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Invited Review Articles

Use of Nonsteroidal Anti-inflammatory Drugs for COVID-19 Infection: Adjunct Therapy?

Zhao, Daniel BA*; Zhang, Sandy BA*; Igawa, Teryn BA*; Frishman, William MD

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doi: 10.1097/CRD.0000000000000340
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Abstract

Severe acute respiratory distress syndrome coronavirus (COVID-19) is a novel coronavirus strain that was first detected in December 2019 and declared the cause of a global pandemic by the World Health Organization on March 11, 2020.1 As of August 2020, there have been more than 21 million cases and 760,000 deaths attributed to COVID-192 in 212 countries.

Coronaviruses are single-stranded, positive-sense RNA viruses responsible for causing diseases ranging from mild upper respiratory infections to the highly fatal Middle East respiratory syndrome (MERS) and severe acute respiratory syndrome (SARS).3 COVID-19 is transmitted through respiratory droplets and enters the human body by binding to angiotensin-converting enzyme 2 (ACE2) receptors. ACE2 receptors are located in multiple tissues, including the lungs, heart, gastrointestinal tract, blood vessels, and kidneys.4,5 Once inside the body, the virus initiates an inflammatory response that both damages tissue and inhibits the body’s natural immune response.3 In 20% of cases, severe disease ensues, and these patients develop organ damage, leading to respiratory failure, cardiogenic shock, coagulopathy, or septic shock.3,6

Elderly patients and those with an underlying disease, including chronic lung disease, asthma, heart disease, diabetes, chronic kidney disease, liver disease, or immunosuppression, are at higher risk of severe illness.7 Each infected person transmits the disease to an average of 2.2 others, and there is an average incubation period of 5.8 days.8 The high infectivity, asymptomatic period, and particular risk to vulnerable populations make COVID-19 a serious public health threat. Although multiple efforts are underway to develop a vaccine that will provide the herd immunity necessary to stop the spread of this disease, the long-term safety and efficacy of the vaccine trials will not be known for months to years.8 Therefore, to alleviate the immediate infections and symptoms, numerous therapeutic strategies, including antiviral medications, anti-inflammatory drugs, nucleoside analogs, antimalarial drugs, and dietary and herbal supplements, have been proposed.9,10

Nonsteroidal anti-inflammatory drugs (NSAIDs) are one of the most common medications used to reduce fevers and treat pain caused by a variety of conditions, including inflammatory pain, muscle aches, backaches, gout, bursitis, and menstrual cramps.11 NSAIDs work by inhibiting cyclooxygenase (COX), an enzyme that converts arachidonic acid to prostaglandins. Prostaglandins play an important role in mediating the inflammatory response.12 There are 2 isoenzymes of COX: COX-1 is constitutively expressed throughout the body, and COX-2 is an inducible enzyme and increases at sites of inflammation, cancer, and infection. It is constitutively expressed in the kidneys, gastrointestinal tract, thymus, and brain.12

The common side effects of COX-2 inhibition are related to a decrease in prostaglandin 2 production in the gastrointestinal tract, leading to mucosal injury.13 Up to 68% of patients on chronic (>3 months) NSAID use experience small intestine mucosal injury, and it is recommended to coadminister a proton pump inhibitor in patients who may need long-term NSAID therapy. The reduced production of other prostaglandins, particularly prostacyclin (PGI2), is linked to an increased risk of adverse cardiovascular events in patients taking NSAIDs.14 The long-term use of NSAIDs, such as selective COX-2 inhibitors and diclofenac, has also been shown to increase the risk of major vascular events, whereas other NSAIDs such as naproxen did not increase the risk of vascular events.15 NSAIDs can also cause nephrotoxicity, which may be especially problematic for severely ill patients with fever and dehydration.16

