The effect on mortality of antipyretics in the treatment of influenza infection: Systematic review and meta-analyis

Abstract

To determine whether antipyretic treatment for influenza infection influences the risk of mortality in animal models and humans.
A systematic search of Medline, Embase and the Cochrane Register of Controlled Trials was undertaken to identify randomized placebo-controlled trials of antipyretic use in influenza infection in animal models or humans that reported mortality. A quantitative meta-analysis of the risk of death using Peto's one step odds ratio with calculation of the pooled risk of death and standard evaluation of heterogeneity was undertaken.
Not applicable.
Not applicable.
Risk of mortality associated with antipyretic use in influenza infection.
Eight studies from three publications met the inclusion criteria. No human studies were identified. The risk of mortality was increased by antipyretic use in influenza-infected animals with a fixed effects pooled odds ratio of 1.34 (95% CI 1.04-1.73). An increased risk was observed with aspirin, paracetamol and diclofenac.
In animal models, treatment with antipyretics for influenza infection increases the risk of mortality. There are no randomized placebo-controlled trials of antipyretic use in influenza infection in humans that reported data on mortality and a paucity of clinical data by which to assess their efficacy. We suggest that randomized placebo-controlled trials of antipyretic use in human influenza infection are urgently required, and that these are sufficiently powered to investigate a potential effect on mortality.

Full text

The effect on mortality of
antipyretics in the treatment of
influenza infection: systematic
review and meta-analyis
Sally Eyers
1,2,3
+Mark Weatherall
2,3
+Philippa Shirtcliffe
1,2
+
Kyle Perrin
1,2
+Richard Beasley
1,2,4
1
Medical Research Institute of New Zealand, Private Bag 7902,Wellington 6242, New Zealand
2
Capital & Coast District Health Board, Wellington, New Zealand
3
University of Otago Wellington, Wellington, New Zealand
4
University of Southampton, Southampton, UK
Correspondence to: Richard Beasley. E-mail: Richard.Beasley@mrinz.ac.nz
Summary
Objective To determine whether antipyretic treatment for influenza
infection influences the risk of mortality in animal models and humans.
Design A systematic search of Medline, Embase and the Cochrane
Register of Controlled Trials was undertaken to identify randomized placebo-
controlled trials of antipyretic use in influenza infection in animal models or
humans that reported mortality. A quantitative meta-analysis of the risk of
death using Peto’s one step odds ratio with calculation of the pooled risk of
death and standard evaluation of heterogeneity was undertaken.
Setting Not applicable.
Participants Not applicable.
Main outcome measures Risk of mortality associated with antipyretic
use in influenza infection.
Results Eight studies from three publications met the inclusion criteria.
No human studies were identified. The risk of mortality was increased by
antipyretic use in influenza-infected animals with a fixed effects pooled odds
ratio of 1.34 (95% CI 1.04–1.73). An increased risk was observed with aspirin,
paracetamol and diclofenac.
Conclusion In animal models, treatment with antipyretics for influenza
infection increases the risk of mortality. There are no randomized placebo-
controlled trials of antipyretic use in influenza infection in humans that
reported data on mortality and a paucity of clinical data by which to assess
their efficacy. We suggest that randomized placebo-controlled trials of
antipyretic use in human influenza infection are urgently required, and that
these are sufficiently powered to investigate a potential effect on mortality.
DECLARATIONS
Competing interests
The Medical
Research Institute of
New Zealand and
the University of
Otago have received
research funding
from
GlaxoSmithKline,
one of the
manufacturers of
paracetamol. RB has
received fees for
consulting and
speaking from
GlaxoSmithKline
Funding
SE and KP are
Health Research
Council of New
Zealand Clinical
Research Training
Fellows. No specific
funding was
obtained for this
work
Ethical approval
Not applicable
RESEARCH
J R Soc Med 2010: 103: 403–411. DOI 10.1258/jrsm.2010.090441 403

