Effect of the Duration of NSAID Use on COVID-19.

Background and Objectives: Non-steroidal anti-inflammatory drugs (NSAIDs) are commonly used to control pain and fever. However, their effect on COVID-19 infected patients has not been fully studied. In this study, we investigated the effect of the duration of NSAIDs use on COVID-19 infection and clinical outcomes. Materials and Methods: In South Korea, 25,739 eligible patients who received COVID-19 testing between 1 January and 31 July 2020, were included in this retrospective observational cohort analysis. Based on the date of the first COVID-19 test for each patient, NSAID prescription dates were used to separate patients into two groups (short-term group: <2 weeks; long-term group: 8−12 weeks). COVID-19 infectivity and clinical outcomes were analyzed. We used the propensity score-matching (PSM) method. Results: Of the 580 patients who had taken NSAIDs before the date of COVID-19 test, 534 and 46 patients were grouped in the short- and long-term NSAID-use groups, respectively. We did not find a statistically significant increased risk of COVID-19 infection (adjustment for age and sex, p = 0.413; adjustment for age, sex, region of residence, comorbidity, Charlson Comorbidity Index, and current use of medication, p = 0.259) or change in clinical outcomes, including conventional oxygen therapy, admission of intensive care unit, artificial ventilation, or death, between the two groups in which the PSM method was applied. Conclusions: The duration of NSAIDs use did not have a statistically significant effect on COVID-19 infectivity or clinical outcomes. However, further studies looking at clinical presentation and laboratory test results in a large number of people should be performed.

Prevalence of NSAID use among people with COVID-19 and the association with COVID-19-related outcomes: Systematic review and meta-analysis.

AIM: Recent reports of potential harmful effects of nonsteroidal anti-inflammatory drugs (NSAIDs) in treating patients with coronavirus disease 2019 (COVID-19) have raised great concern. METHODS: We searched the PubMed, EMBASE, Cochrane Library and MedRxiv databases to examine the prevalence of NSAID use and associated COVID-19 risk, outcomes and safety. RESULTS: Twenty-five studies with a total of 101 215 COVID-19 patients were included. Prevalence of NSAID use among COVID-19 patients was 19% (95% confidence interval [CI] 14-23%, no. of studies [n] = 22) and NSAID use prior to admission or diagnosis of COVID-19 was not associated with an increased risk of COVID-19 (adjusted odds ratio [aOR] = 0.93, 95% CI 0.82-1.06, I2  = 34%, n = 3), hospitalization (aOR = 1.06, 95% CI 0.76-1.48, I2  = 81%, n = 5), mechanical ventilation (aOR = 0.71, 95% CI 0.47-1.06, I2  = 38%, n = 4) or length of hospital stay. Moreover, prior use of NSAIDs was associated with a decreased risk of severe COVID-19 (aOR = 0.79, 95% CI 0.71-0.89, I2  = 0%, n = 7) and death (aOR = 0.68, 95% CI 0.52-0.89, I2 = 85%, n = 10). Prior NSAID administration might also be associated with an increased risk of stroke (aOR = 2.32, 95% CI 1.04-5.2, I2  = 0%, n = 2), but not myocardial infarction (aOR = 1.49, 95% CI 0.25-8.92, I2  = 0, n = 2) and composite thrombotic events (aOR = 1.56, 95% CI 0.66-3.69, I2  = 52%, n = 2). CONCLUSION: Based on current evidence, NSAID use prior to admission or diagnosis of COVID-19 was not linked with increased odds or exacerbation of COVID-19. NSAIDs might provide a survival benefit, although they might potentially increase the risk of stroke. Controlled trials are still required to further assess the clinical benefit and safety (e.g., stroke and acute renal failure) of NSAIDs in treating patients with COVID-19.

Short-term celecoxib (celebrex) adjuvant therapy: a clinical trial study on COVID-19 patients.