There has been conflicting advice regarding NSAID use in patients with COVID-19. On March 14, 2020, the French Minister of Health released a public statement recommending the use of acetaminophen instead of ibuprofen based on a Lancet article hypothesizing ibuprofen could worsen COVID-19 infections.17 The World Health Organization similarly recommended against using ibuprofen initially, but has since reversed this statement.18 Rinott et al19 conducted a large retrospective cohort study exploring the outcomes of 403 patients with confirmed COVID-19 who received ibuprofen versus acetaminophen versus no antipyretic medication, and found no significant differences in mortality rates or need for respiratory support between the groups. Currently, there is a lack of conclusive evidence to recommend for or against the use of NSAIDs for COVID-19 treatment.20

One study conducted by Fu et al21 showed an upregulation of ACE2 receptors with the use of NSAIDs, which has the potential of facilitating COVID-19 entry into the human body. On the contrary, several NSAIDs, including indomethacin and naproxen, have been found to have antiviral activity, which could play an important role in treating patients with COVID-19.20,22 Furthermore, the antiplatelet and anti-inflammatory properties of select NSAIDs may be instrumental in symptomatically treating patients with COVID-19 and reducing the risk of morbidity and mortality.23,24

This article examines various NSAID properties to evaluate their potential beneficial effects in the context of their use as an investigational treatment for COVID-19.

ANTIVIRAL ACTIVITY OF NSAIDs

Currently, there are no specific antiviral treatments for patients with COVID-19. A number of antiviral therapies that were investigated for SARS and MERS, such as ribavirin and lopinavir-ritonavir, are currently being investigated as potential therapies for severe acute respiratory distress syndrome coronavirus (SARS-CoV)-2.25 Broadly, a number of antiviral strategies have been elucidated thus far, including targeting glycoprotein–host cell receptor interactions and the processing of polyproteins by viral proteases.26 The broad groups of therapeutic agents considered include those that block viral entry into host cells, block viral replication and survival in host cells, and dampen the host immune response.25

NSAIDs are promising as a potential therapeutic option due to their demonstrated antiviral properties against RNA viruses. For instance, COX-1 (SC-560) and COX-2 inhibitors (celecoxib) were found to have potent prophylactic antiviral activity on mice models later infected with influenza A.27 In another study, a combination of antiviral therapy and NSAIDs was found to ameliorate severe pulmonary inflammation and survival in H7N9-infected mice.28 In addition, an open-label randomized controlled trial found that a combination of clarithromycin, naproxen, and oseltamivir was optimal for reducing viral load and pneumonia in hospitalized patients with H3N2 infection.29

Perhaps more intriguing, the antiviral properties of NSAIDs have been found in viruses that share greater genetic homogeneity with SARS-CoV-2, such as MERS and SARS-CoV-1. Amici et al investigated the effect of indomethacin on coronavirus replication both in vitro and in vivo by measuring viral titers in human lung epithelial A549 cells and canine coronavirus–infected dogs, respectively. They found indomethacin demonstrated potent, dose-dependent antiviral activity and cytoprotective effects against human SARS-CoV-1 through the inhibition of viral RNA synthesis.30 In contrast, other agents that are currently being investigated as potential COVID-19 therapies, such as interferon (IFN) α and ribavirin, have exhibited no major effect on viral replication in vitro.30

A similar study led by Xu et al31 demonstrated that indomethacin has potent antiviral activity against SARS-CoV-2 in vitro and in vivo, and that a combination of indomethacin and symptomatic treatment dramatically decreased recovery time in CoV-infected dogs. Moreover, these investigators demonstrated that indomethacin achieved greater efficacy than a combination of ribavirin and symptomatic treatment, and similar efficacy as treatments with anti-canine coronavirus serum, canine hemoglobin, canine blood immunoglobulin, and IFN.31