Introduction
In response to the recent global influenza pandemic,
guidelines recommend that paracetamol or ibupro-
fen be used to treat fever and systemic symptoms of
influenza, in both children and adults.
1,2
These rec-
ommendations are qualified by the acknowledge-
ment that there is little scientific evidence for this
approach, but that experience suggests that it may
help and is unlikely to cause harm.
2
However, there
is evidence that fever is a phylogenetically ancient
host response to infection that may result in sur-
vival benefit and that treatment with antipyretics
may adversely influence the course of infectious
diseases.
3,4
In non-human mammals, antipyretic
treatment increases the risk of mortality due to dif-
ferent bacterial, viral and parasitic infections.
5
In
humans, the use of paracetamol for severe sepsis
may increase the risk of mortality,
6
although the
evidence regarding ibuprofen in severe sepsis is un-
certain, with one study showing a non-significant
1.8-fold increased risk
7
and another larger study
reporting similar rates of mortality in ibuprofen and
placebo groups.
8
Paracetamol and/or aspirin in-
crease the duration of viral shedding in rhinovirus
infection,
9,10
prolong parasitemia in malaria
11
and
delay healing of skin lesions in chickenpox.
12
Comparable data for influenza infection in hu-
mans are limited to a retrospective review of six
clinical trials which reported that paracetamol or
aspirin use was associated with an increased dura-
tion of illness in experimental influenza A infec-
tion.
13
The evidence for this association is of modest
strength as in the reviewed trials treatment was not
randomized and antipyretic use may have been con-
founded by illness severity.
13
Non-experimental
studies suggest an association between the use of
aspirin and Reye’s syndrome in febrile illnesses
(including influenza) in children,
14,15
however, the
nature of the association has been debated.
16
The
purpose of this systematic review is to identify ran-
domized placebo-controlled studies of antipyretic
use for influenza infection in animal models or hu-
mans and to investigate whether antipyretic use in-
fluences the risk of mortality in influenza infection.
Methods
Eligibility and search strategy
A search of Medline was conducted from January
1950 to June 2009; of EMBASE from January 1947
to June 2009 and of the Cochrane Central Register
of Controlled Trials in the second quarter of 2009.
Studies were searched for using the keywords
‘paracetamol’, ‘acetaminophen’, ‘NSAID*’, ‘non-
steroidal anti-inflammatory*’, ‘aspirin’, ‘ASA’
or ‘antipyre*’ and combined with the keyword
‘influenza’ (not ‘review*’, ‘letter*’, ‘editorial*’ or
‘conference*’). Relevant studies written in foreign
languages were translated. The reference lists of
the relevant studies were examined.
Studies that met the following criteria were
included in the meta-analysis:
+An in vivo animal study, or randomized
controlled trial in humans of influenza virus
infection;
+Treatment with the antipyretics aspirin, or
paracetamol, or a non-steroidal anti-
inflammatory drug (NSAID), and the dose of
antipyretic was below the potentially lethal
range;
+A placebo or control group was used in
comparison to the antipyretic;
+Mortality data were reported;
+The study was not an influenza vaccine trial.
Data abstraction
One author (SE) examined each paper’s title and
abstract, and the full paper if necessary, to deter-
mine if eligible for inclusion. Four authors (SE, RB,
KP and PS) independently extracted data from
selected studies including animal type and
number, antipyretic used, strain of influenza,
Reye’s syndrome model used and results (mor-
tality outcome).
Statistical methods
Meta-analysis was by Peto’s one step odds
ratio, carried out according the formulae given by
Bradburn and colleagues.
17
Publication bias was
explored by both formal statistical tests and a
funnel plot. Heterogeneity of study estimates was
tested by standard methods with the intention of
performing a meta-regression based on study level
characteristics.
18
These were pre-specified as the
type of animals, whether more than one specific
type of antipyretic was compared with the control
treatment, whether infection was with influenza
A or B and whether the study used an experi-
Guarantor
SE
Contributorship
SE undertook the
systematic review
and together with
PS, KP and RB
extracted the data
for the meta-
analysis which was
undertaken by MW.
All authors
contributed to
drafting the
manuscript
Acknowledgements
We thank Grzegorz
Lis (Kraków, Poland),
Lutz Beckert
(Christchurch, New
Zealand), Mariusz
Wolbinski
(Wellington, New
Zealand) and Ilya
Kardailsky (Hawke’s
Bay, New Zealand)
for translating
manuscripts
Journal of the Royal Society of Medicine
J R Soc Med 2010: 103: 403–411. DOI 10.1258/jrsm.2010.090441
404

