Effect of Antipyretic Drugs in Children with Malaria - Clinical ...

BRIEF REPORT
Effect of Antipyretic Drugs in Children
with Malaria
Bertrand Lell, 1,2,3,a Milena Sovric, 1,2,a Daniela Schmid, 1 Doris Luckner, 1,2
Klaus Herbich, 1 Hua Yan Long, 2 Wolfgang Graninger, 3
and Peter G. Kremsner 1,2
1 Research Unit, Albert Schweitzer Hospital, Lambaréné, Gabon; 2 Department
of Parasitology, Institute of Tropical Medicine, University of Tübingen, Tübingen,
Germany; 3 Department of Infectious Diseases, Internal Medicine I, University
of Vienna, Vienna, Austria
A comparison of different antipyretics in children with malaria
showed a small effect of naproxen, but not of metamizol,
on the reduction of fever peaks. Antipyretic treatment had
no effect on fever clearance and therefore should be used
cautiously in the treatment of malaria.
Fever is the most apparent sign during an acute malaria attack
and can be accompanied by other nonspecific symptoms such
as headache, diarrhea, abdominal pain, vomiting, and nausea.
The physiological role of fever in malaria and other infectious
diseases remains unclear [1], and the value of reducing fever
in children with malaria is controversial [2]. To control fever,
the World Health Organization [3] recommends mechanical
measures such as fanning, tepid sponging, and cooling blankets.
In addition to antimalarial chemotherapy, patients usually also
receive antipyretic treatment to keep fever low [4], despite
growing doubts about the need for this practice [5].
Data from Kwiatkowski [6] and our own recent in vitro data
show that increased temperatures, which correspond to febrile
temperatures in humans, inhibit the growth of Plasmodium
falciparum. It seems that malarial fever is a beneficial reaction
of the host to combat the infection by killing or inhibiting
Received 11 May 2000; revised 28 July 2000; electronically published 23 February 2001.
Informed consent was obtained from the parents or guardians of all children participating
in the study, and the study was approved by the Ethics Committee, International Foundation
of Albert Schweitzer Hospital (Lambaréné, Gabon).
Grant support: This study was supported by a ƒortüne grant from the Medical Faculty,
University of Tübingen, Tübingen, Germany, and by a grant from Gesellschaft für
Chemotherapie, Vienna, Austria.
a B.L. and M.S. contributed equally to this work.
Reprints or correspondence: Professor Peter Kremsner, Institut für Tropenmedizin,
Wilhelmstrasse 27, D-72074 Tübingen, Germany (peter.kremsner@uni-tuebingen.de).
Clinical Infectious Diseases 2001; 32:838–41
� 2001 by the Infectious Diseases Society of America. All rights reserved.
1058-4838/2001/3205-0027$03.00
838 • CID 2001:32 (1 March) • BRIEF REPORTS
growth of the parasite. Thus, reducing fever could have negative
effects on the course of the disease.
We first attempted to test this hypothesis in children treated
with acetaminophen [7]. However, it was not possible to reduce
malarial fever with this drug, and treatment with acetaminophen
was even associated with prolonged parasite clearance
times, possibly by decreasing the production of TNF and oxygen
radicals.
The present study investigated the relationship among fever,
parasite clearance, and immunologic markers (production of
cytokines and oxygen radicals) with use of 2 other nonsteroidal
antipyretic drugs. Metamizol, a pyrazolone derivative, was chosen
because it is widely used to treat fever in Africa. Naproxen,
a propionic acid derivative similar to ibuprofen, was used because
of its reported efficacy against childhood fevers [8]. Both
agents have a similar mode of action through the inhibition of
cyclo-oxygenase and subsequent prostaglandin synthesis.
