This systematic review and meta-analysis has shown that antipyretic treatment increases the risk of mortality in animal models of influenza infection. No randomized placebo-controlled trials of antipyretic use in influenza infection in humans reported data on mortality. We suggest that randomized placebo-controlled trials of the effect of antipyretic use on the risk of mortality with human influenza infection are required.
An increased risk of mortality in animals was reported in studies of aspirin, paracetamol and diclofenac. We were not able to compare the effect of different antipyretics with each other apart from a re-analysis of a single trial which presented sufficiently detailed data.19
For this analysis there was no difference in mortality comparing paracetamol with aspirin. As a result, the data are consistent with the effect on mortality as a class effect of antipyretics.
Not only were there no randomized controlled trials of antipyretic use in influenza infection in humans that reported data on mortality, but there was also a paucity of clinical data by which to assess their efficacy. The human studies identified either lacked a placebo group,30–33
a virologic diagnosis of influenza,27–29
or randomization of antipyretic treatment13
which made interpretation of results difficult. There was also little uniformity of outcomes, with factors such as length of illness, amount of viral shedding and disease complications often not recorded. As a result, there is little evidence on which to assess the effect of antipyretics on the severity and/or duration of influenza infection in humans.
There are a number of potential mechanisms whereby treatment with antipyretics may increase the risk of mortality in influenza infection. The first is that human-tropic influenza viruses replicate in the upper respiratory tract at 33–37°C and that most naturally occurring influenza A strains that infect humans are temperature-sensitive, with inhibition of replication at high temperatures within the physiological range of 38–41°C.34–37
The resulting low infectivity is likely to be due to various molecular defects, including reduced matrix protein, which is important for maintaining the structural integrity of influenza virus particles.37,38
Human influenza A virus genome RNA synthesis is inhibited at temperatures of 41°C, with failure of replication despite transcriptional activity being maintained,39
and impaired assembly of the viral components into infectious virus.37
The degree of temperature sensitivity is also a characteristic that determines virulence, such that strains with a shut-off temperature of 38°C or lower cause mild symptoms, whereas influenza strains with a shut-off temperature of 39°C or more cause severe symptoms.34
As a result, it is likely that antipyretic use leads to a reduction of the physiological febrile response which would otherwise inhibit replication. Furthermore, it suggests that the most virulent strains are those most liable to thrive with antipyretic use, as the high shut-off temperature may not be reached or sustained if an antipyretic is used and thus the virus will replicate without temperature-induced inhibition.
Temperature elevation is also associated with a wide range of immunological effects relevant to the host defence against influenza infection.40–43
These include a greater proliferative response of lymphocytes, and increased production and activity of cytokines such as interferon. Whether reducing the physiological fever with antipyretics modifies these immunological responses, and thereby influences clinical outcomes, remains uncertain.40
However, it is of interest that Crocker et al.
reported that both aspirin and paracetamol decreased the interferon-induced antiviral responses of cultured mammalian cells.19
It is also possible that the increased mortality risk with NSAID and paracetamol treatments may have been partially due to their immunological or anti-inflammatory effects, unrelated to antipyretic activity. This is suggested by the recent study which showed that the reduction in antibody response to vaccination with paracetamol treatment occurred in children with or without febrile responses.44
As temperature responses were not measured in the studies included in this meta-analysis, this issue could not be addressed in this review.
There is also evidence from animal models that antipyretics may impair the response in bacterial pneumonia which may complicate influenza illness. Similar to influenza virus, many strains of Streptococcus pneumoniae
are temperature-sensitive, with thermal death points of between 40–41°C.45–47
Likewise, the capacity to grow at 41°C is a prerequisite, but not the sole factor in determining the virulence of Streptococcus pneumoniae
in animal models.46,47
It has also been demonstrated that treatment with antipyretics may increase the risk of mortality in experimental Streptococcus pneumoniae
In mice, treatment with aspirin prior to or immediately after Streptococcus pneumoniae
inoculation increased mortality rates two to three-fold.48
Furthermore, an elevated temperature within the physiologic range increases antibiotic bactericidal capacity against Streptococcus pneumoniae.49
These findings are potentially relevant to the use of antipyretics for human influenza infection prior to the development of a secondary bacterial pneumonia, and their use during such secondary infections.
There were a number of methodological issues considered in the design and interpretation of the meta-analysis. The first is whether the systematic review identified all relevant studies. We are confident that in our comprehensive search strategy we have identified the eligible published studies including those not written in English, and the funnel plot suggested no publication bias. Two studies in animals were excluded as the actual number of deaths in each treatment group were not reported.25,26
However, both these studies reported an increased risk of mortality with antipyretic use, of between 1.5 and 1.8-fold, consistent with our calculated pooled estimate of risk. Three additional studies were excluded as potentially lethal doses of antipyretics were administered, which explained in part the 9- to 11-fold increased risk of mortality observed with antipyretics in the setting of influenza infection. With these exclusions, there were eight studies involving 1116 animals, which resulted in the study findings being limited by the low power.
The second issue is the use of the Peto's one step as the meta-analytic method to determine the odds ratio for risk of mortality. This method was chosen as it has the best performance of a number of meta-analytic techniques for studies with zero cell counts.17
Another consideration is the generalizability of the findings from animal studies to human influenza infection. The influenza viruses were laboratory-adapted for virulence to achieve a high mortality rate in the animal models used. The markedly lower mortality rate in human influenza infection also meant that the potential effect on mortality could not be examined in the few small randomized controlled clinical trials that have been undertaken of antipyretics in influenza infection. However, if the increased risk of mortality of the magnitude present in animals applies to the antipyretic treatment of influenza infection in humans, then this would be of considerable public health importance due to the widespread use of antipyretics for seasonal and pandemic influenza.
Finally, most of the animal studies included in this review utilized mouse models, which generally have a fall in body temperature with influenza infection.50
This difference limits the generalizability of the study findings, particularly in regard to the potential mechanisms of the effect observed.
In conclusion, this systematic review and meta-analysis has shown an increased mortality rate in animals treated with antipyretics during infection with influenza A or B, with no informative randomized placebo-controlled trials in humans. We propose that randomized placebo-controlled trials of antipyretic use in pandemic and seasonal influenza in humans are urgently needed in order to establish appropriate evidence-based management guidelines.