mental model of Reye’s syndrome. One of the
identified papers (Crocker et al.)
19
had suffi-
ciently detailed data to be re-analysed by logistic
regression to estimate the difference in mortality
between aspirin and paracetamol in mouse models
of influenza infection.
Results
The outcome of the search strategy is shown in
Figure 1. Three publications reported eight trials
that met the inclusion criteria (Table 1).
19–21
All studies involved animal models: mice (n=7),
chickens (n=1). In two studies influenza A was
used and in six studies influenza B was used. In
two studies a chemical (the surfactant toximul)
model of Reye’s syndrome was used. The specific
antipyretic used was aspirin in eight studies, para-
cetamol in four studies, and diclofenac in two
studies. In six studies more than one antipyretic
was compared with control treatment. In total,
1116 animals were studied with 697 in the anti-
pyretic and 419 in the control treatment groups.
In the studies of Crocker et al.,
19
the effects of
aspirin and paracetamol on mortality due to in-
fluenza B infection were investigated in neonatal
and weanling mice, as well as the effects follow-
ing pre-treatment with low doses of the industrial
surfactant Toximul MP8, which produces many of
the features of Reye’s syndrome. In vitro studies
were also undertaken which demonstrated that
both aspirin and paracetamol caused a dose-
dependent reduction in interferon-induced anti-
viral responses. In the studies of Davis et al.,
20
the
effects of single or multiple doses of aspirin on
mortality due to influenza B infection were inves-
tigated in three-week-old mice. Additional experi-
ments were also undertaken in which influenza
infection was shown to interfere with aspirin
metabolism, markedly increasing the aspirin
blood levels. In the studies of Sunden et al.,
21
the
effects of aspirin and diclofenac on mortality due
to influenza A infection were investigated in
murine and poultry models of influenza encepha-
litis. Histology and immunohistochemistry were
also undertaken, demonstrating that antipyretic
treatment aggravated the haematogenous spread
of influenza virus to the central nervous system in
chicks.
Two additional studies in animal models were
excluded as mortality data could not be derived. In
a Romanian study of influenza A infection in
which mice were treated with acetylsalicylic acid,
the protective effect (expressed as the protective
index), was 50% at Day 6, but by the end of the
11-day observation period, mortality was in-
creased by 82%.
22
In a Polish study of influenza A
infection, mice treated with indomethacin or
aspirin had a 90% and 75% mortality at the end of
the 12-day observation period, respectively, com-
pared with a 50% mortality rate in both placebo
groups, representing an 80% and 50% increased
risk of mortality associated with indomethacin and
aspirin, respectively.
23
Three additional studies of influenza infection
in ferrets were excluded as the dose of antipyretics
administered was potentially lethal. In the study of
Linnemann et al.,
24
10 of 19 (53%) ferrets infected
with influenza A or B receiving aspirin died, com-
pared with none of the 11 (0%) untreated ferrets
infected with influenza A or B (odds ratio 9.9, 95%
Figure 1
QUOROM statement showing the flow of study selection
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The effect on mortality of antipyretics in the treatment of influenza infection: systematic review and meta-analyis
J R Soc Med 2010: 103: 403–411. DOI 10.1258/jrsm.2010.090441 405