BACKGROUND: It is known that severe acute respiratory coronavirus 2 (SARS-CoV-2) is the viral strain responsible for the recent coronavirus disease 2019 (COVID-19) pandemic. Current documents have demonstrated that the virus causes a PGE2 storm in a substantial proportion of patients via upregulating cyclooxygenase-2 (COX-2) and downregulating prostaglandin E2 (PGE2)-degrading enzymes within the host cell. AIM: Herein, we aimed to study how short-term treatment with celecoxib (Celebrex), a selective COX-2 inhibitor, affects demographic features, early symptoms, O2 saturation, and hematological indices of cases with COVID-19. METHODS: A total of 67 confirmed COVID-19 cases with a mild or moderate disease, who had been referred to an institutional hospital in south-eastern Iran from October 2020 to September 2021, were enrolled. Demographic characteristics, symptoms, and hematological indices of the patients were recorded within different time periods. One-way ANOVA or Kruskal-Wallis tests were used to determine differences between data sets based on normal data distribution. RESULTS: O2 saturation was statistically different between the control group and patients receiving celecoxib (p = 0.039). There was no marked difference between the groups in terms of the symptoms they experienced (p > 0.05). On the first days following Celebrex therapy, analysis of complete blood counts showed that white blood cell (WBC) counts were markedly lower in patients treated with a high dose of celecoxib (0.4 g/day) than in controls (p = 0.026). However, mean lymphocyte levels in patients receiving a high dose of celecoxib (0.4 g/day) were markedly higher than in patients receiving celecoxib with half of the dose (0.2 g/day) for one week or the untreated subjects (p = 0.004). Changes in platelet count also followed the WBC alteration pattern. CONCLUSION: Celecoxib is a relatively safe, inexpensive, and widely available drug with non-steroidal anti-inflammatory properties. The therapeutic efficacy of celecoxib depends on the administrated dose. Celecoxib might improve disease-free survival in patients with COVID-19.

NSAID use and clinical outcomes in COVID-19 patients: a 38-center retrospective cohort study.

BACKGROUND: Non-steroidal anti-inflammatory drugs (NSAIDs) are commonly used to reduce pain, fever, and inflammation but have been associated with complications in community-acquired pneumonia. Observations shortly after the start of the COVID-19 pandemic in 2020 suggested that ibuprofen was associated with an increased risk of adverse events in COVID-19 patients, but subsequent observational studies failed to demonstrate increased risk and in one case showed reduced risk associated with NSAID use. METHODS: A 38-center retrospective cohort study was performed that leveraged the harmonized, high-granularity electronic health record data of the National COVID Cohort Collaborative. A propensity-matched cohort of 19,746 COVID-19 inpatients was constructed by matching cases (treated with NSAIDs at the time of admission) and 19,746 controls (not treated) from 857,061 patients with COVID-19 available for analysis. The primary outcome of interest was COVID-19 severity in hospitalized patients, which was classified as: moderate, severe, or mortality/hospice. Secondary outcomes were acute kidney injury (AKI), extracorporeal membrane oxygenation (ECMO), invasive ventilation, and all-cause mortality at any time following COVID-19 diagnosis. RESULTS: Logistic regression showed that NSAID use was not associated with increased COVID-19 severity (OR: 0.57 95% CI: 0.53-0.61). Analysis of secondary outcomes using logistic regression showed that NSAID use was not associated with increased risk of all-cause mortality (OR 0.51 95% CI: 0.47-0.56), invasive ventilation (OR: 0.59 95% CI: 0.55-0.64), AKI (OR: 0.67 95% CI: 0.63-0.72), or ECMO (OR: 0.51 95% CI: 0.36-0.7). In contrast, the odds ratios indicate reduced risk of these outcomes, but our quantitative bias analysis showed E-values of between 1.9 and 3.3 for these associations, indicating that comparatively weak or moderate confounder associations could explain away the observed associations. CONCLUSIONS: Study interpretation is limited by the observational design. Recording of NSAID use may have been incomplete. Our study demonstrates that NSAID use is not associated with increased COVID-19 severity, all-cause mortality, invasive ventilation, AKI, or ECMO in COVID-19 inpatients. A conservative interpretation in light of the quantitative bias analysis is that there is no evidence that NSAID use is associated with risk of increased severity or the other measured outcomes. Our results confirm and extend analogous findings in previous observational studies using a large cohort of patients drawn from 38 centers in a nationally representative multicenter database.

Mesalazine induced interstitial pneumonitis in the COVID era.

Mesalazine is the most widely used aminosalicylate for induction and maintenance of remission in patients with mild-to-moderate ulcerative colitis (UC). Drug-induced hypersensitivity pneumonitis is considered very rare (<1/10.000 patients). Due to its rarity and the scarce cases reported, mesalazine-induced lung injury needs to be highly suspected in a patient with onset of respiratory symptoms and UC under treatment with salicylates. It should make the clinician formulate a differential diagnosis that includes not only infections (tuberculosis, bacterial...) or the inflammatory bowel disease itself, but also the current coronavirus disease 2019 (COVID-19) since their clinical and radiological manifestations may be very similar.

Association Between Nonsteroidal Antiinflammatory Drug Use and Adverse Clinical Outcomes Among Adults Hospitalized With Coronavirus 2019 in South Korea: A Nationwide Study.

