key: cord-1047425-nzasmotd
authors: Alakeel, Yousif S.; Alharbi, Ebtihal F.; Alhaidal, Haifa A.; Jumaa, Aisha M.; Albaiahy, Latifah K.; Alsagami, Noura S.; Alshahrani, Shatha A.
title: The Effects of the Antecedent use of Inhaled Steroid on the Clinical Course of COVID-19: A Retrospective Study of Asthmatic Patients
date: 2021-12-08
journal: J Infect Public Health
DOI: 10.1016/j.jiph.2021.12.003
sha: 1e815d93377bdff1c63212ca8ff6164cff39333e
doc_id: 1047425
cord_uid: nzasmotd

BACKGROUND: There is conflicting evidence regarding the effect of asthma and its different therapeutic options on COVID-19 severity and the clinical outcomes. AIM: This study aimed to investigate the relationship between using inhaled corticosteroids (ICS) by asthmatic patients and the severity of COVID-19. MATERIALS AND METHODS: This retrospective observational study was conducted from March 15 to October 23, 2020 and included data of all COVID-19 asthmatic patients (n = 287) at King Abdulaziz Medical City. Twelve patients were excluded due to poor medication history documentation or using ICS for non-asthma indication. Ordinal logistic regression was used to determine the clinical variables that affect COVID-19 severity. The clinical outcomes of ICS and non-ICS users were compared. RESULTS: Of the sample (n = 275), 198 (72%) were using ICS therapy. No significant difference was found between ICS and non-ICS users in disease severity (P = 0.12), mortality (P = 0.45), ICU admission (P = 0.78), and the occurrence of complications. However, the number of days on ventilation were significantly increased in ICS users (P = 0.006). Being prescribed the ICS/LABA combination (adj OR: 0.72 [0.15,1.2]; P = 0.021), being hypertensive (adj OR: 0.98 [0.28,1.6]; P = 0.006), having cancer (adj OR: 1.49 [0.12, 2.8]; P = 0.033), or having diabetes (adj OR: 0.75 [0.09, 1.4]; P = 0.024) could not increase the risk for more severe disease. CONCLUSION: Overall, ICS therapy did not alter the COVID-19 severity or mortality in asthmatic patients. The continued use of ICS during the pandemic should be encouraged to prevent asthma exacerbations.

Coronavirus disease 2019 , caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has become a pandemic. After a median incubation period of five days, the disease occurs in different stages, ranging from mild cases where the disease is limited to the upper and lower airway (80% to 90% of patients) and severe cases with bilateral pneumonia (10% to 20%) (1)(2)(3). Patients with severe COVID-19 may also develop Acute Respiratory Distress Syndrome (ARDS), and require mechanical ventilation in an intensive care (4)(5).

COVID-19 patients with pre-existing comorbid conditions have worse disease outcomes, including a higher incidence of hospitalization, ICU admission, and mortality (2)(6).

Although respiratory viral infections contribute to the majority of exacerbations in asthmatic patients (7) , asthma is underrepresented in literature as a comorbidity in COVID-19 severity (2)(3) (8) . Currently, moderate to severe asthma are classified by the Centers for Disease Control and Prevention (CDC) as a high-risk group that is vulnerable to severe COVID-19.

Theoretically, long-term treatment with systemic corticosteroids (e.g. in transplant patients) increases the risk and severity of viral infections due to immunosuppression (9) . However, in vitro studies suggested that ICS could have a protective effect against SARS-CoV-2 as they dosedependently reduce the expression of the Angiotensin-Converting Enzyme type 2 (ACE-2) on the surface of the lung cells, decreasing the viral entry into the cells (10) . The RECOVERY trial reported that the use of dexamethasone reduced the mortality rate in hospitalized COVID-19 patients who required mechanical ventilation or supplemental oxygen (11) . Based on these findings, the World Health Organization (WHO) and the National Institute of Medicine (NIH) recommended the use of dexamethasone, contrary to their initial recommendation against this practice during the early phases of the pandemic, if not clinically indicated for another disease state (12) . The drug now is added to the treatment guidelines in most centers treating COVID -19 patients. In addition, professional societies in their response to the pandemic, urge asthmatic patients to continue their prescribed medication, including ICS (13) (14) .

These recommendations have caused uncertainty in asthma patients and attending clinicians in terms of maintaining ICS therapy as withholding ICS increases the risk of severe exacerbations.

A recent meta-analysis related to COVID-19 outcomes in patients with chronic respiratory J o u r n a l P r e -p r o o f diseases using ICS, concluded that there is currently insufficient evidence to abandon ICS treatment in asthma (15) .