In light of these findings, several clinicians have begun using indomethacin to treat patients with COVID-19, with preliminary success. Most notably, Rothstein et al have treated more than 60 cases with suspected and confirmed COVID-19 and have reported that 25–50 mg of indomethacin twice daily appears helpful in the symptomatic relief of nonhospitalized patients with incessant coughing, diffuse musculoskeletal pain, and chest pain associated with inspiratory effort.32

Although the mechanism of indomethacin has not been fully elucidated thus far, results of past studies suggest that indomethacin does not act on ACE2 receptors to inhibit viral entry or affect intracellular survival. In addition, its antiviral activity is likely independent of COX inhibition. Rather, the most likely proposed mechanism of indomethacin is inhibition of intracellular viral RNA replication by interfering with the activity of Nsp7, a nonstructural protein of SARS-CoV-2.33 There is also strong evidence to suggest that NSAIDs have similar potent antiviral activity against a variety of RNA viruses through interference with stress-sensitive cellular signal transduction pathways and transcription factors.34 Ultimately, more work needs to be done to investigate the underlying mechanisms of indomethacin-mediated antiviral activity against SARS-CoV-2.

ANTI-INFLAMMATORY ACTIVITY OF NSAIDs

In severe cases of SARS-CoV-2 infection, extreme inflammation induced by the virus can result in a highly lethal acute respiratory distress syndrome (ARDS). ARDS has many causes, including sepsis and pneumonia, but its underlying pathology ultimately involves a “cytokine storm.” A massive release of proinflammatory cytokines recruits additional inflammatory cells that release toxic mediators to cause local damage to the lung.35 One of the major mechanisms by which coronaviruses induce such powerful inflammation is through activation of the MYD88 signaling cascade via host pattern recognition receptors. This causes downstream activation of nuclear factor (NF)-κB, which induces transcription of various proinflammatory cytokines, including tumor necrosis factor-α, interleukin-6, and chemokines.36

These inflammatory cytokines can spill into the circulatory system, resulting in systemic damage and multiorgan dysfunction, including damage to the heart.37 In various studies, cardiac markers and electrocardiogram abnormalities have been positively correlated with inflammatory markers. In a study by Guo et al,38 plasma troponin T levels were positively correlated with plasma high-sensitivity C-reactive protein levels. Ma et al39 also demonstrated levels of cardiac enzymes were positively correlated with C-reactive protein and procalcitonin, and electrocardiogram abnormalities were positively correlated with procalcitonin and lymphocyte counts. These findings suggest the inflammation underlying SARS-CoV-2 infection may be closely related to myocardial injury. As described by Guo et al,38 the release of proinflammatory cytokines after infection may cause reductions in coronary blood flow and an increased risk of thrombosis.

NSAIDs have shown promising anti-inflammatory activity against the development of ARDS. Platelets, an acute-phase reactant, have been found in significant quantities in the lungs of patients with ARDS, where platelet activation, migration, and accumulation in the alveoli are often seen. As an antiplatelet agent, acetylsalicylic acid (ASA), commonly referred to as aspirin, has been proposed as a potential treatment for ARDS and sepsis via several mechanisms: (1) inhibition of COX-1 and COX-2, thereby preventing the formation of thromboxane A2 (TXA2) involved in platelet activation and aggregation, and of proinflammatory prostaglandins; (2) downregulation of NF-κB to prevent synthesis of proinflammatory cytokines; (3) release of nitric oxide (NO), which inhibits leukocyte migration through the endothelium; and (4) production of the anti-inflammatory ASA-triggered 15-epi-lipoxin A4. These last 2 mechanisms appear to be unique to ASA.22 However, all NSAIDS can suppress NF-κB activation to varying degrees.40

