key: cord-333175-klnxnxwm
authors: Hussein, Mohammad H.; Toraih, Eman A.; Attia, Abdallah S.; Burley, Nicholas; Zhang, Allen D.; Roos, Jackson; Houghton, August; Aniemeka, Nedum; Omar, Mahmoud; Aboueisha, Mohamed; Shama, Mohamed A.; Duchesne, Juan; Kandil, Emad
title: Asthma in COVID-19 patients: An extra chain fitting around the neck?
date: 2020-11-11
journal: Respir Med
DOI: 10.1016/j.rmed.2020.106205
sha: 
doc_id: 333175
cord_uid: klnxnxwm

INTRODUCTION: The novel coronavirus disease 2019 (COVID-19) has rapidly spread across the globe. Pre-existing comorbidities have been found to have a dramatic effect on the disease course. We sought to analyze the effect of asthma on the disease progression and outcomes of COVID-19 patients. METHODS: We conducted a multi-center retrospective study of positively confirmed COVID-19 patients. The primary outcome of interest was in-hospital mortality. Secondary outcomes were the Intensive Care Unit (ICU) admission, intubation, mechanical ventilation, and length of hospital stay. RESULTS: A total of 502 COVID-19 adult patients (72 asthma and 430 non-asthma cohorts) with mean age of 60.7 years were included in the study. The frequency of asthma in hospitalized cohorts was 14.3%. Univariate analysis revealed that asthma patients were more likely to be obese (75% versus 54.2%, p = 0.001), with a higher frequency of intubation (40.3% versus 27.8%, p = 0.036), and required a longer duration of hospitalization (15.1 ± 12.5 versus 11.5 ± 10.6, p = 0.015). After adjustment, multivariable analysis showed that asthmatic patients were not associated with higher risk of ICU admission (OR = 1.81, 95%CI = 0.98–3.09, p = 0.06), endotracheal intubation (OR = 1.77, 95%CI = 0.99–3.04, p = 0.06) or complications (OR = 1.37, 95%CI = 0.82–2.31, p = 0.23). Asthmatic patients were not associated with higher odds of prolonged hospital length of stay (OR = 1.48, 95%CI = 0.82–2.66, p = 0.20) or with ICU stay (OR = 0.76, 95%CI = 0.28–2.02, p = 0.58). Kaplan-Meier curve showed no significant difference in the overall survival of the two groups (p = 0.65). CONCLUSION: Despite the increased prevalence of hospitalization in elder asthmatic COVID-19 patients, after adjustment for other variables, it was neither associated with increased severity nor worse outcomes.

Since its initial description in late 2019, the novel coronavirus (COVID- 19) has become a global pandemic, overwhelming our healthcare systems and depleting resource stockpiles [1] . In some pandemic hotspots, physicians have had to make difficult decisions regarding lifesaving interventions due to a lack of supplies such as ventilators [2] . Further complicating management of this disease, COVID-19 has a broad clinical presentation. Patients can be asymptomatic carriers or have mild non-respiratory and respiratory symptoms. On the other hand, the virus can also present with severe pneumonia or lethal respiratory failure. Because of these severe outcomes, gaining an understanding of COVID-19's disease course is essential to guiding treatment approaches and optimizing individual patient outcomes.

Preexisting comorbidities can have a dramatic impact on the course of a COVID-19 infection. It is, therefore, crucial to identify which comorbidities most contribute to severe infections, which may influence individual patient care plans [3] . To better understand these relationships, the Centers for Disease Control and Prevention (CDC) is actively incorporating new and emerging data to update their treatment recommendations for patients with varying comorbid conditions. Currently, the CDC reports that asthma is present in about 17% of hospitalized COVID-19 patients, making it the fourth most prevalent comorbidity behind hypertension, obesity, and diabetes [4] . Obese and diabetic patients have been categorized as high-risk, but there is still limited data regarding the impact of bronchial asthma on COVID-19 outcomes [5] .

