, that are usually prescribed at a high dose in SA (6),
thus a possible explanation to the lack of observed differences in our
cohort.
Despite the severity of asthma and reported comorbidities, no ICU
admissions were reported, and hospital admissions in COVID-19-SA
subjects did not differ from the median rate observed in the same
geographic areas (5). Furthermore, we could observe no difference in the
median monthly hospitalization rate of SA patients in 2019 compared to
2020 in Lombardy region where both hospital-admitted subjects reside
(0.97 vs 0.9%, IRSA data).
Our result is consistent with recent literature, showing that asthma in
Western countries was not associated with an increased hospitalization
rate and ICU admissions due to COVID-19 (3,8). It is still debated if a
protective effect of Th2-inflammation in a significant proportion of
asthma sufferers (7), or concomitant anti-inflammatory therapy could be
the reasons for such outcomes (6). However, if asthma patients with
COVID-19 require intubation, the duration of hospitalization was shown
to be longer than average (8).
As for the role of biologics in COVID-19 disease progression, we could
not observe an increase in hospital admissions in patients with SA
treated with biologics compared to the general population, with the
majority isolating at home and requiring no additional treatment.
Considering that, in areas with high prevalence of SARS-CoV-2 infection,
68.2% of SA subjects were treated with either omalizumab or
mepolizumab, our observations further prove the safety of biologics
during the COVID-19 pandemic.
Lastly, we did not observe any deaths in our cohort, but we speculate
that this outcome is most likely due to the small sample size and
younger average age. In fact, advanced age seems to be the most
determining risk factor on mortality due to COVID-19 compared to other
causes. (9)
Taken together, our results point at a neutral role of SA in the
COVID-19 disease course and hospital admissions. One major strengths of
our study is that, by using a fast and inexpensive tool, we could
outline the salient features of severe asthma and COVID-19 at a national
level, while the major weakness is the limited number of SA subjects
diagnosed with COVID-19, that could lead to sampling bias and low
accuracy. Further confirmation of these results with an increased sample
size is therefore warranted