Today, approximately 300 million individuals globally have asthma (16) and an estimated 11.3% of the Saudi Arabian population are affected by the disease (17) . Acute asthma exacerbations are considered a frequent cause of hospitalization and emergency room visits (18) . More importantly ICS are prescribed in 90.8% of asthma cases (19) . A recent study conducted by Sen et al. disclosed that ICS therapy had no impact on COVID-19 related clinical outcomes or mortality in COPD patients (20) . Asthmatic patients prescribed a low to medium-dose ICS were not at an increased risk of mortality (adjusted HR = 1.14; 95% CI, 0.85-1.54) (21) .

However, COVID-19-related mortality was significantly increased in COPD patients using ICS compared to the group who are maintained with long-acting beta agonist (LABA) and the longacting muscarinic agent (LAMA) combination therapy (adjusted (adj.) HR = 1.39; 95% CI, 1.1-1.76) (21) . COVID-19-related mortality was increased in asthmatic patients prescribed a high-dose ICS compared to patients taking short-acting beta-agonists (SABAs) (adj. HR = 1.55; 95% CI, 1.1-2.18) (21) . Clear evidence regarding the impact of prior or continued use of ICS on the clinical course of COVID-19 in asthma patients is still lacking. It is crucial to understand which asthma patients are particularly at risk of being infected with COVID-19 and how ICS may influence the morbidity and mortality associated with COVID-19. There is also a need to clarify the demographic and clinical characteristics which determine disease severity and outcomes of COVID-19 in asthmatic patients. This is the first study in the Middle East to examine the effect of ICS therapy on asthmatic patients infected with SARS-CoV-2.

This study aimed to investigate the impact of using ICS by asthmatic patients and the latter's clinical characteristics on the severity of COVID-19. We hypothesized that the antecedent use of ICS complicates the clinical course and severity of COVID-19.

This retrospective cross-sectional study was conducted at King Abdulaziz Medical City, Riyadh from March 15 to October 23, 2020, to investigate the association effect of ICS use and other asthmatic patients' characteristics on COVID-19 severity. The data management department was initially approached for data on COVID-19 patients with possible asthma diagnosis based on symptoms (i.e., cough and wheezing) (n=574). Files were then manually checked for documented J o u r n a l P r e -p r o o f asthma diagnosis (n=287) which was based on the hospital's diagnostic and classification criteria that are based on the NIH guidelines (Appendix I): intermittent, mild persistent, moderate persistent, and severe persistent.

Grandbastien et al. reported that 23 (21.7%) of patients admitted with SARS-CoV-2 pneumonia had an established diagnosis of asthma (22) . The sample size was calculated using the OpenEpi calculator and estimated at 262 with a 5% level of significance. The sample size was inflated by 10% to 288 patients due to possible missing data.

The medical records were reviewed and the demographic, clinical, and outcome data were collected. The variables collected included age, weight, body mass index (BMI), gender, comorbidities (i.e., cardiac disease, non-asthmatic pulmonary disease, kidney disease, liver disease, obesity, stroke, and malignancy), and concurrent medications, including the type of ICS.

Details of the disease management were also recorded, including the disease severity, level of care (ward-based, high dependency unit (HDU), or Intensive care units (ICU)), hospital length of stay (LOS), ICU length of stay, ventilation days, complications (e.g., acute respiratory distress syndrome (ARDS), acute kidney injury (AKI), sepsis, septic shock), and mortality.

The severity of COVID-19, for both ICS and non-ICS users in asthmatic patients, based on the This classification was then modified to three major groups to avoid blank cells when subgrouping patients. The groups included asymptomatic, mild-moderate, and severe-critical cases.

The secondary outcomes included the level of care, hospital LOS, ICU LOS, ventilation days, complications (ARDS, AKI, sepsis, septic shock), and mortality.

The sample was analyzed to determine if there was an association between the severity of COVID- 19 and ICS use or other clinical variables. Continuous data were summarized as mean (standard deviation) and categorical data as frequency (percentage).

The sample was divided in two groups: ICS users and non-ICS users and compared in terms of the clinical outcomes (e.g., baseline characteristics, hospitalization, ICU admission oxygenation and ventilation status, complications, and mortality) using a χ2 test or fisher's exact test for the categorical data, or the independent sample t-test for the scale variables (age, height, and weight).

The sample was divided in three groups, based on the disease severity: asymptomatic, mildmoderate, severe-critical. The Mann-Whitney U test or Kruskal-Wallis test was used to analyze the association with the nominal variables, and the categorical data with the χ2 test or fisher's exact test. A Spearman correlation was done to assess the correlation between the groups and the scale/ordinal variables.