BACKGROUND: Nonsteroidal antiinflammatory drugs (NSAIDs) may exacerbate coronavirus disease 2019 (COVID-19) and worsen associated outcomes by upregulating the enzyme that severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) binds to in order to enter cells. METHODS: We conducted a cohort study using South Korea's nationwide healthcare database, which contains data for all individuals who received a COVID-19 test (n = 69 793) as of 8 April 2020. We identified adults hospitalized with COVID-19, where cohort entry was the date of hospitalization. NSAID users were those prescribed NSAIDs in the 7 days before and including cohort entry, and nonusers were those not prescribed NSAIDs during this period. Our primary outcome was a composite of in-hospital death, intensive care unit admission, mechanical ventilation use, and sepsis; our secondary outcomes were cardiovascular complications and acute renal failure. We conducted logistic regression analysis to estimate odds ratio (OR) with 95% confidence intervals (CIs) using inverse probability of treatment weighting to minimize confounding. RESULTS: Of 1824 adults hospitalized with COVID-19 (mean age, 49.0 years; female, 59%), 354 were NSAID users and 1470 were nonusers. Compared with nonuse, NSAID use was associated with increased risks of the primary composite outcome (OR, 1.54; 95% CI, 1.13-2.11) but insignificantly associated with cardiovascular complications (OR, 1.54; 95% CI, 0.96-2.48) or acute renal failure (OR, 1.45; 95% CI, 0.49-4.14). CONCLUSIONS: While awaiting the results of confirmatory studies, we suggest NSAIDs be used with caution for COVID-19 patients as the harms associated with their use may outweigh their benefits.

Lithium toxicity at therapeutic doses as a fallout of COVID-19 infection: a case series and possible mechanisms.

Lithium, a mood stabilizer used in the treatment of bipolar disorder is known for its anti-inflammatory properties with the discussion of its potential use in COVID-19 infection. The SARS-CoV-2 virus causing COVID-19 infection is known to enter the target cells through angiotensin converting enzyme-2 receptors present in abundance in the lung and renal tissue. Recent research supports the evidence for direct renal injury by viral proteins. Here we report two patients with bipolar disorder presenting with lithium toxicity in the presence of COVID-19 infection. Two patients with bipolar disorder, maintaining remission on lithium prophylaxis, presented to the psychiatric emergency with recent-onset fever and altered sensorium. Both the patient's investigations revealed lithium toxicity, elevated serum creatinine, urea and inflammatory markers. Hypernatremia, hyperkalaemia, and hyperchloremia were seen in one patient. Lithium and other psychotropic medications were stopped immediately, and COVID-19 treatment was initiated. Patient with clinical signs of lithium toxicity, hypernatremia, hyperkalaemia, and hyperchloremia developed ventricular tachycardia. He survived and regained consciousness after 2 weeks of aggressive conservative management. However, another patient died of acute respiratory failure on day 3. Possible direct infection of the kidney by SARS-CoV-2 viral proteins can manifest with acute kidney injury and lithium toxicity among patients on long-term lithium therapy. Health professionals treating COVID-19 infection among individuals on lithium therapy should be aware of the possibility of lithium toxicity in the background of renal injury.

NSAIDs and COVID-19: A Systematic Review and Meta-analysis.

BACKGROUND: Nonsteroidal anti-inflammatory drugs (NSAIDs) have been discouraged for the treatment of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections, fearing that they could increase the risk of infection or the severity of SARS-CoV-2. METHODS: Original studies providing information on exposure to NSAIDs and coronavirus disease 2019 (COVID-19) outcomes were retrieved and were included in a descriptive analysis and a meta-analysis with Cochrane Revue Manager (REVMAN 5.4), using inverse variance odds ratio (OR) with random- or fixed-effects models. RESULTS: Of 92,853 papers mentioning COVID-19, 266 mentioned NSAIDs and 61 mentioned ibuprofen; 19 papers had analysable data. Three papers described NSAID exposure and the risk of SARS-CoV-2 positivity, five papers described the risk of hospital admission in positive patients, 10 papers described death, and six papers described severe composite outcomes. Five papers studied exposure to ibuprofen and death. Using random-effects models, there was no excess risk of SARS-CoV-2 positivity (OR 0.86, 95% confidence interval [CI] 0.71-1.05). In SARS-CoV-2-positive patients, exposure to NSAIDs was not associated with excess risk of hospital admission (OR 0.90, 95% CI 0.80-1.17), death (OR 0.88, 95% CI 0.80-0.98), or severe outcomes (OR 1.14, 95% CI 0.90-1.44). With ibuprofen, there was no increased risk of death (OR 0.94, 95% CI 0.78-1.13). Using a fixed-effect model did not modify the results, nor did the sensitivity analyses. CONCLUSION: The theoretical risks of NSAIDs or ibuprofen in SARS-CoV-2 infection are not confirmed by observational data.

