NSAIDs in Acute Respiratory Infection

March 16, 2020

Carl Heneghan, Jon Brassey

Access the Evidence Inventory

Translated in Portuguese by Tatiane Ribeiro, Ana Luiza Cabrera Martimbianco, Rachel Riera, Oxford-Brazil EBM Alliance

Verdict: there is a need for caution when using NSAIDs in the context of acute respiratory infections (ARI). Pre-existing medications and conditions need to be taken account of when deciding to prescribe NSAIDs for symptomatic ARI. The lowest effective dose should be prescribed for the shortest period of time. Parenteral use of NSAIDs during an ARI should be avoided.

NSAIDs do not significantly reduce total symptoms or duration of respiratory infections.

Non-steroidal anti-inflammatory drugs (NSAIDs) are widely used by patients with ARI or common cold for pain and fever relief. Their use needs to be balanced with the risks and benefits. Current research evidence in coronavirus is lacking and therefore evidence from acute respiratory infections have been used to inform this review.

Do NSAIDs increase rates of heart attacks in ARI?

Influenza-like illness and respiratory tract infection are associated with an increase in acute myocardial infarction.  A meta-analysis of 16 case-control studies reported that influenza-like illness was twice as likely in those with an acute heart attack, OR 2.01 (95% CI 1.47 to 2.76).

Long-term use of NSAIDs has been shown to be associated with an increased risk of a heart attack.  Individual data from four studies of  446,763 individuals including 61,460 with acute myocardial infarction showed that taking any dose of NSAIDs for one week or more was associated with a 50% increased risk of a heart attack. Odds ratios for increased: Ibuprofen, 1.48 (1.00 to 2.26); Diclofenac, 1.50 (1.06 to 2.04) and Naproxen  1.53 (1.07 to 2.33).

Use of NSAIDs during acute respiratory infections has been associated with an increased risk of a heart attack:

A retrospective analysis of 9,793 patients with incident acute myocardial infarction in Taiwan between 2007 and 2011 found that the use of NSAIDs during acute respiratory infection was associated with:

• Increased risk of a heart attack; adjusted odds ratio * 3.41; 95% CI 2.80–4.16);
• Without NSAIDs led to a 2.7-fold increased risk (aOR = 2.65; 95% CI = 2.29 to 3.06):
• Parenteral NSAIDs (any non-oral means of administration) was associated with much higher risk (OR = 7.22; 95% CI = 4.07 to 12.81).

Use of NSAIDs during acute respiratory infections has been associated with an increased risk of stroke:

An analysis of 29 518 patients with an incident stroke suggested that NSAIDs were associated with a more than doubling of the risk of stroke,  adjusted odds ratio,* aOR 2.27, 95% CI, 2.00-2.58). Parenteral NSAIDs were associated with a much higher risk of ischemic stroke (aOR 4.24, 95% CI, 2.92‐6.15) or a hemorrhagic stroke (aOR 9.71, 95% CI, 3.79‐24.92).

*Adjusted for discordant use of concomitant medications before the index date

NICE BNF advice 

‘All NSAID use (including cyclo-oxygenase-2 selective inhibitors) can, to varying degrees, be associated with a small increased risk of thrombotic events (e.g. myocardial infarction and stroke) independent of baseline cardiovascular risk factors or duration of NSAID use; however, the greatest risk may be in those receiving high doses long term.’

‘The lowest effective dose of NSAID should be prescribed for the shortest period of time to control symptoms and the need for long-term treatment should be reviewed periodically.’

Do NSAIDs affect the duration of the infection?

A Cochrane Systematic review including 9 trials (n=1,069) of NSAIDs for the common cold found they did not significantly reduce the total symptom score (SMD ‐0.40, 95% CI ‐1.03 to 0.24) or duration of colds. The effect on pain relief  (headache, ear pain, and muscle and joint pain) was significant.

Five studies assessed adverse effects. The pooled analysis for overall side effects suggested they were three-time more likely  (risk ratio (RR) 2.94, 95% CI 0.51 to 17.03), but this effect was not significant. Adverse effects included gastrointestinal adverse effects and lethargy/drowsiness, feeling hyperactive, feeling more awake, flushed face, difficulty sleeping, light‐headedness and dry mouth

Does the use of NSAIDs worsen outcomes in respiratory infections?

We found five studies that link the use of NSAIDs to worsening outcome, all are observational and are difficult to interpret as they may suffer from confounding by indication. patients with more severe disease and more severe symptoms may take more NSAIDs which does not necessarily cause the disease. All five studies suggest that NSAIDs worsen outcomes, which reinforces the need to take the lowest effective dose for the shortest period of time.

1. A small prospective observational study (n=57) reported that NSAIDs for >6 days and the presence of immunosuppression prior to admission were associated with prolonged hospitalization. Patients that received NSAIDs prior to hospitalization used them for a mean of 4.4 days prior to admission.
2. In a cohort of 90  consecutive patients with Community-Acquired Pneumonia (CAP) admitted to one ICU over a four year period, 32 (36%) had taken NSAIDs prior to hospital referral. Patients taking NSADS were younger,  had fewer comorbidities and a longer duration of symptoms before referral. They more often pleural empyema and lung cavitation complications (37.5% vs 7%; P = .0009), and had higher rates of bacteraemia (69% vs 27%, P = .009).
3. In a study of 221 patients with CAP 40 (18%) developed a pleuropulmonary complication. NSAIDs intake prior to admission was reported in 24 patients (11%) who were younger (51 vs. 67yrs), had fewer comorbidities (60 vs. 25%), and had a longer time between the first symptoms of CAP and the start of antibiotic therapy (6.1 vs. 2.8  days; p = 0.001). They also had higher rates of pleuropulmonary complications (33 vs. 16%; p = 0.048).
4. NSAIDs may also mask initial symptoms and delay antimicrobial therapy. A review of medical records of 106 confirmed patients with pneumococcal CAP found 20 received NSAIDs 2 to 6 days before admission. NSAIDs exposed patients were younger (43 vs 62 years), had increased complicated pleural effusions rages  (20% vs 2.3%; P = .01), and required more noninvasive ventilatory support (25% vs 4.6%; P = .003).
5. A  multicentre case-control study in 8 ICUs of 152 adult patients admitted for severe sepsis or septic shock due to bacterial community-acquired infection found that in patients using NSAIDs (27%) The average median time to the prescription of effective antibiotic therapy was longer for NSAID users (6 days, 95% CI = 3 to 7 days) than for nonusers (3 days, 95% CI = 2 to 3 days; P = 0.02).  

Do NSAIDs Impact on overall mortality in ARI? Answer available 18th March

Do NSAIDs increase renal problems and or hypertension in ARI?Answer available 18th March

Disclaimer:  the article has not been peer-reviewed; it should not replace individual clinical judgement and the sources cited should be checked. The views expressed in this commentary represent the views of the authors and not necessarily those of the host institution, the NHS, the NIHR, or the Department of Health and Social Care. The views are not a substitute for professional medical advice.