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The New Zealand Medical Journal

 Journal of the New Zealand Medical Association, 08-July-2011, Vol 124 No 1338

Antipyretic therapy for influenza infection—benefit or harm?
The recent pandemic of a novel influenza A (H1N1) strain, in the absence of widely available specific influenza treatments, has refocused attention on the management of associated symptoms such as fever.
Guidelines recommend that antipyretic treatment with paracetamol or ibuprofen is routinely administered to children and adults who develop an influenza-like illness during an epidemic or pandemic.1 This recommendation is qualified by the acknowledgement that there is little scientific evidence for this approach but that experience suggests that it may help and is unlikely to cause harm.
We propose that this recommendation may not be based on the balance of available evidence, which suggests that the use of antipyretic treatment may increase the risk of an adverse outcome in influenza infection. This evidence can be considered in three parts: what effect temperatures within the physiological febrile range have on the influenza virus, what effect fever has on host defences against influenza infection, and what effect antipyretic treatment has on outcomes in influenza infection in humans and animal models.
Influenza virus and temperature—Human tropic influenza viruses are temperature sensitive, with inhibition of replication at temperatures within the physiological range of fever induced by influenza.2-4 Influenza viruses replicate in the upper respiratory tract at temperatures between 33 and 37oC, with inhibition of replication and structural damage to the influenza virus at 38 to 41°C.
In an animal model, the restriction of viral replication with highly temperature-sensitive influenza strains was more pronounced in the lungs than nasal turbinates, an effect attributed to the higher temperature of the lungs.5
In humans, the virulence of an influenza virus is determined by its temperature sensitivity, whereby infection by strains with a shut-off temperature of ≤38OC result in mild symptoms and those with a shut-off temperature of ≥39OC are more symptomatic.2
These observations suggest that antipyretic treatment would reduce the febrile response which would otherwise inhibit influenza viral replication, thereby potentially worsening the duration and severity of the illness.
Fever and host defence—There is substantive evidence that fever is a phylogenetically ancient host response to infection which may result in survival benefit, and that antipyretic treatment may increase the risk of mortality due to different viral, bacterial and parasitic infections across different animal species.6 In response to infection, fever is associated with a wide range of potentially beneficial and detrimental effects.
Relevant to influenza, temperatures within the febrile range increase the proliferative response of lymphocytes and macrophages to infection, enhances cytotoxic T cell activity, and the production and activity of cytokines such as interferon.7,8
Antipyretic treatment in influenza infection—A recent systematic review has identified that there have been no double-blind placebo-controlled randomised clinical trials of the effect of antipyretic therapy on influenza infection in humans.9 Clinical studies have either lacked a placebo group, a virologic diagnosis of influenza or randomisation of antipyretic treatment. As a result, there is little evidence by which to assess the effect of antipyretics on the duration or severity of influenza infection in humans.
By contrast, there are data from controlled studies of the effects of antipyretics and mortality due to influenza in animals, as quantified in the recent systematic review and meta-analysis.9 This identified from eight studies that antipyretic treatment increased the risk of mortality in animal models of influenza infection, with a fixed effect pooled odds ratio of 1.34 (95% CI 1.04 to 1.73). This was observed in studies of aspirin, paracetamol and diclofenac, suggesting a class effect of antipyretics.
Clearly, the findings from the animal studies are poorly generalisable to humans, as the influenza viruses were laboratory-adapted for virulence to achieve a high mortality rate in the animal models used. Furthermore, most of the animal studies included in the meta-analysis utilised mouse models, which generally but not always, have a fall in temperature with influenza infection. This further limits generalisability, particularly in regard to the potential mechanisms of the effect of antipyretic treatment on temperature-sensitive influenza infection.
In contrast with the above findings, a recent study in a mouse model of influenza infection has demonstrated that paracetamol markedly decreases the airways infiltration of inflammatory cells, reduces pulmonary immunopathology and improves overall lung function.10 This reduction in immunopathology and morbidity did not adversely affect the induction of virus-specific adaptive responses. These data support the utility of paracetamol for reducing morbidity associated with influenza infection, although similar limitations of generalisability to human infection apply.
Conclusion—We conclude that there is an insufficient evidence base to support the use of antipyretics in the treatment of fever from influenza infection. The limited evidence that does exist suggests that the administration of antipyretics may have the potential to increase the severity of influenza illness and the risk of mortality. We suggest that randomised controlled trials of the effect of antipyretics in the treatment of influenza are undertaken as an urgent priority.
Sally Eyers
Medical Research Fellow
Medical Research Institute of New Zealand – and PhD Student, University of Otago Wellington, Wellington
Sarah Jefferies
Medical Research Fellow
Medical Research Institute of New Zealand – and Medical Registrar, Capital & Coast District Health Board, Wellington
Philippa Shirtcliffe
Programme Director
Medical Research Institute of New Zealand – and Internal Medicine Physician, Capital & Coast District Health Board, Wellington
Kyle Perrin
Programme Director
Medical Research Institute of New Zealand – and Internal Medicine Physician, Capital & Coast District Health Board, Wellington
Richard Beasley
Director
Medical Research Institute of New Zealand – and Respiratory Physician, Capital & Coast District Health Board, Wellington
Richard.Beasley@mrinz.ac.nz

Acknowledgement: The Medical Research Institute of New Zealand influenza research programme is funded by the Health Research Council of New Zealand.

References:
  1. Department of Health BTS, British Infection Society, Health Protection Agency. Clinical guidelines for patients with an influenza like illness during an influenza pandemic. 6 June 2006.
  2. Chu CM, Tian SF, Ren GF, et al. Occurrence of temperature-sensitive influenza A viruses in nature. J Virol 1982;41:353-9.
  3. Oxford JS, Corcoran T, Schild GC. Naturally occurring temperature-sensitive influenza A viruses of the H1N1 and H3N2 subtypes. J Gen Virol 1980;48:383-9.
  4. Dalton RM, Mullin AE, Amorim MJ, et al. Temperature sensitive influenza A virus genome replication results from low thermal stability of polymerase-cRNA complexes. Virol J 2006;3:58.
  5. Spring SB, Nusinoff SR, Tierney EL, et al. Temperature-sensitive mutants of influenza. VIII. Genetic and biological characterization of TS mutants of influenza Virus A (H3N2) and their assignment to complementation groups. Virol 1975;66:542-50.
  6. Kluger MJ. Fever: Its Biology, Evolution and Function. Princeton: Princeton University Press 1979.
  7. Manzella JP, Roberts NJ. Human macrophage and lymphocyte responses to mitogen stimulation after exposure to influenza virus, ascorbic acid, and hyperthermia. J Immunol 1979;123:1940-4.
  8. Hirai N, Hill NO, Osther K. Temperature influences on different human alpha interferon activities. J Interferon Res 1984;4:507-16.
  9. Eyers S, Weatherall M, Shirtcliffe P, et al. The effect on mortality of antipyretics in the treatment of influenza infection: systematic review and meta-analysis. J Roy Soc Med 2010;103:403-11.
  10. Lauder SN, Taylor PR, Clark SR, et al. Paracetamol reduces influenza-induced immunopathology in a mouse model of infection without compromising virus clearance or the generation of protective immunity. Thorax 2011;doi:10.1136/thx.2010.150318.
     
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