Because asthma is a chronic lung disease, it follows that asthmatics are at a greater risk for negative outcomes with a respiratory virus. However, there is a debate over the expected outcomes in COVID-19 infected patients with asthma. Some members of the coronaviridiae family that are associated with the common cold have been linked to asthma exacerbations [6] . In J o u r n a l P r e -p r o o f contrast, Jackson et al. reported an observed protective relationship for asthma and atopic conditions in COVID-19 patients [7] . In efforts to explain this phenomenon, it was proposed that patients with asthma and ectopic diseases may exhibit a lower concentration of respiratory tract angiotensin-converting enzyme (ACE) receptors in patients. As has been widely reported, ACE receptors and specifically, ACE2, are known to be the host receptor site for SARS-CoV-2 [7, 8] .

Considering that more than 19 million adults in the United States have asthma [9] , it is crucial to characterize asthma in the setting of COVID-19. Therefore, we retrospectively evaluated hospitalized patients with laboratory-confirmed SARS-CoV-2, focusing on the differing outcomes between asthmatic and non-asthmatic patients. This study aimed to help further understand asthma's impact on COVID-19 outcomes, hopefully enabling physicians to tailor management and resource allocation in response to the ongoing pandemic.

Following Institutional Review Board (IRB) approval, data of hospitalized patients with laboratory-confirmed SARS-CoV-2 infection was gathered and entered into the web-based data collection platform, RedCap. Patients included in the study presented to either University Medical Center New Orleans (UMCNO), Tulane Medical Center (TMC), Saint Francis Medical Center Monroe (SFMC), or Our Lady of the Lake Regional Medical Center (OLOL) during the period between March 15 to June 9, 2020.

A broad range of data was recorded, including but not limited to, the following: demographics, medical history, comorbidities, clinical presentation, daily laboratory values, complications, and J o u r n a l P r e -p r o o f outcomes. Patients were excluded if they were below 18 years of age or did not have recorded outcome data. Obesity was defined as body mass index (BMI) ≥30 Kg/m 2 [10] . For severity assessment, the CURB-65 score was estimated based on confusion status, respiratory rate≥30, blood pressure (systolic <90 mmHg or diastolic ≤60 mmHg), age ≥65 years, and blood urea nitrogen level >19 mg/dL (>7 mmol/L), and ranged from 0 to 5 [11] . Quick Sequential Organ Failure Assessment (qSOFA) score was calculated using Glasgow coma score <15, respiratory rate ≥22, and systolic blood pressure ≤100, and was set to be a positive indicator for the poor outcome if ≥2 [12] . Horowitz index (PaO 2 / FIO 2 ratio) was calculated as the ratio of arterial oxygen partial pressure (PaO 2 in mmHg) to fractional inspired oxygen to determine a patient's respiratory efficiency [13] . The neutrophil-lymphocyte ratio (NLR), an indicator for poor outcome, was also estimated [14] .

A comparison between the asthmatic and non-asthmatic cohorts was performed. The primary outcome of interest was in-hospital mortality. Secondary outcomes were risk of Intensive Care Unit (ICU) admission, risk of endotracheal intubation, duration of mechanical ventilation, and length of hospital stay. Clinical diagnosis of complications was made using standard definitions such as the Risk, Injury, Failure, Loss of Kidney Function, and End-stage kidney disease (RIFLE) score for renal injury [15] . Berlin criteria were also utilized to identify cases of acute respiratory distress syndrome (ARDS) [16] Statistical analysis interquartile ranges, while categorical data were presented as frequencies and percentages. Chisquare or Fisher's Exact tests were used for categorical variables. Student's t and Mann-Whitney U tests were applied for quantitative variables to examine the difference between asthmatic and non-asthmatics groups. Shapiro-Wilk test was used to test the normality of the continuous variables. Kaplan-Meier survival analysis and the Log Rank test was used to compare the inhospital mortality in the two groups. Binary logistic regression analysis was used to assess the role of asthma comorbidity in the outcomes of COVID-19 disease. Age, gender, and obesity were adjusted in the model. Hosmer-Lemeshow test was used to assess goodness-of-fit. Results were reported as odds ratio (OR), and 95% confidence interval (CI) and two-sided p values below 0.05 were set as significant.