Methods. The study was done at Albert Schweitzer Hospital
in Lambaréné, Gabon, which is located in an area where
P. falciparum is highly endemic [9]. Patients attending the outpatient
clinic between October 1997 and July 1998 were included
in the study if they had uncomplicated P. falciparum
malaria and met the following criteria: 2–7 years of age; asexual
parasitemia (20,000–200,000 parasites/mL of blood); temperature
of 138�C at admission or fever during the preceding 24
h; no antipyretic treatment during the preceding 8 h; and no
effective antimalarial treatment for the current infection, as
confirmed by urine tests for chloroquine and quinine (Wilson
and Edeson test) and for sulfonamides (Lignin test). Because
of the high level of chloroquine resistance in the area, patients
with a history of treatment with low doses of chloroquine were
eligible for inclusion in the study. Patients were not included
in the study if they had complicated malaria, as defined by any
of the following criteria: hemoglobin level, !8.0 g/dL; packed-
9
cell volume, !24%; leukocyte count, 112 � 10 cells/L; glucose
level, !50 mg/dL; lactate level, 13.5 mM; schizontemia, 150
9
shizonts/mL; platelet count, ! 50 � 10 cells/L; and signs of other
concomitant infection or other severe disease. Patients with
12% pigment-containing neutrophils were excluded from the
study, to prevent the enrollment of patients with highly synchronized
parasite populations hidden in the deep vasculature
[10, 11]. Children were excluded from the study when they
had a history of febrile or afebrile convulsions.
Patients were hospitalized until 2 successive thick blood
smears were negative. All patients received an infusion of 5%
glucose with 12 mg/kg of quinine dihydrochloride every 12 h.
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A single oral dose of sulfadoxine/pyrimethamine was given at
the time of discharge.
Patients were randomly assigned to 1 of 3 antipyretic treatment
groups by means of a random-numbers table: mechanical
antipyretic treatment consisting of continuous electric fanning
and tepid sponging when rectal temperatures rose above 37.5�C;
metamizol treatment administered by mouth at a dosage of 10
mg/kg every 6 h, in addition to mechanical antipyresis as described
above; and naproxen treatment administered as rectal
suppositories at a dosage of 7.5 mg/kg every 12 h, in addition
to mechanical antipyresis as described above. Expelled suppositories
were immediately readministered.
At the time of admission (day 0) and each subsequent day,
complete physical examination was done, and signs and symptoms
were recorded. Rectal body temperature was measured at
admission and then hourly until discharge (in 19 cases, temperature
was measured only every 6 h). Parasitemia was measured
through a Giemsa-stained thick blood smear by a direct
method described elsewhere [12]. This was performed on admission
and then every 6 h until 2 consecutive blood smears
were negative. Capillary blood samples were obtained on days
0 and 3 for laboratory examination, to determine the following:
hemoglobin level, packed-cell volume, leukocyte and platelet
counts, glucose level, and lactate level.
Venous blood samples (3 mL) were obtained in EDTA-containing
tubes before the start of treatment and 24, 48, and 72
h thereafter for the measurement of plasma levels of TNF, IFNg,
IL-10, and IL-12. In addition, TNF levels were measured, at
the same times, in supernatants of stimulated whole blood.
Immediately after venipuncture, 2 mL of whole blood was stimulated
with phytohemagglutinin (10 mg/mL; Sigma) or lipopolysaccharide
(0.1 mg/mL; Sigma). After 2 h of incubation at
37.5�C, supernatants were harvested and stored at �20�C until
measurement of cytokine levels. All cytokine levels were determined
by ELISA (Flexia, Biosource) according to the manufacturer’s
instructions.
Immediately after venisection, the production of oxygen radicals
was measured by addition of 10 mL of whole blood to
Krebs-Ringer-phosphate-glucose buffer containing 0.1 mg/mL
phorbolmyristate acetate (Sigma) and 11 mM luminol (Sigma)
[13]. Luminescence was measured with a luminometer (Lumat,
EG&G Berthold). The induction of oxygen radicals was expressed
in relative light units per second and was recorded every
5 min until peak values were reached.
Parasite clearance time was defined as the time in hours from
admission until the first of 2 consecutive negative thick blood
smears. Fever was assessed in 2 ways: fever clearance time,
defined as duration in hours from admission to the first time
a patient’s temperature stabilized below an indicated fever
threshold; and fever time, defined as duration in hours that an
individual’s temperature was above an indicated fever thresh-
old. A patient with only 1 fever peak very late in the course of
infection would thus have a long fever clearance time but a
short fever time. This form of analysis was done because our
in vitro study had shown that the extent of inhibition of growth
of P. falciparum depends on the time of exposure to febrile
temperatures (authors’ unpublished data).
Differences between the treatment groups were assessed by
the Kruskal-Wallis nonparametric test or by analysis of variance
with Dunnett’s procedure for post hoc comparisons. The Wilcoxon
signed rank test was used to assess differences between
time points within a group. Correlations were calculated using
Spearman’s rank correlation. Two-sided P values of !.05 were
considered significant.
