Inhaled corticosteroids downregulate SARS-CoV-2-related genes in COPD: results from a randomised controlled trial

Milne, Stephen; Li, Xuan; Yang, Chen Xi; Filho, Fernando Sergio Leitão; Cordero, Ana I Hernández; Cheng, Yang; Shaipanich, Tawimas; Eeden, Stephan F. van; Leung, Janice M.; Lam, Stephen; Sin, Don D.

doi:10.1183/13993003.00130-2021

Cited by 43 publications

(39 citation statements)

References 20 publications

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“…Also, the practice pattern may change as steroids were initially contraindicated to be utilized upon completion of some clinical trials. Steroids demonstrated benefit only in a most severe form of COVID-19 triggered ARDS while their application in sepsis is highly debatable 8 , 38 , 60 , 68 , 69 .…”

Section: Discussionmentioning

confidence: 99%

Longitudinal urinary biomarkers of immunological activation in covid-19 patients without clinically apparent kidney disease versus acute and chronic failure

Laudański

Okeke

Hajj

et al. 2021

Sci Rep

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Kidney function is affected in COVID-19, while kidney itself modulates the immune response. Here, hypothesize if COVID-19 urine biomarkers level can assess immune activation vs. clinical trajectory. Considering the kidney’s critical role in modulating the immune response, we sought to analyze activation markers in patients with pre-existing dysfunction. This was a cross-sectional study of 68 patients. Blood and urine were collected within 48 h of hospital admission (H1), followed by 96 h (H2), seven days (H3), and up to 25 days (H4) from admission. Serum level ferritin, procalcitonin, IL-6 assessed immune activation overall, while the response to viral burden was gauged with serum level of spike protein and αspike IgM and IgG. 39 markers correlated highly between urine and blood. Age and race, and to a lesser extend gender, differentiated several urine markers. The burden of pre-existing conditions correlated with urine DCN, CAIX and PTN, but inversely with IL-5 or MCP-4. Higher urinary IL-12 and lower CAIX, CCL23, IL-15, IL-18, MCP-1, MCP-3, MUC-16, PD-L1, TNFRS12A, and TNFRS21 signified non-survivors. APACHE correlated with urine TNFRS12, PGF, CAIX, DCN, CXCL6, and EGF. Admission urine LAG-3 and IL-2 predicted death. Pre-existing kidney disease had a unique pattern of urinary inflammatory markers. Acute kidney injury was associated, and to a certain degree, predicted by IFNg, TWEAK, MMP7, and MUC-16. Remdesavir had a more profound effect on the urine biomarkers than steroids. Urinary biomarkers correlated with clinical status, kidney function, markers of the immune system activation, and probability of demise in COVID-19.

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Section: Discussionmentioning

confidence: 99%

Longitudinal urinary biomarkers of immunological activation in covid-19 patients without clinically apparent kidney disease versus acute and chronic failure

Laudański

Okeke

Hajj

et al. 2021

Sci Rep

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“…15 Inhaled corticosteroids have been shown to downregulate angiotensin-converting enzyme 2 expression. 6 Ciclesonide has been shown to inhibit the PAK1 enzyme in cells, a pathogenic pathway for COVID-19 that is associated with angiotensin-converting enzyme 2. By inhibiting PAK1, ciclesonide reduces immune suppression and decreases lung inflammation.…”

Section: Discussionmentioning

confidence: 99%

“…5 Inhaled corticosteroids have also been shown to cause downregulation of COVID-19 genes. 6 Among the available inhaled corticosteroids, ciclesonide has emerged as a potential treatment option for COVID-19. In vitro, ciclesonide has been shown to have antiviral properties against COVID-19 and blocks COVID-19 viral replication.…”

mentioning

confidence: 99%

Efficacy of Inhaled Ciclesonide for Outpatient Treatment of Adolescents and Adults With Symptomatic COVID-19

