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Asthma in COVID-19 Hospitalizations: An Overestimated Risk Factor?

Richard Broadhurst1*, Ryan Peterson2*, Juan P. Wisnivesky3‡, Alex Federman3, Shanta M.

Zimmer4, Sunita Sharma5, Michael Wechsler4,6, Fernando Holguin1

1Anschutz Medical Campus, University of Colorado at Denver, Aurora, Colorado; 2Department

of Biostatistics and Informatics, 4Department of Medicine, 5Department of Pulmonary, Critical

Care, and Sleep Medicine, University of Colorado, Denver, Colorado; 3Icahn School of Medicine

at Mount Sinai, New York, New York; 6National Jewish Health, Denver, CO

*The first and second author contributed equally to the manuscript.

‡ JPW is Associate Editor of AnnalsATS. His participation complies with American Thoracic

Society requirements for recusal from review and decisions for authored works.

Corresponding Author:

Fernando Holguin MD MPH

Email: Fernando.holguin@cuanschutz.edu

This article is open access and distributed under the terms of the Creative Commons Attribution

Non-Commercial No Derivatives License 4.0 (http://creativecommons.org/licenses/by-nc-

nd/4.0/). For commercial usage and reprints please contact Diane Gern (dgern@thoracic.org).

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To the Editor:

As of July 24th, 2020, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which

causes novel coronavirus disease 19 (COVID-19), has caused over 15,000,000 confirmed cases

and over 600,000 deaths globally.1 Risk factors for severe illness such as obesity, hypertension,

and diabetes have been described.2 According to the Centers for Disease Control (CDC),

individuals with asthma are also at higher risk for hospitalization and other severe outcomes

from COVID-193; however, the low numbers of asthmatics among hospitalized patients across

many international available studies challenges this assumption. In this study, we compared the

asthma prevalence among patients hospitalized for COVID-19 reported in 15 studies to that of

the corresponding population asthma prevalence and to the 4-year average asthma prevalence

in influenza hospitalizations in the United States. Further, using a cross sectional analysis of 436

COVID-19 patients admitted to the University of Colorado Hospital, we evaluated the likelihood

of intubation in asthmatics compared to non-asthmatics.

Methods and Results

We performed a focused literature review of the English literature to identify studies reporting

asthma prevalence among patients hospitalized for COVID-19 infection and published prior to

May 7, 2020, identified in PubMed, EMBASE, Cochrane, Medline, and CDC’s Mortality Morbidity

Weekly Review (MMWR). Unpublished literature was not considered. Review included studies

published in English that reported COVID-19 hospitalizations with reported asthma prevalence.

asthma or chronic respiratory disease prevalence (not COPD alone). Three independent

reviewers agreed upon 11 studies to be included initially; an additional 4 studies were

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subsequently included after the review dates mentioned above. (Figure 1). The search criteria

identified 686 unique studies. Duplicates were removed, leaving 670 unique articles. After the

above criteria were applied, 45 articles were assessed with full text review. Finally, 15 studies

were included in our analysis. We used the Clopper-Pearson method to create 95% confidence

intervals for asthma prevalence within each study (Figure 1). Additionally, using local data from

patients in our hospital (Table 1), we performed a multivariable logistic regression model using

multiple imputation to determine the effect of asthma status on intubation status after

controlling for age, sex, and body mass index.

Based on Figure 2, the proportion of asthmatics among hospitalized patients with

COVID-19 is relatively similar to that each study site’s population asthma prevalence. This

finding is in stark contrast to influenza, in which asthmatics make up more than 20% of those

hospitalized in the United States. Using data from our hospital, we observed that among

COVID-19 patients, those with asthma (12% prevalence), identified using ICD 10 code - J45, do

not seem to be more likely than non-asthmatics to be intubated (odds ratio: 0.69 (95% CI: [0.33,

1.45]), after adjusting for age, sex, and BMI.

Discussion

Our findings suggest that asthma prevalence among those hospitalized with COVID-19 appears

to be similar to population asthma prevalence and significantly lower than asthma prevalence

among patients hospitalized for influenza. Asthma also does not appear to be an independent

risk factor for intubation among hospitalized COVID-19 patients, even after adjusting for BMI

and age, which are well-known risk factors for severity.