In a systematic review of 15 preclinical studies conducted by Panka et al,41 various studies on animal models demonstrated ASA improved oxygenation and decreased inflammation and pulmonary edema. In a mouse model of acute lung injury, Zarbock et al42 found inhibition of TXA2 by pretreatment with ASA reduced platelet–neutrophil interactions, resulting in decreased neutrophil recruitment and improved oxygenation and survival. Panka et al41 also conducted a meta-analysis of 3 clinical studies which showed an association between ASA use and a reduced incidence of ARDS. In one such cohort study of medical intensive care unit admissions, Erlich et al43 demonstrated prehospitalization antiplatelet therapy, which included ASA, was associated with a reduced incidence of ARDS. In another prospective study of patients with ARDS, ASA use before and/or during an intensive care unit stay was associated with a significant reduction in mortality.44 While clinical trials need to be conducted to further elucidate the role of aspirin in the management of ARDS, the available animal models and observational studies suggest aspirin use may be able to reduce the inflammation and mortality associated with acute lung injury.

Selective COX-2 inhibitors have also been proposed to attenuate viral inflammation.23 Zheng et al45 demonstrated that the COX-2 inhibitors celecoxib and mesalazine used in combination with the neuraminidase inhibitor zanamivir improved outcomes in mice with H5N1 influenza infection. Triple combination therapy with zanamivir, celecoxib, and mesalazine resulted in significant improvements in survival and inflammatory markers (e.g., interleukin-6, IFN-γ, and tumor necrosis factor-α) when compared with zanamivir alone. Thus, COX-2 inhibitors may serve as a useful adjuvant therapy when used in combination with antiviral agents.

Much remains to be learned about the anti-inflammatory properties of NSAIDs in the context of ARDS. Although the available data on NSAIDS are not yet sufficient to justify its use in preventing and treating ARDS, the current research does suggest future studies investigating the role of NSAIDs, and perhaps other COX inhibitors, in reducing viral-mediated acute lung inflammation and its downstream effects may yield promising results.

ANTITHROMBOTIC ACTIVITY OF ASPIRIN

Thrombi form from the aggregation and activation of platelets at the site of endothelial injury.46 Virchow’s triad has classically been used to describe the factors contributing to thrombosis: endothelial damage, venous stasis, and a hypercoagulable state.47 All 3 of these factors are present in patients with COVID-19. For instance, underlying health conditions such as hypertension, diabetes, and cardiovascular disease are contributors to baseline endothelial inflammation. In addition, immobilization during prolonged hospitalizations and hypoxia-induced changes in red blood cell structure can contribute to venous stasis and a hypercoagulable state, respectively.48

The complications of severe coagulopathy are numerous and severe. Patients with COVID-19 have been observed to clot off venous catheters, develop clots in their dialysis filters, and have a high rate of thrombotic complications, including stroke, venous thromboembolism, ischemic limbs, and disseminated intravascular coagulation. In light of these findings, a number of clinicians have called for trials to further investigate the role of prophylactic anticoagulants, including low-molecular-weight heparin and unfractionated heparin, in patients at higher risk of severe coagulopathy.49

Although an inflammation-induced hypercoagulable state likely plays a role, more research is ultimately needed to fully elucidate the mechanism of thromboembolic events in patients with COVID-19. As an acute-phase reactant, platelets and their subsequent activation likely play an important role in early stages of the viral infection and may directly contribute to a hypercoagulable state and subsequent thromboembolic events.24 Past studies have shown platelet activation is highly prevalent in pneumonia, which is present in 80–100% of patients hospitalized for COVID-19.50 The acute phases of pneumonia are marked by increased levels of platelet activation markers, such as CD40L, P-selectin, and platelet thromboxane, as well as artery dilatation, a contributor to vascular endothelial damage and subsequent thrombosis.51–53 Therefore, as an antiplatelet agent, ASA may be a therapeutic option for COVID-19 patients with pneumonia at risk of further thromboembolic complications.

Low-dose ASA (81 mg “baby aspirin”) primarily exerts its antithrombotic effects through irreversible inhibition of COX-I, which decreases downstream synthesis of TXA2, a potent platelet activator and recruiter and prothrombotic agent. Other NSAIDs, in contrast, reversibly inhibit COX-I, and this temporary inhibition of COX-I is insufficient to significantly decrease TXA2 synthesis.14 Therefore, ASA is the only approved antiplatelet agent among NSAIDs.