Results. Ninety patients (30 patients per group) were enrolled
in the study. The 3 groups were similar at admission
with respect to demographics and clinical and laboratory data
(data not shown). All children recovered completely, and there
were no differences in terms of adverse events during hospitalization
in the 3 treatment groups.
At the time of admission, rectal temperatures were similar
in all 3 groups. After the start of treatment, 28, 29, and 27
patients in the mechanical antipyretic, metamizol, and naproxen
treatment groups, respectively, had temperatures of
138.0�C, and 14, 10, and 14 patients, respectively, had temperatures
of 140�C. In contrast to metamizol, naproxen consistently
reduced fever clearance times over a wide range of
fever thresholds (37.8�C, 38�C, 38.5 �C, and 39.5 �C). However,
this reduction was significant only at a fever threshold of 38.0�C
(mechanical antipyresis, 39 h; metamizol treatment, 39 h; naproxen
treatment, 24 h; figure 1). The fever time was significantly
lower for children receiving naproxen treatment (4.5 h
at a fever threshold of 38.5�C; P p .009)
than for those receiving
mechanical antipyresis (10.4 h at a fever threshold of
Figure 1. Mean fever clearance times and fever times at different
fever thresholds in 3 groups of children with malaria who were treated
with mechanical antipyresis only (black bar), metamizol (gray bar), or
naproxen (white bar). Vertical lines projecting from bars indicate upper
95% CI. * P ! .05,
compared with mechanical antipyresis.
BRIEF REPORTS • CID 2001:32 (1 March) • 839
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38.5�C). This finding was significant over a wide range of fever
thresholds (37.8�C, 38�C, 38.5�C, 39�C, 39.5�C, and 40�C).
Treatment with metamizol led to shortening of the fever time
at any fever threshold (6.8 h at a fever threshold of 38.5�C),
but this decrease was never significant compared with that associated
with mechanical antipyresis.
At admission, body temperature and parasitemia were significantly
correlated ( r p .34; P p .002).
Twelve and 18 h after
the onset of therapy, however, they were clearly inversely correlated
( r p �.46 and P ! .001 and r p �.26 and P p .015,
respectively).
The mean time to parasite clearance was 63 h, with no
significant difference in the time to parasite clearance in any
treatment group (mechanical antipyresis, 60 h; metamizol treatment,
63 h; naproxen treatment, 66 h). Even though parasitemia
in the mechanical treatment group was consistently lower
than that in the naproxen treatment group during the first 30
h of treatment, the difference was not significant (figure 2).
The initial clearance of parasitemia was faster in the mechanical
treatment group, in which parasitemia already had decreased
significantly 6 h ( P p .047) and 12 h ( P p .008)
after the start
of treatment, compared with parasitemia at admission. In both
the metamizol and naproxen treatment groups, a significant
decrease was first observed 18 h after the start of treatment.
A simple correlation between fever and parasite clearance
times is not meaningful, since long courses of parasitemia necessarily
lead to long courses of fever, as shown by a positive
correlation between the 2 variables in our study ( r p .74;
fever
threshold, 38.5�C). To determine the effect of fever on the
course of parasitemia, we corrected for the duration of parasitemia
by calculating the proportion of time with parasitemia
during which fever occurred (fever time/parasite clearance
time). No correlation between the corrected fever time and the
parasite clearance time was found for any fever threshold
( r p .02;
fever threshold, 38.5�C).
In all patients, plasma levels of the cytokines TNF, IFN-g, IL-
10, and IL-12 were elevated at admission. No significant differences
among the treatment groups were seen at any time point.
Parasitemia at admission was significantly positively correlated
with plasma levels of TNF ( r p .28) and IL-10 ( r p .43)
and
negatively correlated with plasma levels of IL-12 (r p �.25). On
all 3 days, temperature was highly correlated with plasma levels
of both IL-10 ( r p .78 on day 1 to r p .44 on day 4) and IFN-
g ( r p .29 on day 1 to r p .39 on day 4). No consistent cor-
relations over time were found with the other cytokines.
There were no significant differences in phytohemagglutininand
lipopolysaccharide-induced TNF concentrations between
the 3 treatment groups at any time. A common feature in all
90 cases was that ex vivo cytokine production 48 h after the
onset of therapy was significantly greater than cytokine production
at admission.
840 • CID 2001:32 (1 March) • BRIEF REPORTS
Figure 2. Course of parasitemia in 3 groups of children with malaria
who were treated with mechanical antipyresis only (�), metamizol (�),
or naproxen (�).
