Nonsteroidal anti‐inflammatory drugs in acute viral respiratory tract infections: An updated systematic review

Abstract In this systematic review, we aimed to assess the efficacy and safety of nonsteroidal anti‐inflammatory drugs (NSAIDs) in treating respiratory tract infections in adults and children. PubMed, Scopus, Web of Science, Cochrane, and Embase databases were searched. A total of 34 randomized clinical trials were included in this systematic review. We assessed the risk of bias of all included studies using the Cochrane tool for risk of bias assessment. The evidence on ibuprofen, naproxen, aspirin, diclofenac, and other NSAIDs were rated for degree of uncertainty for each of the study outcomes and summarized using the grading of recommendations assessment, development, and evaluation (GRADE) approach. Our findings suggest that high‐quality evidence supports the use of NSAIDs to reduce fever in both adults and children. However, the evidence was uncertain for the use of NSAIDs to reduce cough. Most studies showed that NSAIDs significantly relieved sore throat. The evidence for mortality and oxygenation is limited. Regarding the adverse events, gastrointestinal discomfort was more frequently reported in children. For adults, our overall certainty in effect estimates was low and the increase in gastrointestinal adverse events was not clinically significant. In conclusion, NSAIDs seem to be beneficial in the outpatient management of fever and sore throat in adults and children. Although the evidence does not support their use to decrease mortality nor improve oxygenation in inpatient settings, the use of NSAIDs did not increase the rate of death or the need for ventilation in patients with respiratory tract infections. Further studies with a robust methodology and larger sample sizes are recommended.


| Risk of bias
Appendices 2-6 present the risk of bias of individual studies for each of the NSAIDs. The overall risk of bias for ibuprofen and diclofenac studies was low. In the naproxen group, the risk of bias was unclear for 3 studies and low for 1 study. 13 In aspirin studies, only 2 out of 9 studies provided details about blinding of outcome assessment, therefore, the risk of bias due to inadequate blinding of outcome assessment is unclear. The overall risk of bias in the aspirin studies was unclear to low (Appendices 2-6).

| Findings
Below, we present an overview of the effects of each of the NSAIDs on our outcomes: fever, cough, sore throat, respiratory distress, hospital stay, and adverse events.

| Ibuprofen
Twelve studies that assessed the efficacy of Ibuprofen on signs and symptoms of ARTI were finally included in our systematic review. Tables 2 and 3 present the results of each of these studies. [14][15][16][17][18][19][20][21][22][23][24][25] Fever Four studies investigated the effectiveness of ibuprofen for fever control in children in the outpatient setting. Kim et al 19 compared ibuprofen with dexibuprofen and found that ibuprofen reduced fever by 1.38˚C ± 0.84˚C and was not significantly different from dexibuprofen. Yoon et al 25 compared ibuprofen with dexibuprofen for fever reduction during a 6-hour period and found that ibuprofen reduced fever by 0.9˚C ± 0.9˚C and was not significantly different from dexibuprofen. Hay et al 18

Sore throat
Four studies investigated ibuprofen effects on the sore throat in adults. Two out of 4 studies used ibuprofen as an add-on to other drugs. Gwaltney 17

Length of stay
Hay et al 18 investigated the clinical recovery of outpatient children from the disease on the second and fifth day; 33% and 40% of patients in ibuprofen and paracetamol groups recovered, respectively.
We did not find any study to investigate LOS and ibuprofen in adults.

Mortality
Only 1 study assessed mortality as an outcome with the use of ibuprofen. Bernard et al 14 reported a nonsignificant small reduction in mortality.

| Naproxen
Four studies investigated the efficacy of naproxen in ARTIs, and the results are presented in Table 4. 13, 26-28

Fever
Sperber et al 28 examined the effect of naproxen on subjective chilliness score (0-4) and the presence of fever on individuals inoculated with rhinovirus. They reported that naproxen effectively prevented fever (RR, 0.14; 95% CI, 0.03 to 0.59) and improved chilliness scores in a 4-day trial.

