Breathing doesn’t always come easily to those with asthma, but they may be able to breathe a little easier during the COVID-19 pandemic based on recent studies suggesting that asthma is not a risk factor for developing severe COVID-19. Some studies even suggest that asthma may protect patients from severe infection.
Respiratory infections such as the cold and flu are generally bad news for those with asthma. Viral infection worsens their symptoms, and in some cases, causes pneumonia. Early in the pandemic, researchers and clinicians anticipated that asthma would increase risk for developing severe COVID-19. But physicians didn’t want assumptions; they wanted data.
“I needed to know how to advise my patients with respect to COVID-19, other than to tell them to try to avoid it,” said Michael Wechsler, a pulmonologist at National Jewish Health. “My goal was really to work with colleagues to try to understand whether or not people [with asthma] were at greater risk, or what we should be doing differently for those patients.”
As the COVID-19 pandemic progressed, more patient data accumulated, giving researchers a clearer picture of the connection between asthma and COVID-19. Many physicians now feel comfortable easing patient concerns given the growing wealth of data.
“This has been very helpful to me when talking to my patients and reassuring them that they're not more at risk. We looked at this worldwide study and did not find that it puts them at increased risk, but it also helps to emphasize to them that they need to keep their asthma under good control,” said Rajiv Dhand, a pulmonologist and researcher at the University of Tennessee.
Scientists are still trying to understand why COVID-19 may not aggravate asthma symptoms like other viral respiratory infections, especially since related respiratory diseases like chronic obstructive pulmonary disorder (COPD) seem to. Some think that the answer lies in the effect of the inhaled steroids often prescribed to patients, while others postulate that the extreme precautions people with asthma took early in the pandemic protected them. Now that COVID-19 patient data is available, researchers plan to look back in time to find the answers.
A connection between asthma and COVID-19
In early March last year, patients flocked to the Asthma and Allergy Foundation of America’s (AAFA’s) blog to find clarity about the risk their condition and medications posed. Patients were worried that the corticosteroids they used to control their disease would increase their chances for severe COVID-19 infection.
Corticosteroids combat asthma attacks by reducing inflammation in the airways, which essentially dampens the immune system, potentially weakening the body’s defenses against viruses.
Mitchell Grayson, a clinician researcher at Nationwide Children’s Hospital and chair of the AAFA Medical Scientific Council, published a blog post clarifying that data did not suggest poor COVID-19 outcomes for asthma patients taking corticosteroids. In fact, he pointed out that in two separate studies conducted in China (one including 1,099 patients), no hospitalized COVID-19 patients had asthma (1-2).
His overall message was “just chill out people; relax. Take care of your asthma. Make sure your asthma is under control, and everything else will be fine,” he said.
Grayson clarified that patients’ concerns were not unfounded at the time. Scientists estimate that viral infections cause half of all asthma exacerbations. Viruses such as rhinoviruses that are responsible for colds can severely exacerbate asthma. However, diseases such as diabetes and heart disease were more significant risk factors than asthma for SARS-CoV during the 2003 epidemic (3).
Scientists did not want to predict the susceptibility of asthma patients to COVID-19 based on other viruses, however. Many researchers and clinicians, including Grayson, conducted small studies to put the first pieces of this complex puzzle in place.
Grayson looked back at the charts of the 49 COVID-19 positive patients, six with asthma, admitted to Nationwide Children’s Hospital between March and July 2020 (4). Only two of the 49 patients required intubation, neither of which had asthma. Asthma patients were not admitted to the ICU more frequently, nor did they require supplemental oxygen more often than non-asthmatic patients.
Similar studies including anywhere from four to 1,298 patients published as early as March 2020 reported similar findings (5-6). However, most of these studies were small and focused on patients admitted to individual hospitals. Recently, researchers began combining the data from these studies to understand if these results applied to the global population.
Christine Jenkins, a pulmonologist and researcher at The George Institute for Global Health, analyzed 57 studies, including a total of 587,280 patients, to understand if people with asthma had poorer outcomes once diagnosed with COVID-19 (7).
“We looked at the prevalence of asthma amongst people who had COVID-19,” said Jenkins. “That’s a good way to start looking at whether or not people with asthma are more likely to get COVID. If they were, you would expect them to be overrepresented in that population, and we did not find that. We found that the prevalence of people with asthma amongst people either confirmed or suspected as having COVID-19 was about the same as it is in general populations.”
