Preprint: Clinical outcomes of early aspirin versus non-aspirin NSAID use in adults hospitalized with influenza: A retrospective study

Photo Credit –CDC PHIL

Note: Nothing in this blog post should be construed as specific medical advice - as individual needs may vary - and everyone should consult their own doctor. The following is presented for educational uses only.

 

#19,296

Sixteen years ago, in A Hot Topic For Further Research, we saw a retrospective analysis in the Journal of the Royal Society of Medicine showing the risk of mortality increased by roughly 33% when antipyretics (aspirin, paracetamol, and diclofenac) were used in influenza-infected (non-human) animals.

While the mechanism behind this reported increased mortality wasn't established, it was suggested that the reduction of the natural host response to infection - fever - may have been a contributing factor.

There were a lot of limitations to that study, not the least of which is that research on mice, chickens, and even ferrets isn’t always applicable to humans. Over the next few years, we saw several other studies emerge, including:

• In 2011, in A Feverish Debate, the well respected Wellington based Medical Research Institute of New Zealand, published a paper (Antipyretic therapy for influenza infection—benefit or harm?) in the New Zealand Medical Journal that questioned the conventional wisdom of using these antipyretic drugs with influenza.

• Also from 2011 - the American Academy of Pediatrics (AAP) released a report on the use of antipyretics in children, suggesting that we ought not over-treat fevers (Clinical Report—Fever and Antipyretic Use in Children)

• And in 2013, in Adding To A Feverish Debate, we looked at a study in the Journal of Pediatrics on another possible (albeit, rare) adverse effect seen in a small number of young children with fever and dehydration at a hospital in Indiana who received treatment with NSAIDs - AKI or Acute Kidney Injury.

Somewhat related to all of this have been studies suggesting that the concurrent use of antipyretics may inhibit the immune response when receiving vaccines (see Anti-Inflammatory Meds And Vaccines and Common Pain Relievers May Dampen Vaccination Benefits).

While none of these studies provided definitive proof of harm, they (and others) have raised some interesting questions.

We revisited the topic in 2015's JJID: Evaluating The Mortality Risks Of Taking NSAIDs & ASA With Influenza, which - while subject to a number of limitations - provided some reassurance on the use of antipyretic drugs with influenza, finding that:

We found no compelling evidence that NSAID or ASA use influenced mortality in severe pH1N1.

A 2020 Danish study, published in JAMA (Association of Nonsteroidal Anti-inflammatory Drug Use and Adverse Outcomes Among Patients Hospitalized With Influenza) was similarly unable to find a link between NSAID use and increased mortality with influenza.

In this study, NSAID use was not associated with a clinically significant increased risk of ICU admission or death in patients hospitalized with influenza. While studies on the association of NSAIDs with the disease course of COVID-19 are clearly needed, the currently available data, including the present study, do not seem to support strong recommendations against using NSAIDs in patients with viral pneumonia. 

That said, this study did not establish that NSAIDs are harmless in every patient or scenario, as long-term use of NSAIDs was associated with ICU admission.

While the data has been mixed, there has also been little evidence to suggest taking NSAIDs following vaccination blunts the immune response (see  No Evidence That Analgesic Use after COVID-19 Vaccination Negatively Impacts Antibody Responses), although prophylactic use remains a concern. 

All of which brings us to a new preprint (not yet peer reviewed) by researchers at the University of Minnesota, which goes as far as to suggest possible benefits from NSAIDs in treating influenza -  although their study was small, single-center, and nonrandomized - making their findings preliminary at best. 

I've reproduced the abstract and a brief excerpt below. Follow the link to read the full report.  I'll have a postscript after the break.

Clinical outcomes of early aspirin versus non-aspirin NSAID use in adults hospitalized with influenza: A retrospective study
Suk Yin Chan-Colenbrander, Qi Wang
doi: https://doi.org/10.64898/2026.08.05.26359840
This article is a preprint and has not been peer-reviewed [what does this mean?].

Preview PDF

Abstract

Seasonal influenza remains a major cause of morbidity and mortality worldwide. Although neuraminidase inhibitors improve clinical outcomes, influenza-related deaths persist. We evaluated the associations of early aspirin and non-aspirin nonsteroidal anti-inflammatory drug (NSAID) use with clinical outcomes in adults hospitalized with influenza. This retrospective study included adults admitted to the University of Minnesota Medical Center from 2016 to 2018.

Multivariable logistic and Cox regression models adjusted for age, sex, race, smoking status, influenza vaccination status, and cardiovascular burden were used to evaluate the associations of early aspirin and NSAID use with clinical outcomes. Among 2,816 patients screened, 320 had laboratory-confirmed influenza.

Compared with unvaccinated patients, vaccinated patients had lower rates of ICU admission (11% vs. 24%; P = 0.003) and ventilatory support (6% vs. 15%; P = 0.009).

In unadjusted analyses, aspirin users had higher rates of cardiovascular complications (27% vs. 16%; P = 0.028) and lower 3-year survival (57% vs. 72%; P = 0.008).

In contrast, NSAID users had lower rates of ICU admission (7% vs. 18%; P = 0.042), cardiovascular complications (4% vs. 23%; P = 0.001), and renal complications (9% vs. 25%; P = 0.010), and higher 1-year (98% vs. 78%; P = 0.0004) and 3-year survival (89% vs. 63%; P = 0.0001).

After adjustment, aspirin use was not independently associated with any study outcome.

Early NSAID use was independently associated with lower odds of renal complications (aOR, 0.35; 95% CI, 0.13–0.97; P = 0.044) and lower hazards of 1-year (aHR, 0.11; 95% CI, 0.01–0.81; P = 0.030) and 3-year mortality (aHR, 0.33; 95% CI, 0.14–0.77; P = 0.011).

Sensitivity analyses using the Charlson Comorbidity Index yielded similar findings. Prospective studies are needed to determine whether early non-aspirin NSAID use improves clinical outcomes in adults hospitalized with influenza.

       (SNIP)

In this study, early non-aspirin NSAID use was independently associated with lower risks of renal complications and reduced 1- and 3-year mortality, whereas early aspirin use was not independently associated with clinical outcomes after multivariable adjustment. These findings emphasize the importance of distinguishing aspirin from non-aspirin NSAIDs in influenza research and raise the possibility that  earlier initiation of non-aspirin NSAIDs during influenza infection may be associated with improved clinical outcomes.

Prospective studies are warranted to determine whether these observed associations are causal and to define the optimal timing, dosage and role of non-aspirin NSAIDs as adjunctive therapy in adults hospitalized with influenza. 

        (Continue . . . ) 

While claims of potential benefits from non-aspirin NSAIDs in treating adult influenza patients may be premature, the pendulum (for now) appears to have swung away from concerns that it may be causing increased mortality.

Further research is needed, of course.

But this tortured route is a reminder why we don't cherry pick one scientific paper, and stubbornly cite it year after year. Science evolves, and our understanding of the world around us inevitably changes over time.