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Seasonal coronaviruses typically do not contribute significantly to hospitalizations due

to asthma exacerbations since they primarily cause upper respiratory infections.4 In the case of

SARS-CoV (not COVID-19), asthmatics did not seem to be disproportionately affected, although

minimal data is available to make this comparison.5,6 In MERS, asthma patients may be at

higher risk, although again data are sparse.5

During the 2019-2020 influenza season, 24.1% of people hospitalized with influenza had

asthma, which is slightly higher than the 4-year 21% average from 2016-2020; however, this is

considerably higher than the pooled prevalence estimate across studies the 15 COVID-19

studies (6.8% (95% CI: [3.7, 10.7]) shown in Figure 2 .7 Despite early concern about

disproportionately high morbidity and mortality for those with asthma8, data presented here

and elsewhere show minimal evidence of a clinically significant relationship.9,10

Data from our hospital does not show a significant association between asthma

diagnosis and greater intubation odds among patients with COVID-19, even after adjusting for

BMI and age, which are well-known risk factors for severity, and were significantly associated

with intubation in our model.

One possible explanation as to why COVID-19 is not associated with greater

hospitalization rates among asthmatics may depend on the distribution of the ACE2 receptor in

the respiratory airway epithelium. It has been suggested that diabetes mellitus and

hypertension may increase ACE2 expression, while inhaled corticosteroid (ICS) use may

decrease ACE2 expression, hence leading to more difficulty with viral entry.11,12 Additionally,

asthma patients in general, and particularly those with a predominantly allergic phenotype,

may have significantly lower expression of ACE2.12 While the contribution of ACE2 receptor

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expression levels to overall COVID-19 susceptibility and disease severity is still unclear, it is

certainly worth further investigation. Unfortunately, we do not have ICS data available on

patients in our review or in our hospital to further elucidate possible benefit of these

medications as has been suggested.13 In contrast to asthma, having COPD increases the risk for

severe COVID-19 among hospitalized patients.14 This comorbidity is associated with increased

ACE2 expression in the lung tissue and small airways.15

Given the variable prevalence of asthma among hospitalized COVID-19 populations

across these studies, it is possible that reporting of comorbidities was done inconsistently

across different studies, particularly since authors did not describe how asthma or chronic

respiratory disease diagnoses were gathered in each of these studies. Like asthma, studies

have reported lower than population average COPD prevalence rates, which is in contrast to

the higher than expected rates of hypertension and diabetes mellitus among hospitalized

patients, which are comorbidities known to be associated with severe COVID-19.

Finally, we acknowledge that our findings may result from insufficient sample size, and

more data investigating asthma and intubation risk would be beneficial.

While there is variable asthma prevalence among COVID-19 published studies, it

appears similar to population prevalence, and certainly much lower than what would be

expected during seasonal flu. The results of this study suggest that asthma does not appear to

be a significant risk factor for developing severe COVID-19 requiring hospitalization or

intubation.

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Table 1. Sample population characteristics of patients with and without asthma among covid-

related admissions at University of Colorado.

No Asthma Asthma Total

(N=383) (N=53) (N=436) p value
88% 12%
Age (N = 435) 0.209
Mean (SD) 55.1 (16.7) 52.0 (18.1) 54.7 (16.9)
Range 19 - 100 21 - 92 19 - 100
Sex (N = 434) 0.002
Male 221 (57.9%) 18 (34.6%) 239 (55.1%)
Female 161 (42.1%) 34 (65.4%) 195 (44.9%)
BMI (N = 351) < 0.001
Mean (SD) 30.8 (7.2) 35.7 (12.3) 31.4 (8.2)
Range 15.0 - 66.2 17.8 - 82.7 15.0 - 82.7
Intubation Status (N = 338) 0.461
No 196 (66.4%) 31 (72.1%) 227 (67.2%)
Yes 99 (33.6%) 12 (27.9%) 111 (32.8%)
Sent to ICU (N = 351) 0.424
No 183 (59.6%) 29 (65.9%) 212 (60.4%)
Yes 124 (40.4%) 15 (34.1%) 139 (39.6%)

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FIGURES

Figure 1. PRISMA diagram detailing focused review of the literature and excluded studies.

Initial number of studies identified after focused review was 11. Additional 4 studies were

added after initial review.

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Figure 2. Comparing the prevalence of asthma in a series of COVID-19 studies compared to

population level prevalence. Grey line corresponds to the 4-year average US asthma prevalence

within flu hospitalizations (CDC FluView Data).7 Full study list provided in Review References

below. *Overall (or “pooled”) prevalence (6.8 (95% CI: [3.7, 10.7]) and associated confidence

interval assumes random study-level effects.