Cough
Sperber et al 28

Sore throat
Sore throat was investigated in three studies. However, because of inadequate reporting, we were unable to determine effect estimates. In the Sperber et al trial, 28 naproxen did not significantly relieve sore throat (MD, 0.5; 95% CI, −0.93 to 1.9).

ARDS
Hung et al 13 used a combination of naproxen, clarithromycin, and oseltamivir in patients with influenza compared with oseltamivir alone.

Length of stay
Patients who received clarithromycin and naproxen as an add-on to oseltamivir in the Hung et al trial 13

| Diclofenac
Three studies investigated the efficacy of diclofenac in ARTIs. [29][30][31] Fever Two studies investigated fever control using diclofenac. In the study  Table 5.
Overall, diclofenac effectively reduced fever in adults with ARTI symptoms.

Cough
No studies in the diclofenac group investigated cough-related outcomes.

Sore throat
Two studies investigated the effectiveness of diclofenac in the treatment of sore throat. Bettini et al 29  adults with influenza-like symptoms.

ARDS, LOS, and mortality
No studies involving diclofenac investigated these outcomes.

Gastrointestinal adverse events
Three studies investigated GI outcomes. Weckx et al 31

| Aspirin
Nine studies investigated the efficacy of aspirin in ARTIs and the results are presented in Tables 6 and 7 Abbreviations: CI, Confidence interval; RR, Risk ratio. *The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).

Fever
Three articles assessed fever reduction for aspirin and all showed a significant reduction of fever.

Sore throat
Six studies assessed the effects of aspirin on sore throat using a variety of measures and tools. 32 Although Penicillin is used in both groups, the Ibuprofen group had a significant reduction in sore throat. Ibuprofen likely results in a large decrease in pediatric sore Throat.

ARDS -not reported
No studies investigated the efficacy of viral ARDS in the pediatric population.

GRADE Working Group grades of evidence:
High certainty: We are very confident that the true effect lies close to that of the estimate of the effect Moderate certainty: We are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different Abbreviations: CI, Confidence interval; RR, Risk ratio.
*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
reported a moderate reduction in pain, whereas the rest of the studies did not show a significant difference with placebo.

ARDS, mortality, and LOS
The study by Kor et al in 2016, 38 assessed the effects of aspirin compared with placebo in 390 adult patients at risk of ARDS. The study did not show a significant reduction in respiratory distress, ICU admission, ventilation support, or mortality with aspirin.

GI adverse events
Seven studies investigated GI adverse events in adults. 32,[34][35][36][38][39][40] Kor et al 38 reported that gastrointestinal bleeding was not significantly related to a 7-day intravenous use of low-dose aspirin. These 7 studies showed differing results with great imprecision.
We pooled six studies for the meta-analysis that used 1000 mg aspirin for up to 3 days on adult patients in the outpatient setting.

GRADE Working Group grades of evidence:
High certainty: We are very confident that the true effect lies close to that of the estimate of the effect Moderate certainty: We are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different Low certainty: Our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect Very low certainty: We have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect Explanations: a. fever in this study is not reported as mean temperature. A 4-score subjective scale and consecutive dichotomous temperature measurement are reported; b. The total number of participants is below 100; c. Surrogate outcomes are used for ARDS. a co-intervention of clarithromycin was used along with naproxen; d. A co-intervention of clarithromycin was used along with naproxen and e. Effect estimates in 3 studies demonstrate a wide confidence interval; this could be due to a sample size of less than 100 patients per trial. Also, effect estimates are not consistent in larger trials.
*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). 0%