Randomized, placebo controlled, double blinded pilot superiority phase 2 trial to evaluate the effect of curcumin in moderate to severe asthmatics.

BACKGROUND: Curcumin, a derivative of the spice turmeric, has been adopted by Eastern medicine for centuries as an adjunct to treat several medical conditions (e.g., anorexia and arthritis) because of its well-established anti-inflammatory properties. Studies have shown that the use of curcumin in mice models has led to reduction in several inflammatory markers as well as key inflammatory pathway enzymes. As a result, studies in Western medicine have developed to determine if this recognized benefit can be utilized for patients with inflammatory lung diseases, such as asthma. This study will seek to better understand if curcumin can be used as an adjunctive therapy for improving asthma control of patients with moderate to severe asthma; a finding we hope will allow for a more affordable treatment. METHODS: This study will utilize a randomized, placebo controlled, double blinded pilot superiority phase 2 trial at an outpatient pulmonary clinic in Southern California, USA. Subjects will be receiving Curcumin 1500 mg or matching placebo by mouth twice daily for the study period of 12 weeks. Subjects will be randomized to either a placebo or intervention Curcumin. Subjects will have 6 clinic visits: screening visit, a baseline visit, monthly clinic visits (weeks 4, 8, and 12), at weeks 4, 8, and a follow-up clinic visit or phone-call (week 16). Changes in asthma control test scores, number of days missed from school/work, FEV1 (% predicted), FEV1/FVC ratio, FVC (% predicted), blood eosinophil count, blood total IgE, and FeNO levels will be compared by group over time. DISCUSSION: The therapeutic effects of curcumin have been studied on a limited basis in asthmatics and has shown mixed results thus far. Our study hopes to further establish the benefits of curcumin, however, there are potential issues that may arise from our study design that we will address within this paper. Moreover, the onset of the COVID-19 pandemic has resulted in safety concerns that have delayed initiation of our study. This study will contribute to existing literature on curcumin's role in reducing lung inflammation as it presents in asthmatics as well as patients suffering from COVID-19. TRIAL REGISTRATION: This study protocol has been approved by the Institutional Review Board at Loma Linda University Health, (NCT04353310). IND# 145101 Registered April 20th, 2020. https://clinicaltrials.gov/ct2/show/NCT04353310 .

NSAIDs in patients with viral infections, including Covid-19: Victims or perpetrators?

Taking anti-inflammatory drugs, including non-steroidal (NSAIDs), during Covid-19 infection, how much is risky? The French Minister of Health, who has raised an alarm on a possible risk deriving from the use of ibuprofen for the control of fever and other symptoms during the disease, opened the debate a few days ago. In this paper we examine available evidence from preclinical and clinical studies that had analysed the role of COX in the inflammatory process and the effects of NSAIDs in patients with infections. Most of the published studies that suggested not protective effects of NSAIDs were mainly performed in vitro or on animals. Therefore, their meaning in humans is to be considered with great caution. Based also on data suggesting protective effects of NSAIDs, we concluded that currently there is no evidence suggesting a correlation between NSAIDs and a worsening of infections. Further studies will be certainly needed to better define the role of NSAIDs and particularly COX2 inhibitors in patients with infections. In the meantime, we must wait for results of the revision started by the PRAC on May 2019 on the association ibuprofen/ketoprofen​​​​​​ and worsening of infections. Since nowadays no scientific evidence establishes a correlation between NSAIDS and worsening of COVID-19, patients should be advice against any NSAIDs self-medication when COVID-19 like symptoms are present.

Ibuprofen and COVID-19 disease: separating the myths from facts.

Introduction: The Coronavirus disease 2019 (COVID-19) poses novel challenges in the healthcare systems around the world. Concern about the role of Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) and, in particular, ibuprofen has led to significant speculation.Areas covered: A literature search was conducted to evaluate ibuprofen's potential benefits and harms in the COVID-19 disease. Angiotensin-Converting Enzyme 2 (ACE-2) is crucial entry receptor for Severe Acute Respiratory Syndrome coronavirus-2 (SARS-CoV-2) in host cells. We found no scientific evidence linking ibuprofen use and an ACE-2 overexpression. Ibuprofen suppresses the production of various pro-inflammatory cytokines that are implicated in the 'cytokine storm' and subsequent ARDS in COVID-19 disease. Nevertheless, the exact role of ibuprofen in the immune response in COVID-19 disease is still unknown. There are no double-blind, placebo-controlled studies assessing the effect of ibuprofen on COVID-19 disease progression.Expert opinion: The studies that have been performed so far demonstrate no association between ibuprofen use and increased mortality rates or an increased risk for respiratory support. Accordingly, we recommend ibuprofen to be used for managing COVID-19 symptoms.