Lipopolysaccharide-induced TNF production at admission
was significantly inversely correlated with parasite clearance
time ( r p �.30; P p .028).
There were no significant differences in production of oxygen
radicals between the 3 antipyretic treatment groups on any day.
Peak production and the time of peak production were also
similar in the 3 treatment groups (data not shown).
Discussion. A previous study from our group showed that
it is not possible to reduce malarial fever with acetaminophen
[7]. In the present study, drugs with antipyretic properties that
are generally thought to be superior to those of acetaminophen
were used to determine whether it is possible to reduce malarial
fever and whether a reduction has an effect on the course of
parasitemia. The results show that treatment with naproxen
can, to some extent, lead to faster fever clearance than treatment
with metamizol, which had no effect. The antipyretic effect of
naproxen was more pronounced, as shown by the drug’s ability
to reduce a child’s fever time, suggesting that the drug exerts
its effect mainly by suppressing fever peaks rather than by
clearing malarial fever. If antipyretic treatment for malarial fever
is desired, then naproxen is preferable to either acetaminophen
or metamizol.
The question of whether reduction of fever is clinically meaningful
remains. Animal studies have shown both the beneficial
effect of fever and the negative effect of antipyretic treatment
in the course of infectious diseases (reviewed in [14]).
Clinical studies involving humans suggested a beneficial effect
of fever on sepsis [15] and bacterial peritonitis [16] and a
negative effect of treatment with antipyretics on rhinovirus [17]
and varicella-zoster virus [18] infections. The present study
shows that differences in body temperature do not lead to
differences in the course of P. falciparum parasitemia. This finding
is surprising in view of the clear results of in vitro studies
of this parasite, which showed a strong growth inhibitory effect
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at febrile temperatures [6]. The time spent with febrile temperatures
may not have been long enough for a visible effect.
Our in vitro studies showed that a 6-h exposure to temperatures
of 40�C at late stages leads to significant growth inhibition.
Longer exposure is needed to inhibit parasite growth at 39�C.
In the present study, however, only 6 patients (7%) had a
cumulative exposure to temperatures of 140�C for at least 6 h,
and 20 (22%) had an exposure to temperatures of 139�C for
this period of time. One reason for the small numbers of patients
exposed to these temperatures might have been the exclusion
of patients with severe malaria, who presumably would
have higher temperatures or prolonged fever. Furthermore, an
effect of fever on the course of parasitemia would be masked
by the effect of quinine, which is undoubtedly much more
effective against P. falciparum than are febrile temperatures;
thus, a beneficial effect of fever on parasitemia perhaps could
be seen in yet untreated malaria.
Antipyretics are commonly given to children with infectious
diseases, to prevent febrile convulsions. However, with P. falciparum
malaria, in which convulsions are common, more than
one-half of convulsions occur at rectal temperatures of !38�C,
suggesting that the infection, not the fever, induces convulsions
(which thus cannot be prevented by reducing fever) [19].
Plasma levels of TNF and IFN-g were, not surprisingly, associated
with fever. In addition, we found a high correlation
between plasma levels of IL-10 and body temperature. TNF
leads to the production of IL-10, which suggests a rapid
counterregulatory response to inflammatory and pyrogenic cytokines
in these children with mild malaria [20].
Our earlier study showed decreased production of radical
oxygen intermediates after acetaminophen treatment [7]. Treatment
with naproxen or metamizol did not lead to a comparable
phenomenon.
The positive correlation between temperature and parasitemia
that we found at admission has been described earlier
for a large population [21]. The initial drop in parasitemia was
faster in the mechanical antipyretic treatment group than in
the other treatment groups. The reason for this finding remains
unexplained; however, the effect was not due to fever or production
of cytokines or oxygen radicals, since there was no
significant difference in these parameters between the treatment
groups during the first 6 h of therapy. An effect of the drugs
themselves was excluded by in vitro studies showing no effect
of metamizol or naproxen treatment on the growth of P. falciparum
(authors’ unpublished data).
Taken together, the benefits from not taking antipyretics do
not seem large. However, the relative ineffectiveness of commonly
used antipyretics, the high risk of overdosing [22], and
the need to reduce drug interactions strongly argue against the
widespread practice of giving adjuvant antipyretic drugs indiscriminately
to every child with P. falciparum malaria.
Acknowledgments
We thank the children and their parents or guardians for
their participation in this study and the staff of Albert Schweitzer
Hospital (Lambaréné, Gabon) for their support.
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