The research team led by professor Ju-Young Shin, together with researchers Han Eol Jeong and Hyesung Lee, from the School of Pharmacy, Sungkyunkwan University, South Korea found that use of nonsteroidal anti-inflammatory drugs (NSAIDs) resulted in worsened clinical outcomes among adults hospitalized with coronavirus 2019 (COVID-19) by using South Korea’s nationwide healthcare data. These results were concluded by including 18 kinds of NSAIDs which is widely used in South Korea, for example ibuprofen.

COVID-19, which was first identified in late 2019, is an ongoing pandemic and respiratory disease that is caused by the infection from the Severe Acute Respiratory Syndrome-Coronavirus 2 (SARS-CoV-2). As of August 25, 2020, there are a total of 214 countries affected worldwide, with more than 24 million confirmed cases and 82 thousand deaths. With the main symptoms of COVID-19 being high fever, cough, shortness of breath, NSAIDs are widely used to in these patients to manage their symptoms of fever and muscle pain.

In March, 2020, the French Health Minister raised concerns regarding the potential harms NSAIDs may have when used in patients with COVID-19. This was based on case reports of four COVID-19 patients who developed worsened clinical outcomes following NSAIDs use. In addition, findings from previous studies reported lower incidence of adverse outcomes associated with acetaminophen than NSAIDs. Thus, the French Health Minister recommended acetaminophen be used as first-line agents to alleviate fever symptoms, which was also supported by the World Health Organization (WHO).

These claims were based on one animal study, which increased angiotensin-converting enzyme 2 (ACE2) expressions with NSAIDs in various organs, where, ACE2 upregulation induced by NSAIDs could theoretically heighten the infectivity of SARS-CoV-2 to worsen clinical outcomes. Other mechanisms have also been suggested of which, NSAIDs could aggravate infections by upregulating COX-2 in activated B lymphocytes to interfere with antibody productions, or by selectively inhibiting interferon-γ productions that are vital for immunity against foreign pathogens.

However, with no conclusive clinical evidence on this topic available, regulatory bodies such as the United States (US) Food and Drug Administration and the European Medicines Agency have released statements that there is insufficient evidence to draw conclusions regarding this safety concern and the WHO revised their initial statement accordingly. For such reasons, current clinical practice should not be changed until further evidence becomes available. Despite the widespread use of NSAIDs, to our knowledge, there is currently no published observational study that specifically assessed the association between NSAIDs use and clinical outcomes among COVID-19 patients.

To investigate such concerns, professor Ju-Young Shin assembled an international collaborative research team comprised of a world renown clinical researcher from Harvard University, US, and an esteemed pharmacoepidemiologist from McGill University, Canada, and used the Health Insurance Review and Assessment Service (HIRA) database of South Korea, provided as part of the #OpenData4Covid19 project on March 27, 2020, by the Ministry of Health and Welfare and HIRA. Briefly, this data provided through this platform is real-world data (RWD) of all COVID19 patients in South Korea that contains healthcare utilization information based on a fee-for-service reimbursement system.

Study participants were adults (aged ≥19 years) hospitalized with COVID-19 as of April 8, 2020. Based on the history of NSAIDs use in the 7 days before and including the date of hospitalization, patients were classified as either NSAIDs users or nonusers. Moreover, we balanced any differences in sociodemographic or clinical characteristics between NSAIDs users and nonusers by applying the propensity score as weights, which was estimated based on age, sex, health insurance type, history of comorbidities and use of co-medications, to evaluate the risk of adverse clinical outcomes.

This study found that there were 1,824 adults hospitalized with COVID-19, of which, there were 354 NSAIDs users and 1,470 nonusers. NSAIDs users, as compared with nonusers, had a 54% increased risk of in-hospital death, intensive care unit admission, mechanical ventilation use, or sepsis. In addition, the study findings suggest the possibility of an elevated risk of cardiovascular complications, comprised of heart failure, myocardial infarction, and stroke, and acute renal failure associated with NSAIDs users.

Professor Ju-Young Shin, corresponding author of the study, stated that, “I am excited that our study findings could serve as important scientific and real-world evidence to help clinicians in the decision to use NSAIDs for the treatment of fever or pain among patients with COVID-19 as the harms associated with their use may outweigh their benefits”. Moreover, researchers Han Eol Jeong and Hyesung Lee, joint co-authors of the study, noted that, “We are highly pleased by being able to provide meaningful real-world evidence to clinicians during such difficult times due to the COVID-19 pandemic, and further inform the world of the greatness of South Korea’s healthcare data”.

This research was published in Clinical Infectious Diseases (IF=8.313, JCR Ranking 3.2%), a leading journal in the field of infectious disease with a broad international readership, on Monday, July 27, 2020.

※ Research Title:
Association Between Nonsteroidal Anti-inflammatory Drug Use and Adverse Clinical Outcomes Among Adults Hospitalized With Coronavirus 2019 in South Korea: A Nationwide Study

※ Research Web Site:
https://academic.oup.com/cid/article/doi/10.1093/cid/ciaa1056/5876905?searchresult=1

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