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The coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has led to substantial changes in healthcare utilization, morbidity, intensive care resources, and mortality. [1] [2] [3] [4] [5] [6] [7] The entry point for this novel coronavirus for its further pathogenesis in humans is thought to be through an angiotensin-converting enzyme 2 (ACE2) receptor found in the lungs, arteries, heart, kidney, and intestines. 8 Non-steroidal antiinflammatory drugs (NSAIDs) might facilitate and aggravate infection with COVID-19. 9-10 The mechanisms may include upregulation of the ACE2 enzyme expression and delayed diagnostics by masking inflammation and fever. [9] [10] Initially, the World Health Organization (WHO) and national health boards issued a warning against the use of NSAIDs in COVID-19 patients and that paracetamol or acetaminophen should be administered instead. However, later and current WHO and European Medicine Agency recommendations do not call for avoidance of ibuprofen to treat COVID-19 symptoms, based on the lack of evidence to support the initially recommended warning. 10 The American Food and Drug Administration (FDA) has stated their awareness of reports of potential worsening of COVID-19 infection based on NSAID use, but the agency also stresses that there is currently insufficient evidence to support that NSAID should worsen the clinical course of COVID-19 infection. Therefore, given the current uncertainty about whether NSAID should be avoided in COVID-19 patients, we performed a nationwide register-based study to evaluate the risk of severe COVID-19 infection with recent ibuprofen prescription claims. Since very few patients were prescribed other NSAIDs, we only studied the association between ibuprofen prescription claims and outcome.
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In Denmark, all citizens hold a unique civil registration number used in all healthcare and social contacts and recorded in national administrative registries. From the Danish National Patient Registry, we identified COVID-19 positive patients between the end of February 2020 and May 16, 2020, through the use of ICD-10 diagnosis codes DB342, DB342A, and DB972 for unspecific COVID-19 infection and DB972A for COVID-19 infection with severe acute respiratory syndrome. 11 Patients below 30 years of age, as well as patients with heart failure, in whom ibuprofen is not recommended, were excluded. Finally, only 57 patients were prescribed other NSAIDs, and these patients were excluded.
From the Danish National Prescription Registry, data on prescription medication was available until April 30, 2020. We assessed ibuprofen prescription claims between January 1, 2020, and April 30, 2020, and the latest filled prescription before COVID-19 diagnosis or April 30, 2020, was used.
Ibuprofen prescription claims were further divided into >14 days before COVID-19 diagnosis versus ≤14 days before COVID-19 diagnosis. Finally, since we do not have exact data on doses available from the Danish National Prescription Registry, we defined strengths of the latest package of 200-400mg versus 600-800mg, respectively, as low-medium versus high dosage. These two groups may be viewed as proxies for daily doses of 600-1200mg and 1800-2400mg, respectively. Indications for ibuprofen and concomitant prescription for paracetamol were also assessed.
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We included information on patient age and sex from the Danish Civil Registration System. We assessed the following comorbidities: Hypertension, diabetes, prior myocardial infarction, chronic obstructive pulmonary disease, hypertension, any malignancy, and rheumatic disease.
Hypertension was defined as a redemption of at least two antihypertensive drugs in two consecutive 100-day periods prior to the COVID-19 diagnosis, as done previously. 12 All other comorbid conditions were identified from the Danish National Patient Registry up to five years prior to COVID-19 diagnosis.
The study outcome was a 30-day composite of severe COVID-19 diagnosis (ICD-10: DB972A), admission to an intensive care unit (ICU), or death. The Danish National Patient Registry was used to identify the first two components of the composite endpoint, whereas vital status was identified from the Danish Civil Registration System. Patients admitted to an ICU three days before the COVID-19 diagnosis up to 30 days after the COVID-19 diagnosis were defined as admitted to an ICU and incorporated into the composite endpoint. For cases where the ICU admission was ahead of the COVID-19 diagnosis, risk time began at the time of COVID-19 diagnosis.
Continuous variables are reported using median and 25-75 percentiles. Categorical variables are reported using counts and percentages. Thirty-day absolute risks and average risk ratios
This article is protected by copyright. All rights reserved (treatment effects) for the ibuprofen versus non-ibuprofen COVID-19 patient groups standardized to the age, sex, and comorbidity distribution of all patients were derived from multivariable Cox regression. 13 The models included the following covariates: age (in groups 30-50, >50-60, >60-70, >70-80 and >80 years), sex, diabetes, prior myocardial infarction, chronic obstructive pulmonary disease, hypertension, cancer and rheumatic disease. Data management and analyses were performed using SAS, version 9.4 (NC, Cary, USA) and R, version 3.6.1. 14
According to Danish legislation, register-based studies do not require ethical committee approval or patient consent. In accordance with the General Data Protection Regulation (GDPR), the data responsible institute in the Capital Region of Denmark has approved the use of the data sources for research purposes (approval number P-2019-191). Data are accessed on secure servers under Statistics Denmark and cannot be shared according to Danish legislation.
Of a total of 4,842 patients with COVID-19 infection between the end of February and May 16, 2020, 4,002 patients formed the study population. A total of 264 patients (6.6%) filled an ibuprofen prescription claim prior to COVID-19 diagnosis. Patients with preexisting heart failure (n=208), <30 years (n=575), or who filled a prescription for other non-steroidal anti-inflammatory drugs (n=57) were excluded.
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Characteristics of age, sex and comorbidities were generally comparable between the two study groups (Table 1) . Patients with ibuprofen prescription claims tended to be older and more likely to have hypertension, though insignificant, as well as the prevalence of diabetes, myocardial infarction, chronic obstructive pulmonary disease, and cancer were numerically higher for patients with ibuprofen prescription claims. Characteristics between patients with ibuprofen prescription claims >14 days before COVID-19 versus ≤14 days before COVID-19 were also comparable ( Table   2 ). Indications for ibuprofen prescription were available for 220 patients of 264 patients who were prescribed ibuprofen: 13 (5.9%) patients were prescribed ibuprofen due to rheumatic disease/inflammation and the remaining 207 (94.1%) patients due to pain. Of these 220 patients, 156 (70.9%) were also prescribed paracetamol.