A total of 502 confirmed positive COVID-19 patients were identified from multiple hospitals in Louisiana, including 72 bronchial asthma patients and 430 non-asthmatic controls. Their mean age was 60.6 ± 13.9 years and 60.8 ± 15.7 years, respectively (p = 0.89). There was no observed age or gender difference. Females accounted for 54.2% (39 patients) in the asthma group versus 52.0% (222 patients) in the non-asthma group (p = 0.79). The frequency of obesity among asthmatic patients (75%) was significantly higher than those without current asthma (54.2%), p = 0.001. On admission, asthma cohorts presented with greater respiratory rate (24.14 ± 7.03 vs 21.77 ± 7.20 breaths per minute, p = 0.015) and lower bicarbonate level (21.73 ± 5.41 vs 24.67 ± 3.57 mEq/L, p = 0.022). No other significant differences were found regarding clinical and laboratory features ( Table 1) .

Univariate analysis of COVID-19 outcomes revealed that asthma was significantly associated with higher rate of endotracheal intubation (40.3% vs 27.8%, p = 0.036), mechanical ventilation (both invasive and non-invasive) (70.7% vs 52.2%, p = 0.039), and longer hospital length of stay (15.14 ± 12.48 days vs 11.51 ± 10.58 days, p = 0.015). Asthma was not associated with a higher rate of Intensive Care Unit (ICU) admission (22.2% vs 14.9%, p = 0.12), acute respiratory distress syndrome (37.5% vs 30.9%, p = 0.27), or death (9.7% vs 13.5%, p = 0.45) among COVID-19 patients. No other clinical and laboratory findings were different between patients with and without asthma ( Table 2) .

Comparison stratified by obesity showed both asthmatic and non-asthmatic patients had overall similar demographic features, presenting manifestations and comorbidities in each subgroup.

However, clinical courses differed significantly between some groups. On comparison to nonasthmatic obese patients, obese asthmatic patients were more likely to develop sepsis (25.9% vs 14.2%, p = 0.042), had higher risk of ICU admission (48.1% vs 33.2%, p = 0.042), and required prolonged intubation (2.73 ± 3.63 days vs 1.38 ± 2.07, p = 0.032).

Using multivariate regression analysis, bronchial asthma was not associated with higher risk of 

As the COVID-19 pandemic evolves, countries consider policies to protect those at increased risk of severe disease. To the best of our knowledge, this is the first study evaluating the relationship between asthma and COVID-19 outcomes in hospitalized patients in Louisiana. In the 502 patients included, the prevalence of asthma was 14.3%. This rate is higher than the national prevalence of asthma reported by the CDC (7.7%), but in line with CDC reports on the prevalence of asthma in COVID-19 patients [17] . This increased prevalence of asthma in COVID-19 patients may be attributable to increased disease awareness and concern to increased severity of the disease course among asthmatics.

Our initial univariate analysis of asthmatic patients showed significantly higher rates of endotracheal intubation and mechanical ventilation, and increased duration of hospital stay.

Patients with asthma were also more likely to be obese, a finding consistent with prior studies [18, 19] . As has been well-documented and widely reported, obesity alone has been associated with poor clinical outcomes in hospitalized COVID-19 patients [4] . Fittingly, in initial univariate analysis of obese asthmatic, there were significantly elevated rates of sepsis, ICU admission, and prolonged intubation. However, after multivariate adjustment, asthma comorbidity did not drive poor outcomes for our primary and secondary endpoints of interest -ICU admission, intubation, mechanical ventilation, ARDS, and case fatality rate. Although these results may not be expected, there is a plausible mechanism, the downregulation of ACE2 receptors, that could hypothetically account for these observations [20] .