7.5% of COVID-19 patients had asthma, which is close to the estimated 8.5% in the global population. Further, 9.6% of COVID-19 patients had mild asthma, while 4.13% had severe asthma, mirroring the 5% of people in the general population with severe asthma.
The prevalence of asthma varies greatly between countries. Dhand did the extra math. He analyzed 150 studies and compared the prevalence of asthma amongst COVID-19 positive patients to the prevalence of asthma in that specific geographic region. He also found that asthma patients were no more prevalent amongst hospitalized COVID-19 patients or patients with severe or lethal cases.
Although the CDC still states that people with asthma are more likely to be hospitalized for COVID-19, they now define the evidence supporting asthma as a risk factor as “mixed,” citing the studies recently published by Dhand and Jenkins (8). Of the twelve studies they cite, more than half report no significant correlation between asthma and poor outcomes related to COVID-19 infection.
However, some researchers believe that different types of asthma pose different risks.
Allergies and COVID-19
What triggers someone’s asthma guides how it is diagnosed and treated. Allergic asthma is triggered by allergens such as pet dander or pollen, and is often diagnosed using a skin test, where an allergist exposes a patient to various allergens to see if they develop a rash. Non-allergic asthma can be triggered by a variety of factors such as exercise, viruses, or cigarette smoke. Differentiating between allergic and non-allergic asthma can be challenging, and often patients have both.
“It’s a very heterogenous and dynamic disease, and many patients who have asthma have different stimuli at different time points,” said Wechsler. “You can go visit your aunt’s cat, and your asthma will exacerbate because of the allergy to the cat. Two weeks later, your kid may come home from daycare, and bring a virus, and your asthma can be exacerbated by that.”
According to Liming Liang, a biostatistician from Harvard University, distinguishing between allergic and nonallergic asthma is important when calculating an asthma patient’s risk for developing a severe case of COVID-19.
Liang analyzed data from a UK Biobank to determine the clinical outcomes of COVID-19 positive patients previously diagnosed with asthma (9). Nearly 500,000 patients enrolled in the biobank between 2006 to 2010. The researchers followed these patients, constantly updating their data over time. Starting in March 2020, clinicians started reporting if patients tested positive for COVID-19.
This resource includes more than just the medical records of the patients, but sequencing data as well. Liang used this data to calculate polygenic risk scores, a measure of the accumulation of genes that correlate to a given disease, for people with allergic and non-allergic asthma.
“Typically, you have hundreds or even thousands of genetic variants in the scores. So, it's not one single gene dominated genetic risk for obesity or asthma. But together they can make a big difference. They can also have a good prediction accuracy,” said Liang.
Liang reported that people with asthma were more likely to develop severe COVID-19. When he broke it down by type, non-allergic asthma increased a person’s risk of a severe case of COVID-19 by almost 50% while people with allergic asthma had no increased risk.
“What we classify as non-allergic asthma tends to be in older people with asthma without allergies, and I question whether it’s really COPD. And in our study and many others, COPD was a risk factor,” said Grayson.
Don Sin, a pulmonologist specializing in COPD, published a meta-analysis study demonstrating that COPD patients were at greater risk for hospitalization and death than the general population (10). Some studies report that COPD is not a risk factor for severe COVID-19, but he thinks that the lack of consensus lies in the difficulty of diagnosing COPD.
“Even today, a lot of physicians don't know COPD very well. If you're not thinking about the diagnosis, you're not going to make the diagnosis,” said Sin.
One of the main components of diagnosing COPD is conducting a breathing test. When patients come into the hospital with severe COPD symptoms like difficulty breathing, conducting a breathing test is challenging. Additionally, a CT scan of the lungs is often needed to identify symptoms such as holes in the lungs, which are often found in emphysema patients. Sin said that spotting these holes takes a “trained eye.”
COPD is often found in smokers, so there is sometimes stigma associated with the diagnosis. Patients may be less likely to report it to their physicians and physicians may not test for COPD unless the patient has a history of smoking.
“Some of [the challenge] is systemic in nature. It has to do with medical education, physician bias, patient understanding, and frankly, inability of patients to do lung function tests in an acute setting,” said Sin.
If COPD isn’t diagnosed or included on a medical record, it’s impossible to exclude it from an analysis focused on defining the risk of COVID-19 infection for asthma patients. Additionally, since most COPD patients are over the age of 40, they are more likely to be included in the non-allergic asthma category, since allergic asthma is generally found in younger patients. This distinction in age further complicates the relationship between asthma subtypes and COVID.