A total of 688 patients met the 30-day composite endpoint, 42 (15.9%) in the ibuprofen group, and 646 (17.3%) in the non-ibuprofen group ( 
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The average risk ratio for patients with versus without a recent ibuprofen prescription claim prior to COVID-19 diagnosis standardized to the age, sex, and comorbidity distribution of all patients was 0.96 [95% CI 0.72-1.23]. The corresponding average risk ratio for ibuprofen prescription claims ≤14 days before the COVID-19 diagnosis versus >14 days before COVID-19 diagnosis (reference) was 0.90 [95% 0.39-1.57].
The dosage of ibuprofen was not directly available from the Danish National Prescription Registry. 
In this nationwide study on the association between ibuprofen prescription claims and severe COVID-19 infection, defined as a COVID-19 diagnosis with severe acute respiratory syndrome, intensive care unit admission, or fatal trajectory, we found no significant association between recent ibuprofen prescription claims and the composite endpoint.
This article is protected by copyright. All rights reserved Respiratory, septic, and cardiovascular complications and prolonged recovery have been linked to NSAID use in COVID-19 infectious disease. 9, 15 In addition to the changing recommendations regarding ibuprofen and other NSAID use in the context of COVID-19 from the WHO and several national health boards, several experts have advocated against the use of these drugs in COVID-19 infected patients and suggested paracetamol or acetaminophen as alternative treatments. 15 Currently, the WHO do not call for avoidance of ibuprofen to treat COVID-19 symptoms. The European Medicine Agency as well as the American FDA also do not advocate against the use of ibuprofen, and the FDA calls for more evidence to support the drug safety of NSAIDs including ibuprofen. Our results do not provide sufficient evidence to change the current recommendations. Reassuringly, the overall results were consistent with results in which ibuprofen prescription claims were divided into >14 days before COVID-19 diagnosis versus ≤14 days before COVID-19 diagnosis. Finally, although the dosage of ibuprofen was not directly available from the Danish National Prescription Registry, we used the strength of the ibuprofen package of 200-400mg and 600-800mg, respectively, to divide patients into low-medium versus high dosage groups. In these analyses, we did not find any significant differences in severe COVID-19 outcome between the two dosage groups.
In our study, ibuprofen users were defined based on prescription fills and information on whether or how many ibuprofen pills the patients actually took is not available.
However, the proxies for ibuprofen dosage mentioned above did not provide evidence to suggest a dose-response relationship between ibuprofen strength and severe COVID-19 outcome. In addition, patients on prescription ibuprofen are presumably more likely to actually use the medication on a more regular and even daily basis. As such, the lack of an association with outcome for patients who claimed a prescription for ibuprofen within 14 days of the COVID-19
This article is protected by copyright. All rights reserved diagnosis is likely to be valid. Since ibuprofen also can be purchased as an over-the-counter (OTC) drug in Denmark, we cannot exclude potential misclassification of ibuprofen exposure, as patients in the non-ibuprofen group may have used OTC ibuprofen. We did not have data on the medication used during hospitalization for COVID-19. As such, we do not have information on whether ibuprofen use was continued or discontinued, which may have had an impact on our results. Whether patients actually were using ibuprofen or they avoided it on the basis of physician advice and/or the public attention in March 2020 on the potential negative effect on COVID-19 infection severity remain unknown. In support of our study findings, a limited number of recent studies including reviews have also not found any evidence suggesting worsening of COVID-19 infection in relation to ibuprofen or NSAID use. 10, [16] [17] [18] [19] Follow-up data on outcome was limited to May 16, 2020, which may limit the registration of severe COVID-19 infection for patients diagnosed with COVID-19 at the end of the study period. However, the majority of patients hospitalized for COVID-19 were in hospital in the beginning of April ensuring that the greater majority of the included patients had sufficient follow-up to allow the study of the 30-day outcome measure. Although we adjusted for several confounding factors, we cannot rule out residual or unmeasured confounding. Given the observational design, results are associations, and no conclusions concerning causality can be made. However, we applied average treatment effect analyses with standardization of the age, sex and comorbidity distribution in an attempt to minimize confounding by indication issues and mimic a randomized controlled trial setting. For these reasons, patients of younger age and with heart failure, in whom ibuprofen was not used, were excluded per study design. In addition to a lack of laboratory data to confirm that each case had a positive swab test, our sample is based on hospital registries, including only cases evaluated for hospitalization needs and/or hospital-based staff. Although most COVID-19 infections in
This article is protected by copyright. All rights reserved Denmark are located in the capital region and more densely populated areas, the use of nationwide data minimizes selection bias based on geographical differences.
In this nationwide study, we did not find recent ibuprofen drug prescription claims prior to COVID-19 diagnosis to be significantly associated with severe, including fatal trajectory of COVID-19
infection.
What is the current knowledge on the topic?
-Recommendations regarding ibuprofen use in relation to coronavirus disease 2019 (COVID-19) have been conflicting and to date, no studies have addressed the risk of severe COVID-19 between ibuprofen and non-ibuprofen users.
What question did this study address? -Is ibuprofen prescription redemption associated with severe outcome of COVID-19?
What does this study add to our knowledge? -In this nationwide study, there was no significant association between ibuprofen prescription claims and severe COVID-19.
-Ibuprofen prescription to patients with COVID-19 does not appear to be associated with severe COVID-19 trajectory. 