Early data published by Jackson et al. suggested that patients with allergic asthma have decreased ACE2 expression in nasal and bronchial epithelial cells [7] . The possible explanation for this observation is two-fold. First, it has been postulated that that type II immune modulation J o u r n a l P r e -p r o o f decreases the expression of the receptor for cellular entry of COVID-19 -ACE2 [22] . Second, individuals with chronic respiratory conditions often use inhaled corticosteroids (ICS). The Severe Asthma Research Program (SARP) demonstrated that ICS use in asthmatic patients leads to decreased expression of ACE2 and TMPRSS2 -a host serine protease which primes host cells for entry via the spike protein [23] . Additional in vitro studies have demonstrated that treatment with ciclesonide, an ICS used for suppressing asthma attacks, demonstrated viral suppression of SARS-CoV-2 [24] . It must be remembered that these experimental studies occurred in non-COVID-19 patients; nonetheless, the results suggest further investigation is necessary to understand the possible protective role of type 2 inflammation in asthma and COVID-19. Based on these studies, it may be possible that ICS treatment is protective via viral suppression or ACE2/TMPRSS2 reduction. These protective effects may explain the lack of significant difference in outcomes among asthmatic and non-asthmatic patients.

The potential limitations of this study include self-reporting of asthma history and the inability to identify the severity of asthma. To prevent false reporting, each patient's home medications were reviewed to confirm the diagnosis. Asthma severity may be assessed retrospectively based on symptoms or via risk assessment requiring measurement of airflow limitation using spirometry or Peak flow meter. However, these Aerosol Generating Procedures (AGPs) may put healthcare workers at an increased risk of coronavirus exposure.

The results of the current study show that while pre-existing asthma is more prevalent in our COVID-19 cohort than in the general population, after adjustment for other covariates, it was neither associated with disease severity nor negative outcomes. Therefore, although a seemingly poor prognosis, asthma does not imply a worse outcome than non-asthmatics. This information can help physicians and researchers identify people with other underlying medical conditions at J o u r n a l P r e -p r o o f risk for more severe COVID-19 disease.

The authors declare the absence of conflict of interest.

None of the authors have any funding regarding this publication.

We thank numerous doctors, nurses, government, and civilians working together to fight against the SARS-CoV-2. 

Novel coronavirus disease (COVID-19): a pandemic (epidemiology, pathogenesis and potential therapeutics)

Duty to Plan: Health Care, Crisis Standards of Care, and Novel Coronavirus SARS-CoV-2. NAM Perspectives. Discussion paper. National Academy of Medicine

Comorbidity and its impact on 1590 patients with

COVID-19 in China: a nationwide analysis

Hospitalization Rates and Characteristics of Patients Hospitalized with Laboratory-Confirmed Coronavirus Disease

COVID-19): are you at higher risk for severe illness? Atlanta, GA: US Department of Health and Human Services, CDC

Regional, age and respiratory-secretion-specific prevalence of respiratory viruses associated with asthma exacerbation: a literature review

Association of respiratory allergy, asthma, and expression of the SARS-CoV-2 receptor ACE2

SARS-CoV-2 Cell Entry Depends on ACE2 and TMPRSS2 and Is Blocked by a Clinically Proven Protease Inhibitor

tables A-2b, A-2c

BMI classification percentile and cut off points. StatPearls

External Validation of the qSOFA Score in Emergency Department Patients With Pneumonia

Comparison of CRB-65 and quick sepsis-related organ failure assessment for predicting the need for intensive respiratory or vasopressor support in patients with COVID-19

Sequential oxygenation index and organ dysfunction assessment within the first 3 days of mechanical ventilation predict the outcome of adult patients with severe acute respiratory failure

The diagnostic and predictive role of NLR, d-NLR and PLR in COVID-19 patients

Importance of RIFLE (Risk, Injury, Failure, Loss, and End-Stage Renal Failure) and AKIN (Acute Kidney Injury Network) in Hemodialysis Initiation and Intensive Care Unit Mortality

Acute respiratory distress syndrome: the Berlin Definition

A review of obesity and asthma across the life spac

Obesity and asthma

Inhaled Corticosteroids Downregulate The SARS-Cov-2 Receptor ACE2 In COPD Through Suppression of Type I Interferon. bioRxiv preprint

Prevalence and characterization of asthma in hospitalized and non-hospitalized patients with COVID-19

Angiotensin-converting enzyme 2 is a functional receptor for the SARS coronavirus

COVID-19-related Genes in Sputum Cells in Asthma. Relationship to Demographic Features and Corticosteroids

The inhaled corticosterois ciclesonide blocks coronavirus RNA replication by targeting viral NSP15