The Benefit and Harm of Fever Suppression by Antipyretics in Influenza

The purpose of this study is to investigate the potential benefits and risks of antipyretics use in naturally occurring influenza virus infections in humans.

Background:

Being one of the commonest conditions encountered in modern medical practice, fever is commonly regarded as an illness that has to be treated, both by medical professionals and patients. However, objective and convincing evidence is lacking that naturally occurring fever is harmful, and there is growing evidence that fever may serve an important host defense mechanism in infections and the risks of its suppression may far outweigh its apparent benefits. In acute respiratory infections including influenza, antipyretics are commonly being prescribed as a symptomatic treatment. Evidence from different randomized controlled trials, however, had challenged the actual amount of clinical benefit achievable by fever suppression for improving the patients' comfort and behavior. On the other hand, evidence from animal and human challenge studies has suggested that antipyretic therapy may actually prolong the duration of illness, suppress humoral antibody response, and increase the level and duration of viral shedding.

The knowledge gap:

Most of the currently available evidence on the harms and benefits of antipyretic treatment of upper respiratory tract infections (URTIs) are from either experimental animal studies, or human challenge studies with various respiratory viruses, or from randomized controlled trials (RCTs) on patients with fever of presumed viral origin. There has yet been no RCT that has investigated on the effect of antipyretics on the clinical course, disease duration, and the pattern of viral shedding in naturally occurring acute URTIs of viral origin in humans. Whereas acute URTIs can be caused by a range of viral and non-viral causes, influenza virus infection is one of its leading cause, and its pathogenesis is relatively well understood compared to some other respiratory viruses.

Aim:

To investigate the potential benefits and risks of antipyretic use in naturally occurring influenza virus infections in humans.

Design and subjects:

The study is a double-blind, randomized controlled trial. Four hundred young adults aged 18-30 years will be recruited when they present with symptoms of acute respiratory infection within 48 hours of symptoms onset to university health clinics, and being tested positive with a QuickVue rapid influenza test. They will receive their clinical consultation and prescriptions as indicated as usual, and being randomized to receive either paracetamol or placebo, and given back-up NSAID for intolerable fever when required. Blood specimen, nasal and throat swabs will be collected on the same day (day 1). They will be followed-up on day 4, day 7 and day 10 for further collection of nasal and throat swabs, and on day 28 for a final blood taking. A symptom diary will be kept by each participant for 10 days for monitoring the clinical course of the infection.

Potential significance:

This will be the first RCT to investigate the effect of antipyretics on the clinical course, disease duration, and the pattern of viral shedding in naturally occurring influenza virus infection in humans. Findings from this study will have important contribution to our understanding on the role of fever as a host defense mechanism, and help to inform the appropriate clinical management approach in human influenza virus infection.

Eligibility Criteria:
Inclusion Criteria:

* Adults aged between 18-30
* Presenting with symptoms of acute URTI (at least two among the following symptoms: body temperature ≥37.8°C, cough, rhinorrhea, sore throat, headache, myalgia/arthralgia) within 48 hours of illness onset
* being tested positive with a QuickVue rapid influenza test

Exclusion Criteria:

* Allergic to paracetamol or any other antipyretics
* Have any underlying immunocompromized condition or be receiving immunosuppressive agents.
* Have any history of chronic liver disease, or any active lung, heart or renal diseases requiring regular medication.