| DISCUSS ION
The findings of our review provide a comprehensive evidence profile on the use of NSAIDs in ARTIs. Our results have been presented across different settings and populations to ensure convenience for practical reference by clinicians. Our review suggests that the current evidence supports the use of most NSAIDs with high-certainty in fever control and with moderate certainty for sore throat. However, for ARDS-related outcomes, mortality, duration, and course of the disease, the certainty of the evidence are low.
Our findings confirm that ibuprofen is an effective antipyretic in adults and children and may start acting in a shorter interval after administration compared to paracetamol. However, the evidence does not support that it can reduce fever more effectively than paracetamol. The effects of ibuprofen on cough differed substantially across trials; Probably because the pathophysiological pathways that generate cough are complicated and diverse, and ibuprofen affects them differently. Older studies suggested the use of ibuprofen for cough, but newer and higher-quality evidence does not support its prescription for the sole purpose of relieving sore throat.
The evidence supports the use of naproxen for fever in adults, but its use for cough, sore throat, and more severe adverse outcomes like hospitalization, ARDS, and mortality is not supported by evidence. Naproxen prescription in children may be associated with an increased risk of gastrointestinal adverse events.
Diclofenac is also effective for fever reduction and may have a longer duration of effect compared with aspirin. However, its use for Diclofenac likely does not increase GI upset.

GRADE Working Group grades of evidence:
High certainty: We are very confident that the true effect lies close to that of the estimate of the effect

Moderate certainty:
We are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different Abbreviations: CI, Confidence interval.
*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
cough and sore throat cannot be suggested based on current evidence. Diclofenac has shown more common gastrointestinal adverse effects compared with celecoxib, and less common compared with aspirin. However, our confidence in these findings is low because of the low event rates in the underlying studies.
While the antipyretic effects of aspirin are confirmed in our systematic review, the evidence is uncertain regarding its precise effects on cough and sore throat and studies have conflicting results. It can also cause a small increase in the rate of gastrointestinal adverse effects.  Abbreviations: CI, Confidence interval; RR, Risk ratio.
*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).

Vaja et al 6 published a systematic review and meta-analysis on
the safety of NSAIDs for usage in LRTIs, which examined mortality and the need for ventilation support. Their review that mainly consists of observational studies suggests a decline in mortality. In contrast, our review from 3 RCTs suggests no effect in either mortality or ventilator support for low-dose aspirin. Salah et al 47 in a recent meta-analysis of aspirin efficacy in Covid-19 also reported that aspirin did not affect mortality. Our findings suggest that ibuprofen may reduce mortality, however, our confidence in current evidence is low.
Vaja et al 6  NSAIDs effectively reduced pain in URTIs. Our results for diclofenac strongly suggest a large reduction in sore throat pain; however, the evidence for ibuprofen and naproxen is not as certain and shows a smaller magnitude of effect. Also, the evidence with moderate certainty shows that low-dose aspirin did not affect sore throat pain.
In a meta-analysis of 2 RCTs, Kim  Explanations: a. lacking information on allocation and randomization, also the intervention was not blinded to participants nor the examiners; b. blinding, randomization and concealment not explained and c. very small sample sizes.
*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).

| Limitations
The wide scope of this review and use of nonhomogeneous variables by included studies prevented pooling of the data and meta-analysis.
The results of a systematic review are limited by the quality of included studies. Some of the included studies had significant methodological flaws, which can decrease our confidence in the results of this systematic review. Particularly, small sample sizes and low event rates were key concerns in many of the included studies.
RCTs that exclusively investigate the efficacy of naproxen, diclofenac, and celecoxib in viral respiratory infections are limited, and thus we need further robust studies to reach a consensus on their efficacy.

| CON CLUS ION
In conclusion, NSAIDs seem to be beneficial in the outpatient management of fever and sore throat in adults and children. However, they do not seem to decrease mortality or improve oxygenation in inpatient settings. Further RCTs with robust methodology and a larger sample size are recommended.

E TH I C S A PPROVA L S TATE M E NT
Ethics code: IR.IUMS.FMD.REC.1399.507.

ACK N OWLED G EM ENT
None.

D I SCLOS U R E
The authors declare no conflict of interest. ww.google.com%252F.

DATA AVA I L A B I L I T Y S TAT E M E N T
The data that support the findings of this study are openly avail-