et al. 2022

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IMPORTANCE Systemic corticosteroids are commonly used in treating severe COVID-19. However, the role of inhaled corticosteroids in the treatment of patients with mild to moderate disease is less clear.OBJECTIVE To determine the efficacy of the inhaled steroid ciclesonide in reducing the time to alleviation of all COVID-19-related symptoms among nonhospitalized participants with symptomatic COVID-19 infection.DESIGN, SETTING, AND PARTICIPANTS This phase 3, multicenter, double-blind, randomized clinical trial was conducted at 10 centers throughout the US and assessed the safety and efficacy of a ciclesonide metered-dose inhaler (MDI) for treating nonhospitalized participants with symptomatic COVID-19 infection who were screened from June 11, 2020, to November 3, 2020.INTERVENTIONS Participants were randomly assigned to receive ciclesonide MDI, 160 μg per actuation, for a total of 2 actuations twice a day (total daily dose, 640 μg) or placebo for 30 days.MAIN OUTCOMES AND MEASURES The primary end point was time to alleviation of all COVID-19-related symptoms (cough, dyspnea, chills, feeling feverish, repeated shaking with chills, muscle pain, headache, sore throat, and new loss of taste or smell) by day 30. Secondary end points included subsequent emergency department visits or hospital admissions for reasons attributable to COVID-19.RESULTS A total of 413 participants were screened and 400 (96.9%) were enrolled and randomized (197 [49.3%] in the ciclesonide arm and 203 [50.7%] in the placebo arm; mean [SD] age, 43.3 [16.9] years; 221 [55.3%] female; 2 [0.5%] Asian, 47 [11.8%] Black or African American, 3 [0.8%] Native Hawaiian or other Pacific Islander, 345 [86.3%] White, and 1 multiracial individuals [0.3%]; 172 Hispanic or Latino individuals [43.0%]). The median time to alleviation of all COVID-19-related symptoms was 19.0 days (95% CI, 14.0-21.0) in the ciclesonide arm and 19.0 days (95% CI, 16.0-23.0) in the placebo arm. There was no difference in resolution of all symptoms by day 30 (odds ratio, 1.28; 95% CI, 0.84-1.97). Participants who were treated with ciclesonide had fewer subsequent emergency department visits or hospital admissions for reasons related to COVID-19 (odds ratio, 0.18; 95% CI, 0.04-0.85). No participants died during the study. CONCLUSIONS AND RELEVANCEThe results of this randomized clinical trial demonstrated that ciclesonide did not achieve the primary efficacy end point of reduced time to alleviation of all COVID-19-related symptoms.TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT04377711

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“…One plausible explanation is that people with COPD may be stricter in practicing physical distancing or mask-wearing [43] , [44] . Alternatively, the inhaled corticosteroids and bronchodilators COPD patients use may suppress coronavirus replication [45] , [46] , [47] , [48] . Systemic corticosteroid usage has been associated with decreased odds of COVID-19 diagnosis [49] .…”

Section: Introductionmentioning

confidence: 99%

Diseased lungs may hinder COVID-19 development: A possible reason for the low prevalence of COPD in COVID-19 patients

Yong

2021

Medical Hypotheses

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Presently, it remains unclear why the prevalence of lung diseases, namely chronic obstructive pulmonary disease (COPD), is much lower than other medical comorbidities and the general population among patients with coronavirus disease 2019 (COVID-19). If COVID-19 is a respiratory disease, why is COPD not the leading risk factor for contracting COVID-19? The same odd phenomenon was also observed with other pathogenic human coronaviruses causing severe acute respiratory distress syndrome (SARS) and Middle East respiratory syndrome (MERS), but not other respiratory viral infections such as influenza and respiratory syncytial viruses. One commonly proposed reason for the low COPD rates among COVID-19 patients is the usage of inhaled corticosteroids or bronchodilators that may protect against COVID-19. However, another possible reason not discussed elsewhere is that lungs in a diseased state may not be conducive for the severe acute respiratory distress syndrome coronavirus 2 (SARS-CoV-2) to establish COVID-19. For one, COPD causes mucous plugging in large and small airways, which may hinder SARS-CoV-2 from reaching deeper parts of the lungs (i.e., alveoli). Thus, SARS-CoV-2 may only localize to the upper respiratory tract of persons with COPD, causing mild or asymptomatic infections requiring no hospital attention. Even if SARS-CoV-2 reaches the alveoli, cells therein are probably under a heavy burden of endoplasmic reticulum (ER) stress and extensively damaged where it may not support efficient viral replication. As a result, limited SARS-CoV-2 virions would be produced in diseased lungs, preventing the development of COVID-19.

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Inhaled corticosteroids downregulate SARS-CoV-2-related genes in COPD: results from a randomised controlled trial

Cited by 43 publications

References 20 publications

Longitudinal urinary biomarkers of immunological activation in covid-19 patients without clinically apparent kidney disease versus acute and chronic failure

Longitudinal urinary biomarkers of immunological activation in covid-19 patients without clinically apparent kidney disease versus acute and chronic failure

Efficacy of Inhaled Ciclesonide for Outpatient Treatment of Adolescents and Adults With Symptomatic COVID-19

Diseased lungs may hinder COVID-19 development: A possible reason for the low prevalence of COPD in COVID-19 patients

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