Effect of aspirin on short-term outcomes in hospitalized patients with COVID-19.

Coronavirus disease 2019 (COVID-19) caused by SARS-CoV-2 is an ongoing viral pandemic marked by increased risk of thrombotic events. However, the role of platelets in the elevated observed thrombotic risk in COVID-19 and utility of antiplatelet agents in attenuating thrombosis is unknown. We aimed to determine if the antiplatelet effect of aspirin may mitigate risk of myocardial infarction, cerebrovascular accident, and venous thromboembolism in COVID-19. We evaluated 22,072 symptomatic patients tested for COVID-19. Propensity-matched analyses were performed to determine if treatment with aspirin or nonsteroidal anti-inflammatory drugs (NSAIDs) affected thrombotic outcomes in COVID-19. Neither aspirin nor NSAIDs affected mortality in COVID-19. Thus, aspirin does not appear to prevent thrombosis and death in COVID-19. The mechanisms of thrombosis in COVID-19, therefore, appear distinct and the role of platelets as direct mediators of SARS-CoV-2-mediated thrombosis warrants further investigation.

In adults, NSAID use vs. nonuse in the past 4 mo was not linked to increased risk for COVID-19-related mortality.

SOURCE CITATION: Wong AY, MacKenna B, Morton CE, et al. Use of non-steroidal anti-inflammatory drugs and risk of death from COVID-19: an OpenSAFELY cohort analysis based on two cohorts. Ann Rheum Dis. 2021. [Epub ahead of print.] 33478953.

Rationales and uncertainties for aspirin use in COVID-19: a narrative review.

OBJECTIVES: To review the pathophysiology of COVID-19 disease, potential aspirin targets on this pathogenesis and the potential role of aspirin in patients with COVID-19. DESIGN: Narrative review. SETTING: The online databases PubMed, OVID Medline and Cochrane Library were searched using relevant headlines from 1 January 2016 to 1 January 2021. International guidelines from relevant societies, journals and forums were also assessed for relevance. PARTICIPANTS: Not applicable. RESULTS: A review of the selected literature revealed that clinical deterioration in COVID-19 is attributed to the interplay between endothelial dysfunction, coagulopathy and dysregulated inflammation. Aspirin has anti-inflammatory effects, antiplatelet aggregation, anticoagulant properties as well as pleiotropic effects on endothelial function. During the COVID-19 pandemic, low-dose aspirin is used effectively in secondary prevention of atherosclerotic cardiovascular disease, prevention of venous thromboembolism after total hip or knee replacement, prevention of pre-eclampsia and postdischarge treatment for multisystem inflammatory syndrome in children. Prehospital low-dose aspirin therapy may reduce the risk of intensive care unit admission and mechanical ventilation in hospitalised patients with COVID-19, whereas aspirin association with mortality is still debatable. CONCLUSION: The authors recommend a low-dose aspirin regimen for primary prevention of arterial thromboembolism in patients aged 40-70 years who are at high atherosclerotic cardiovascular disease risk, or an intermediate risk with a risk-enhancer and have a low risk of bleeding. Aspirin's protective roles in COVID-19 associated with acute lung injury, vascular thrombosis without previous cardiovascular disease and mortality need further randomised controlled trials to establish causal conclusions.

The risk of mortality in patients with COVID-19 with pre-diagnosis use of NSAIDs: a meta-analysis.

The notion that the use of non-steroidal anti-inflammatory drugs (NSAIDs) may lead to adverse outcomes upon acquisition of coronavirus disease 2019 (COVID-19) should be discredited with a review of the real-life evidence. We aimed to perform a meta-analysis to summarize the risk of mortality with the preadmission/pre-diagnosis use of NSAIDs in patients with COVID-19. A systematic literature search was performed to identify eligible studies in electronic databases. The outcome of interest was the development of a fatal course of COVID-19. Adjusted hazard ratio or odds ratio/relative risk and the corresponding 95% confidence interval from each study were pooled using a random-effects model to produce pooled hazard ratio and pooled odds ratio, along with 95% confidence interval. The meta-analysis of 3 studies with a total of 2414 patients with COVID-19 revealed no difference in the hazard for the development of a fatal course of COVID-19 between NSAID users and non-NSAID users (pooled hazard ratio = 0.86; 95% confidence interval 0.49-1.51). Therefore, NSAIDs should not be avoided in patients who are appropriately indicated during the COVID-19 pandemic.