Ordinal logistic regression was then used to adjust for asthma severity and to assess the association between COVID-19 severity and the different patient and clinical variables. All four assumptions were met for creating the model. A McNemar's test was used to analyze the change in ventilation mode.

All analyses were two-tailed and were performed at a significance level of 0.05. IBM SPSS Statistics version 25.0 was used for statistical analysis.

After excluding non-eligible subjects (Figure 1) , the sample size realized as 275 patients with a 1:1 gender distribution. However, Most of the ICS users were female (n=107, 54%) (P = 0.04).

The mean age of the participants was 37.7 (23.3) years. The ICS users were significantly older J o u r n a l P r e -p r o o f than the non-ICS users (P = 0.002), and had a higher weight, 71.02 (27.9) kg (P = 0.015). There were more obese patients among the ICS user group (n=109, 55%) compared to non-ICS users group (P =0.003).

The most prevalent comorbidities in the sample were diabetes (n=72, 26.2%), hypertension (n=64, 23 .3%), and obesity (n=62, 22.5%). The ICS user group had more renal failure (P = 0.038), cardiovascular diseases (P = 0.04), and hypertension (P =0.012). However, more dyslipidemia occurred in the non-ICS user group (P = 0.02). No significant difference was found for any other comorbidities. The majority of the sample had mild-persistent asthma. The asthma severity considerably varied between ICS and non-ICS users, more intermittent cases occurred in the non-ICS users (P < 0.001), with more moderate and severe cases in the ICS users (P < 0.001).

A small proportion of the sample was using other medications, 9 (3.3%) were using beta-blockers, 27 (9.8%) ACE inhibitors, and 1 immunosuppression. The majority were using other asthma medication than ICS, including salbutamol (n=215, 78.2%) and ipratropium (n=65, 23.6%). These medications were also used with ICS, 169 (85.4%) were using salbutamol and 58 (29.3%) ipratropium (P < 0.001). The majority of the ICS users were using the ICS/LABA combination, 90 (45.5%) fluticasone/salmeterol, and 45 (22.7%) budesonide/formoterol. The most frequently used ICS monotherapy was fluticasone (n=47, 23.7%) (Figure 2 ).

The variability of COVID-19 severity was assessed in terms of the variables related to the patient, disease, and medication ( Table 2 ). The disease severity was similar in the ICS and non-ICS user groups (P = 0.12). However, the use of the combination ICS/LABA therapy resulted in more mild to moderate (n=89, 55.6%), and severe-critical cases (n=12, 85.7%), compared to the asymptomatic cases in the ICS monotherapy users (P < 0.001). No significant difference in disease severity was noted with salbutamol (P = 0.75), Ipratropium/ tiotropium (P = 0.53), or gender (P = 0.24). The COVID-19 severity was significantly different between smokers and non-smokers (P = 0.015), with 2 (14.3%) of the severe-critical patients currently smoking compared to 4 (4%) in the asymptomatic group and only 2 (1.3%) in the mild to moderate cases. COVID-19 disease severity was significantly increased in patients presenting with non-asthmatic pulmonary disease (P = 0.006), renal failure (P= 0.03), cardiovascular disease (P = 0.003), hypertension (P < 0.001), J o u r n a l P r e -p r o o f diabetes (P < 0.001), and malignancy (P = 0.008). There was no significant difference in the disease severity in patients suffering from liver disease (P = 0.064), stroke (P = 0.056), dyslipidemia (P = 0.48), or hypothyroidism (P = 0.31). COVID-19 severity was also not significantly different in patients taking beta-blockers (P = 0.18), ACE inhibitors (P = 0.15), and immunosuppressing therapy (P = 0.58). Lastly, the BMI category and asthma severity were positively correlated with COVID-19 severity (Spearman: 0.12; P = 0.042) and (Spearman: 0.165; P = 0.006) respectively. Increased age was also significantly correlated with a more severe presentation of the disease (Spearman: 0.39; P <0.001).

After adjusting for asthma severity in the ordinal logistic regression ( Table 3) 