CI 2.1–46.4); 6 of 13 (46%) ferrets given only aspirin
died. In the study of Deshmukh et al.,
25
which used
an arginine-deficient dietary model of Reye’s syn-
drome, 12 of 16 (75%) ferrets infected with influ-
enza receiving aspirin died, compared with 1 of 5
(20%) untreated ferrets infected with influenza B
(odds ratio 9.2, 95% CI 1.2–69.4); 2 of 6 (33%)
ferrets given only aspirin died. In the study of
Mukhopadhyay et al.,
26
which used an arginine-
deficient dietary model of Reye’s syndrome, 4 of 7
(57%) ferrets infected with influenza B receiving
ibuprofen died, compared with 0 of 5 (0%) un-
treated ferrets infected with influenza B (odds ratio
10.6, 95% CI 1.0–108.6); 1 of 5 (20%) ferrets given
only ibuprofen died.
No randomized placebo-controlled trials of
antipyretics in influenza infection in human par-
ticipants reported mortality outcomes. Three ran-
domized placebo-controlled trials were identified
that investigated the effects of antipyretics in the
treatment of suspected influenza.
27–29
In these
studies antipyretic treatment reduced fever and
symptoms compared with placebo, however, in
none was influenza positively diagnosed by
virologic means. There were four randomized con-
trolled trials of antipyretics in diagnosed influ-
enza, but none included a placebo control
group.
30–33
Three of these trials compared amanta-
dine or rimantidine with various antipyretics;
30–32
one showed amantadine was more effective than
aspirin in reducing signs and symptoms of influ-
enza,
30
another reported that rimantadine reduced
fever and symptoms of influenza early in the
course of the illness but resulted in greater viral
shedding late compared with paracetamol,
31
while
the third found no difference in the clinical course
of influenza between rimantadine and paraceta-
mol groups, although rimantadine resulted in
reduced viral shedding early in the course of the
illness.
32
There was one publication which included
data from six clinical trials of intranasal challenge
with influenza A, in which aspirin or paracetamol
were offered for symptomatic relief. Influenza
infected subjects who received antipyretics were
sick on average 3.5 days longer than those not
receiving such treatment. In a multivariate analy-
sis which considered clinical variables such as
maximum temperature and maximum number of
symptoms, only antipyretic therapy exhibited a
statistically significant relationship with duration
of illness. However, antipyretic treatment was not
Table 1
Characteristics of studies included in meta-analysis
Study Animal type Animal numbers
*
Antipyretic Strain of
influenza
Model
†
Number Reference
1Crockeret al.
19
Newborn mice T=155 Aspirin or paracetamol B –
C=98
2Crockeret al.
19
Weanling mice T=114 Aspirin or paracetamol B –
C=74
3 Davis et al.
20
Mice T=61 Single dose aspirin B –
C=60
4 Davis et al.
20
Mice T=30 Multiple dose aspirin B –
C=25
5 Sunden et al.
21
Mice T=16 Aspirin or diclofenac A Encephalitis
C=4
6 Sunden et al.
21
Chicks T=24 Aspirin or diclofenac A Encephalitis
C=6
7Crockeret al.
19
Newborn mice T=149 Aspirin or paracetamol B Reye’s syndrome
†
C=88
8Crockeret al.
19
Weanling mice T=148 Aspirin or paracetamol B Reye’s syndrome
†
C=64
*
T = Treatment group; C = Control group
†
Reye’s syndrome model: chemical (the surfactant toximul)
Journal of the Royal Society of Medicine
J R Soc Med 2010: 103: 403–411. DOI 10.1258/jrsm.2010.090441
406