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References

1. COVID-19 United States Cases by County. Johns Hopkins Coronavirus Resource Center.
Accessed May 15, 2020. https://coronavirus.jhu.edu/us-map
2. Richardson S, Hirsch JS, Narasimhan M, et al. Presenting Characteristics, Comorbidities, and
Outcomes Among 5700 Patients Hospitalized With COVID-19 in the New York City Area.
JAMA. Published online April 22, 2020. doi:10.1001/jama.2020.6775
3. CDC. Coronavirus Disease 2019 (COVID-19). Centers for Disease Control and Prevention.
Published February 11, 2020. Accessed May 8, 2020.
https://www.cdc.gov/coronavirus/2019-ncov/need-extra-precautions/asthma.html
4. Jartti T, Bønnelykke K, Elenius V, Feleszko W. Role of viruses in asthma. Semin
Immunopathol. 2020;42(1):61-74. doi:10.1007/s00281-020-00781-5
5. Yin Y, Wunderink RG. MERS, SARS and other coronaviruses as causes of pneumonia. Respirol
Carlton Vic. 2018;23(2):130-137. doi:10.1111/resp.13196
6. Lau AC-W, So LK-Y, Miu FP-L, et al. Outcome of coronavirus-associated severe acute
respiratory syndrome using a standard treatment protocol. Respirology. 2004;9(2):173-183.
doi:10.1111/j.1440-1843.2004.00588.x
7. Laboratory-Confirmed Influenza Hospitalizations. Accessed May 7, 2020.
https://gis.cdc.gov/grasp/fluview/FluHospChars.html
8. Johnston SL. Asthma and COVID-19: is asthma a risk factor for severe outcomes? Allergy.
n/a(n/a). doi:10.1111/all.14348
9. Razzaghi H, Wang Y, Lu H, et al. Estimated County-Level Prevalence of Selected Underlying
Medical Conditions Associated with Increased Risk for Severe COVID-19 Illness — United
States, 2018. MMWR Morb Mortal Wkly Rep. 2020;69(29):945-950.
doi:10.15585/mmwr.mm6929a1
10. Zhu Z, Hasegawa K, Ma B, Fujiogi M, Camargo CA, Liang L. Association of asthma and its
genetic predisposition with the risk of severe COVID-19. J Allergy Clin Immunol. Published
online June 2020:S009167492030806X. doi:10.1016/j.jaci.2020.06.001
11. Peters MC, Sajuthi S, Deford P, et al. COVID-19 Related Genes in Sputum Cells in Asthma:
Relationship to Demographic Features and Corticosteroids. Am J Respir Crit Care Med.
Published online April 29, 2020. doi:10.1164/rccm.202003-0821OC
12. Jackson DJ, Busse WW, Bacharier LB, et al. Association of respiratory allergy, asthma, and
expression of the SARS-CoV-2 receptor ACE2. J Allergy Clin Immunol. Published online April
22, 2020. doi:10.1016/j.jaci.2020.04.009
13. Halpin DMG, Faner R, Sibila O, Badia JR, Agusti A. Do chronic respiratory diseases or their
treatment affect the risk of SARS-CoV-2 infection? Lancet Respir Med. 2020;8(5):436-438.
doi:10.1016/S2213-2600(20)30167-3

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14. Guan W-J, Liang W-H, Zhao Y, et al. Comorbidity and its impact on 1590 patients with Covid-
19 in China: A Nationwide Analysis. Eur Respir J. Published online March 26, 2020.
doi:10.1183/13993003.00547-2020
15. Leung JM, Yang CX, Tam A, et al. ACE-2 expression in the small airway epithelia of smokers
and COPD patients: implications for COVID-19. Eur Respir J. 2020;55(5).
doi:10.1183/13993003.00688-2020

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Online Supplements

Asthma in COVID-19 Hospitalizations: An Overestimated Risk Factor?

Richard Broadhurst, Ryan Peterson, Juan P. Wisnivesky, Alex Federman, Shanta M. Zimmer,
Sunita Sharma, Michael Wechsler, Fernando Holguin

Review references and asthma population prevalence references (both related to studies in
Figure 2) are listed in our Supplement.

A complete list of studies considered, analysis code, and regression table are available as
supplemental materials upon request.

Review References (for studies in Figure 2):

1. Jacobs JP, Stammers AH, St Louis J, et al. Extracorporeal Membrane Oxygenation in the
Treatment of Severe Pulmonary and Cardiac Compromise in COVID-19: Experience with 32
patients. ASAIO J. Published online April 17, 2020. doi:10.1097/MAT.0000000000001185

2. Borba MGS, Val FFA, Sampaio VS, et al. Effect of High vs Low Doses of Chloroquine
Diphosphate as Adjunctive Therapy for Patients Hospitalized With Severe Acute Respiratory
Syndrome Coronavirus 2 (SARS-CoV-2) Infection: A Randomized Clinical Trial. JAMA Netw Open.
2020;3(4):e208857. doi:10.1001/jamanetworkopen.2020.8857

3. Zhang J, Dong X, Cao Y, et al. Clinical characteristics of 140 patients infected with SARS-CoV-2
in Wuhan, China. Allergy. 2020;n/a(n/a). doi:10.1111/all.14238

