The Benefit and Harm of Fever Suppression by Antipyretics in Influenza
Condition: Influenza
MeSH terms: Influenza, Human
Study type: Interventional
Phase: Phase 4

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

Detailed description: 
      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.
    

Intervention name(s): Paracetamol; Placebo; Backup NSAID ibuprofen
Intervention type(s): Drug; Drug; Drug
Intervention description(s): Paracetamol 1 tablet (500mg) four times daily. For a maximum period of 5 days if the patient is still having fever. When required, participants may take up to 2 tablets (1gm) in each dose.; (Identical-looking) Placebo 1 tablet four times daily. For a maximum period of 5 days if the patient is still having fever. When required, participants may take up to 2 tablets in each dose.; Backup NSAID ibuprofen 200mg orally every 8 hourly will also be provided to all participants, which can be taken when necessary (PRN) if the participant finds the fever intolerable.
Other intervention name(s): Acetaminophen; ibuprofen
Intervention MeSH terms: Acetaminophen; Ibuprofen
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Double (Participant, Care Provider)
Primary purpose: Treatment
Keywords: Influenza; Antipyretics; Fever