randomized, and subjects treated with antipyretics
had higher maximum temperatures and more
marked symptoms, suggesting that the association
is likely to have been confounded by the severity of
the illness.
13
Table 2 shows the mortality for each of the arms
of the trials together with the calculated odds ratio
and 95% confidence intervals for mortality with
antipyretics versus placebo. Table 3 shows the
pooled estimates of mortality risk together with
the heterogeneity analysis of these trials. Both the
fixed and random effects estimates show that anti-
pyretic use is associated with an increased risk of
mortality in influenza infection in animal models.
There was no statistical evidence of heterogeneity,
and as a result we were unable to explore whether
there was any difference in effect by animal age,
which was suggested by the studies of Crocker
et al.,
19
in which the increase in mortality with
antipyretics appeared to preferentially occur in
newborn rather than weanling mice. Figure 2
shows the forest plot for these estimates. Formal
tests of publication bias were not statistically sig-
nificant and the funnel plot (not shown) did not
suggest publication bias.
In the study by Crocker et al.
19
the mortality risk
for paracetamol versus aspirin could be calculated
and there was no difference in mortality compar-
ing these two different antipyretics, odds ratio for
death: 1.0 (95% CI 0.7–1.5).
Discussion
This systematic review and meta-analysis has
shown that antipyretic treatment increases the risk
of mortality in animal models of influenza infec-
tion. No randomized placebo-controlled trials of
antipyretic use in influenza infection in humans
reported data on mortality. We suggest that ran-
domized 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 suf-
ficiently 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
Table 3
Pooled odds ratios and I
2
statistic relating risk of death and
antipyretic use in influenza-infected animals
Type of estimate OR (95% CI)
Fixed effects 1.34 (1.04 to 1.73)
Random effects 1.34 (1.04 to 1.73)
Heterogeneity
Chi-square statistic Degrees of freedom Pvalue
6.34 7 0.50
I-squared statistic
(95% CI)
0(0–64.2)
Table 2
Risk of mortality associated with antipyretic treatment in individual studies
Study Mortality/Total (%) OR (95% CI)
Number Reference Antipyretic Control
1Crockeret al.
19
70/155(45.2) 33/98(33.6) 1.6(1.0–2.7)
2Crockeret al.
19
32/114(28.1) 19/74(25.7) 1.1(0.6–2.2)
3 Davis et al.
20
40/61(65.6) 32/60(53.3) 1.7(0.8–3.4)
4 Davis et al.
20
12/30(40.0) 12/25(48.0) 0.7(0.3–2.1)
5 Sunden et al.
21
3/16(16.7) 0/4(0) 4.0(0.2–80.5)
6 Sunden et al.
21
4/24(16.7) 0/6(0) 4.0(0.3–53.6)
7Crockeret al.
19
80/149(53.7) 36/88(40.9) 1.7(1.0–2.8)
8Crockeret al.
19
50/148(33.8) 24/64(37.5) 0.9(0.5–1.6)
The effect on mortality of antipyretics in the treatment of influenza infection: systematic review and meta-analyis
J R Soc Med 2010: 103: 403–411. DOI 10.1258/jrsm.2010.090441 407

either lacked a placebo group,
30–33
a virologic diag-
nosis of influenza,
27–29
or randomization of anti-
pyretic treatment
13
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 complica-
tions often not recorded. As a result, there is little
evidence on which to assess the effect of anti-
pyretics 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 repli-
cate 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 tempera-
tures 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 tempera-
tures 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 symp-
toms, whereas influenza strains with a shut-off
temperature of 39°C or more cause severe symp-
toms.
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 tempera-
ture may not be reached or sustained if an anti-
pyretic 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 paraceta-
mol 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 re-
sponse to vaccination with paracetamol treatment
occurred in children with or without febrile re-
sponses.
44
As temperature responses were not
Figure 2
The forest plot shows the point estimates for each trial (in the
centre of the shaded box) and its confidence interval (the ends of
the lines).The size of the box is inversely proportional to the
individual study variance. Studies with high variance have smaller
boxes.The studies with small variance (large boxes) contribute
more to the pooled study estimate, represented by the diamond.
The odds ratios for risk of mortality are presented on the
logarithm scale and the trials are ranked in order of the size of the
odds ratio.The pooled estimate presented is the fixed effect
estimate
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Journal of the Royal Society of Medicine
J R Soc Med 2010: 103: 403–411. DOI 10.1258/jrsm.2010.090441
408

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 animals.
48
In mice,
treatment with aspirin prior to or immediately
after Streptococcus pneumoniae inoculation in-
creased mortality rates two to three-fold.
48
Fur-
thermore, an elevated temperature within the
physiologic range increases antibiotic bactericidal
capacity against Streptococcus pneumoniae.
49
These
findings are potentially relevant to the use of anti-
pyretics 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 con-
fident 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 re-
ported an increased risk of mortality with anti-
pyretic 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 exclu-
sions, there were eight studies involving 1116 ani-
mals, 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 infec-
tion. However, if the increased risk of mortality of
the magnitude present in animals applies to the
antipyretic treatment of influenza infection in hu-
mans, 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 gener-
ally have a fall in body temperature with influenza
infection.
50
This difference limits the generalizabil-
ity 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 infec-
tion 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.
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