“We need more information to really categorically say that the type of asthma is influencing [COVID-19 severity] because there's so many variables. What kind of treatment do they have? Is the disease controlled or not? They need to be teased out before we can make any firm statements,” said Dhand.
COVID-19 Protection?
In addition to her findings that people with asthma were not more at risk for developing severe COVID-19, Jenkins reported that people with asthma were 14% less likely to become infected. However, she’s not sure if the reason lies in the disease itself.
“I'm not suggesting that inherently, people with asthma are more or less likely to get COVID-19. Not at all. In fact, now there's some evidence that people with asthma may be less likely to get COVID because they take inhaled steroids,” said Jenkins.
Several studies reported that patients hospitalized due to severe COVID-19 who were treated with the corticosteroid dexamethasone were less likely to die than patients receiving usual care. This offers physicians a cheap, accessible treatment for critically ill patients (11-12).
Researchers also reported that patients with asthma who regularly take steroids have lower levels of two proteins required for COVID-19 entry into cells, ACE2 receptor and transmembrane protease serine 2 (TMPRSS2), providing a plausible explanation for lower rates of infection (13).
“One other factor I like to mention is that people with asthma were probably a lot more careful about maintaining hygiene and social distancing and mask wearing because they were probably more apprehensive that they would get the infection,” said Dhand.
In early March 2020, pharmacies saw an 80% increase in the number of inhaler refill requests. This indicates that patients with asthma may have been more adamant about keeping their asthma under control during the pandemic, amplifying the potential protective effects of their medication.
“They were taking their medication more regularly because they felt that they might be vulnerable to getting the infection,” Dhand said. “Whether or not your asthma is under control is probably a more significant factor than what kind of asthma you have.”
Clinicians don’t want patients to let their guard down quite yet. With the new delta variant on the loose, a COVID-19 vaccine, and lightened restrictions around the world, some researchers think that it’s time to take a second look at the relationship between asthma and COVID-19 severity.
“We need to evaluate what the risk factors are for developing COVID in specific patient populations, in patients who have been vaccinated, and patients who haven't been vaccinated. What’s the effect of corticosteroids, inhaled or oral? What's the effect of biologic therapies?” said Wechsler.
References
- Huang, K. et al. Prevalence, risk factors, and management of asthma in China: a national cross-sectional study. Lancet. 394, 407-418 (2019).
- Zhang, J.-J. et al. Clinical characteristics of 140 patients infected with SARS?CoV?2 in Wuhan. Allergy. 75, 1730-1741 (2020).
- Akenroye, A.T. et al. Asthma, biologics, corticosteroids, and coronavirus disease 2019. Annals of Allergy, Asthma, and Immunol. 125, 12-13 (2020).
- Timberlake, D. et al. COVID-19 Severity in Hospitalized Pediatric Patients with Atopic Disease. J. Allergy Clin. Immunol.147, AB79 (2021).
- Codispoti, C.D. et al. Clinical course of asthma in 4 cases of coronavirus disease 2019 infection. Annals of Allergy, Asthma, and Immunol. 124, 208-210 (2020).
- Lovinsky-Desir, S. et al. Asthma among hospitalized patients with COVID-19 and related outcomes. Asthma and Lower Airway Disease. 146, 1027-1034 (2020).
- Sunjaya, A.P. et al. Asthma and risk of infection, hospitalization, ICU admission and mortality from COVID-19: Systematic review and meta-analysis. J. of Asthma. (2021).
- CDC. Science Brief: Evidence used to update the list of underlying medical conditions that increase a person’s risk of severe illness from COVID-19. (2021).
- Zhu, Z. et al. Association of asthma and its genetic predisposition with the risk of severe COVID-19. J. Allergy Clin. Immunol. 146, 327-329 (2020).
- Gerayli et al. COPD and the risk of poor outcomes in COVID-19: A systematic review and meta-analysis. EClinicalMedicine. 33, 100789 (2021).
- The WHO Rapid Evidence Appraisal for COVID-19 Therapies (REACT) Working Group. Association Between Administration of Systemic Corticosteroids and Mortality Among Critically Ill Patients With COVID-19: A Meta-Analysis. JAMA. 324, 1330-1341 (2020).
- The RECOVERY Collaborative Group. Dexamethasone in Hospitalized Patients with Covid-19. N. Engl. J. Med. 384, 693-704 (2021).
- Peters, M.C. et al. COVID-19-related Genes in Sputum Cells in Asthma. Relationship to Demographic Features and Corticosteroids. Am. J. Respir. Crit. Care Med. 202, 83-90 (2020).