4. Richardson S, Hirsch JS, Narasimhan M, et al. Presenting Characteristics, Comorbidities, and

Outcomes Among 5700 Patients Hospitalized With COVID-19 in the New York City Area. JAMA.
Published online April 22, 2020. doi:10.1001/jama.2020.6775

5. Petrilli CM, Jones SA, Yang J, et al. Factors associated with hospital admission and critical
illness among 5279 people with coronavirus disease 2019 in New York City: prospective cohort
study. BMJ. 2020;369. doi:10.1136/bmj.m1966

6. Li X, Xu S, Yu M, et al. Risk factors for severity and mortality in adult COVID-19 inpatients in
Wuhan. J Allergy Clin Immunol. Published online April 12, 2020. doi:10.1016/j.jaci.2020.04.006

7. Haberman R, Axelrad J, Chen A, et al. Covid-19 in Immune-Mediated Inflammatory Diseases

— Case Series from New York. New England Journal of Medicine. Published online April 29,
2020. doi:10.1056/NEJMc2009567

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8. Guan W-J, Liang W-H, Zhao Y, et al. Comorbidity and its impact on 1590 patients with Covid-
19 in China: A Nationwide Analysis. Eur Respir J. Published online March 26, 2020.
doi:10.1183/13993003.00547-2020

9. Gold JAW. Characteristics and Clinical Outcomes of Adult Patients Hospitalized with COVID-
19 — Georgia, March 2020. MMWR Morb Mortal Wkly Rep. 2020;69.
doi:10.15585/mmwr.mm6918e1

10. Garg S. Hospitalization Rates and Characteristics of Patients Hospitalized with Laboratory-
Confirmed Coronavirus Disease 2019 — COVID-NET, 14 States, March 1–30, 2020. MMWR
Morb Mortal Wkly Rep. 2020;69. doi:10.15585/mmwr.mm6915e3

11. Es K, Bs C, Ck K, et al. Clinical Course and Outcomes of Patients With Severe Acute
Respiratory Syndrome Coronavirus 2 Infection: A Preliminary Report of the First 28 Patients
From the Korean Cohort Study on COVID-19. Journal of Korean medical science.
doi:10.3346/jkms.2020.35.e142

12. Docherty AB, Harrison EM, Green CA, et al. Features of 20 133 UK patients in hospital with
covid-19 using the ISARIC WHO Clinical Characterisation Protocol: prospective observational
cohort study. BMJ. 2020;369. doi:10.1136/bmj.m1985

13. CDCMMWR. Preliminary Estimates of the Prevalence of Selected Underlying Health

Conditions Among Patients with Coronavirus Disease 2019 — United States, February 12–
March 28, 2020. MMWR Morb Mortal Wkly Rep. 2020;69. doi:10.15585/mmwr.mm6913e2

14. Argenziano MG, Bruce SL, Slater CL, et al. Characterization and clinical course of 1000
patients with coronavirus disease 2019 in New York: retrospective case series. BMJ. 2020;369.
doi:10.1136/bmj.m1996

15. Arentz M, Yim E, Klaff L, et al. Characteristics and Outcomes of 21 Critically Ill Patients With
COVID-19 in Washington State. JAMA. Published online March 19, 2020.
doi:10.1001/jama.2020.4326

Asthma Population Prevalence References (for population prevalence values in Figure 2):

1. dos Santos FM, Viana KP, et al. Trend of self-reported asthma prevalence in Brazil from 2003
to 2013 in adults and factors associated with prevalence. J. bras. pneumol. 2018;44(6):491-497.
doi:10.1590/s1806-37562017000000328

2. Huang K, Yang T, Xu J, et al. Prevalence, risk factors, and management of asthma in

China: a national cross-sectional study. Lancet. 2019;394(10196):407‐418.
doi:10.1016/S0140-6736(19)31147-X

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3. Ha J, Lee SW, Yon DK. 10-year trends and prevalence of asthma, allergic rhinitis, and
atopic dermatitis among the Korean population, 2008-2017 [published online ahead of
print, 2020 Jan 29]. Clin Exp Pediatr. 2020;10.3345/cep.2019.01291.
doi:10.3345/cep.2019.01291

4. Mukherjee, M., Stoddart, A., Gupta, R.P. et al. The epidemiology, healthcare and
societal burden and costs of asthma in the UK and its member nations: analyses of
standalone and linked national databases. BMC Med. 2016;14(113). doi:10.1186/s12916-
016-0657-8

5. Centers for Disease Control and Prevention (CDC). Behavioral Risk Factor Surveillance
System Survey Data. Atlanta, Georgia: U.S. Department of Health and Human Services, Centers
for Disease Control and Prevention, 2018.
https://www.cdc.gov/asthma/brfss/2018/current_C1-H.pdf

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