The COVID-19 related clinical outcomes of the sample were compared between ICS and non-ICS users ( Table 4 ). The majority of the sample (n=227, 82.5%) were home-isolated, compared to 33 (12%) admitted to the ward, and 14 (5.1%) admitted to the ICU. There was no significant difference in the care setting, based on ICS use. In total, 19 (6.9%) of the admitted group were ventilated, 9 used ICS with 10 non-ICS users (P = 0.56). No significant difference was observed in the type of ventilation support (i.e., invasive versus non-invasive) between the groups (P = 0.082). However, the mean days of ventilation were lower in the non-ICS users 2.25 (0.95) days compared with the ICS users 16.07 (18.74) (P = 0.006). The mode of ventilation at baseline and after three days were either PRVC/VC+, BiLevel, and BiPAP, with PRVC/VC+ mostly used at baseline, 8 (2.9%), and after 3 days, 10 (3.6%), which was not statistically significant for the two groups. The change in the type of ventilation mode between days 0 and 3 was different between ICS and non-ICS users. No change in the three ventilation modes was observed in the ICS users, but subsequently a significant change to BIPAP occurred after 3 days of ventilation (P < 0.0001) ( Table 5) . Oxygen use was similar between the two groups (P = 0.74). The oxygen devices used included NC (n=7, 2.5%), and HFNC (n=7, 2.5%) (P = 0.704), also similar in the two groups. The majority of the hospitalized group were ICS users, yet this finding was not statistically significant J o u r n a l P r e -p r o o f (P = 0.65). The mean LOS was comparable between the two groups (P = 0.43). Of the 19 (6.9%) patients admitted to the ICU, 14 (73.7%) were ICS users compared to 5 (6.5%) non-ICS users (P = 0.78). The mean ICU LOS was slightly higher in the ICS users (n=11. 9, 9.4 ), compared to the non-ICS users (n=7.8, 5.3) (P = 0.43). ARDS (n=6, 2.2%), and AKI (n=6, 2.2%) were the most frequent complications, followed by septic shock (n=5, 1.8%); however, no statistically significant difference in complications between ICS and non-ICS users was noted. The mortality rate was 9 (3.3%) and the majority were ICS users (n=8, 4%) (P = 0.45).

The prevalence of asthma in patients with COVID-19 is 5.6% in Italy (23), 5.2% in Spain (24), 14% in the UK (25) , and 17% in the USA (26) . Similar findings were reported for the general population in these countries (27)(28) presenting with respiratory problems. In the current study, there was no difference in ICU admission between the two groups (P = 0.78), and the ICU LOS was comparable between the groups (P = 0.43). Two additional studies reported that the risk of ICU transfer were similar between the two groups (22, (43) (44) (45) . In the current study, there was no significant difference in the rate of complications (i.e., ARDS, AKI, and septic shock), oxygenation, ventilation, type of oxygen device mode, and type of ventilation when ICS was used. However, the days of ventilation were significantly increased in ICS users (P = 0.006) and the improvement in ventilation mode after three days from baseline was evident in the non-ICS users (P < 0.0001). According to literature, asthma was significantly associated with a longer intubation time, with or without ICS therapy (P = 0.002) (33) . We posit that the duration of ventilation is more indicative of the disease prognosis than the hospital or ICU LOS.

According to Williamson et al. most comorbidities (i.e., cardiovascular diseases, diabetes, severe asthma, obesity, malignancy, kidney and liver diseases, and autoimmune conditions) were associated with an increased risk of COVID-19 related mortality. In the current study, the COVID-19 case fatality rate (CFR) was 3.3% in asthmatic patients. This rate is slightly higher than the CFR reported in the general population (2%)(2), however, it is lower than the mortality rate reported by Lohia et al. in patients with antecedent respiratory diseases (adj OR: 1.36 [1.08-1.72], P = 0.01) (35) . Notably, no difference was observed between ICS and non-ICS users (P = 0.45). According to Feng et al., critical patients had a higher mortality rate compared to severe or moderate cases (6) .

Several limitations of this study need to be addressed in further research. Firstly, although the baseline characteristics were varied, a limited number of patients from a single center was recruited J o u r n a l P r e -p r o o f which may affect the generalizability of the study. Another key limitation is that most patients had mild persistent asthma; and ICS and non-ICS users were not perfectly matched. Such variations may ultimately affect the representativeness of the sample. Additionally, the severity of the disease was not investigated in terms of the ICS dose and frequency. The data collected were based on previously written clinical notes which may be subject to information bias. For more accurate results, these findings should be validated with larger sample size in a prospective study setting, targeting post-COVID-19 respiratory sequelae and the effect of the ICS dose changes, in addition to evaluating other asthma medications which were minimally used in the current study.

Overall, more severe or critical cases occurred in patients using the ICS/LABA combination, as well as hypertensive and cancer patients. However, the ICS therapy had no effect on the severity of the COVID-19, disease complications, and mortality in asthmatic patients. The continued use of ICS during this pandemic should be encouraged to prevent asthma exacerbations.

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

The authors have no conflicts of interest to declare concerning the research, authorship, and/or publication of this article.

The study was approved by the Institutional Review Board of the King Abdullah International Medical Research Center (KAIMRC) (RC 20/504/R). 

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