Clinical studies have supported the use of ASA in pneumonia as well. A previous study by Corrales-Medina et al54 demonstrated the early phase of pneumonia might be complicated by myocardial infarction (MI), a thromboembolic event. A later study by Cangemi et al55 found a significant association between MI as an early complication of pneumonia and in vivo platelet activation and serum thromboxane B2 levels. Falcone et al56 investigated the effects of ASA in elderly patients with community-acquired pneumonia. The study found ASA users had lower 30-day mortality rates, compared with non-ASA users. Among ASA users, the study also found a marked reduction in cardiovascular complications, such as MI and stroke. Ultimately, Falcone et al56 concluded that in patients with pneumonia, COX-1 activation may serve as a trigger for MIs. In light of these findings, early treatment with ASA and other antiplatelet agents may serve as a viable antithrombotic treatment in patients with COVID-19 at risk of developing cardiopulmonary complications.57

However, caution is needed when prescribing other NSAIDs in patients at risk of thromboembolic events. While ASA exerts antiplatelet effects, there is a concern for an increased risk of thrombosis with nonselective NSAID use. Due to their nonselective COX inhibition, COX-2 inhibition results in decreased PGI2 synthesis. PGI2 is a major regulator of vasodilation, and decreased levels of PGI2 are associated with an accelerated thrombotic response. Vascular COX-2 deletion has been shown to accelerate thrombosis and elevate blood pressure in vivo.14 Low levels of ASA, on the contrary, inhibit TXA2 to a greater degree than its inhibition of PGI2, supporting the use of “baby aspirin” to maximize its antiplatelet effects while minimizing the risk of thrombosis.58 Thus, it is important for physicians to weigh the known risks of increased thrombosis with nonselective NSAID use versus the potential antiplatelet benefits associated with COX-1 inhibition seen with ASA use when considering it as a therapy for COVID-19. Further research is ultimately needed to determine the lowest therapeutic dose and duration of NSAID therapy that will minimize the risk of adverse effects while maximizing any potential benefits in the context of SARS-CoV-2 infection.

CONCLUSIONS

The available literature does not recommend for or against the use of NSAIDs in patients at risk of or with SARS-CoV-2 infection. Our review of the literature suggests NSAIDs may be beneficial as an adjunct treatment in combating COVID-19. Most notably, NSAIDs have demonstrated antiviral properties. Indomethacin, in particular, has been shown to inhibit viral replication in a variety of RNA viruses, including SARS-CoV-1 and SARS-CoV-2. Furthermore, NSAIDs also have anti-inflammatory properties and may attenuate the cytokine storm that ultimately results in ARDS, an often fatal sequela of severe viral infection. ASA, in particular, has demonstrated reduced leukocyte recruitment in animal models of acute lung injury and reduced mortality due to ARDS in observational studies. As an antiplatelet agent, ASA may also reduce the risk of thromboembolic complications associated with COVID-19 infection. Based on the available evidence, we recommend further studies to evaluate the efficacy and safety of various NSAIDs as potential pharmacologic interventions for SARS-CoV-2. One such study is already underway in the United Kingdom, where researchers are conducting a multicenter, randomized clinical trial investigating ibuprofen’s role in preventing respiratory failure due to COVID-19 infection.59 Similarly, another randomized clinical trial in France is currently investigating naproxen’s role in reducing 30-day mortality in critically ill patients hospitalized for COVID-19 infection.60 Ultimately, as readily available and cost-effective agents, NSAIDs warrant further investigation regarding its potential role as adjunct therapy for patients with COVID-19, in addition to supportive care.

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Keywords:

coronavirus; COVID-19; nonsteroidal anti-inflammatory drugs; adjunct therapy

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