E D I T O R I A L C O M M E N T A R Y

Accurate Diagnosis of Cerebral Malaria: A Role for

Parasite Histidine-Rich Protein 2?
Chandy C. John
Division of Global Pediatrics, University of Minnesota Medical School, Minneapolis
(See the article by Seydel et al, on pages xxxxx.)
The World Health Organization (WHO)
denition of cerebral malaria requires Plas-
modium falciparum parasitemia and coma
not attributable to convulsions, sedatives,
hypoglycemia, or another detectable non-
malarial cause [1]. In a series of elegant
autopsy-based studies, Taylor and col-
leagues demonstrated that as many as 23%
of children who meet this WHO denition
of cerebral malaria actually die from other
causes and that the presence of malaria
retinopathy has a >90% sensitivity and
specicity for predicting true cerebral
malaria, in which parasite sequestration is
documented in cerebral capillaries [2]. As-
sessment of malaria retinopathy in cerebral
malaria has led to signicant research ad-
vances, but the assessment requires highly
specialized training and equipment, so it
has not been practical in clinical settings in
most low-income countries.
Parasite histidine-rich protein 2
( pHPR2) is produced by P. falciparum
throughout its life cycle [3]. It is released
from infected erythrocytes as a water-
soluble protein [4]. In areas of low to
moderate transmission, plasma concen-
trations of pHRP2 appear to correspond
well to body parasite biomass [5]. Elevat-
ed pHRP2 concentrations may, there-
fore, reect a high level of sequestered
parasites. In the current issue of the
journal, Seydel and colleagues provide
evidence that high pHRP2 concentra-
tions are an excellent marker for biopsy-
or retinopathy-conrmed cerebral malaria
[6]. The study design has several strengths
that boost condence in the accuracy of its
ndings, including the use of 3 study
groups, which allowed for initial testing,
establishment of an optimized pHRP2
cutoff level, and prospective assessment of
the sensitivity and specicity of that cutoff
level. The rst study group consisted of
children with WHO-dened cerebral
malaria who died. The pHRP2 concentra-
tions in children with autopsy-conrmed
parasite sequestration were compared with
the pHRP2 concentrations in those
without sequestration. The pHRP2 con-
centrations distinguished almost perfectly
between the 2 groups (area under receiver
operating characteristic curve, 0.98). The
second study group consisted of children
from an earlier study who had WHO-
dened cerebral malaria and who did
(cases) or did not (controls) have malaria
retinopathy. The pHRP2 concentrations
in this group were used to identify a cutoff
pHRP2 concentration that yielded optimal
sensitivity and specicity for malaria
retinopathy. The third study group was a
cohort of children with WHO-dened
cerebral malaria who were examined
prospectively for malaria retinopathy. The
pHRP2 cutoff concentration established in
the second study group was assessed in
this third study group. The established
pHRP2 cutoff concentration (1700 ng/
mL) had a positive predictive value of 94%
and a negative predictive value of 79% for
malaria retinopathy. With these positive
and negative predictive values, a pHRP2
value above the cutoff in a child with a di-
agnosis of cerebral malaria would greatly
strengthen condence in the diagnosis,
whereas a value below the cutoff might
prompt more vigorous investigation of
other potential causes of coma. Because
almost a quarter of children classied as
having cerebral malaria actually have
other reasons for coma, a pHRP2 cutoff
test may prompt the clinician to seek and
address other diagnoses early in the
disease process. This application is one for
which a simple pHRP2 concentration-
based test holds real promise as a tool that
could improve disease outcome.
So, are we ready to move to eld use
of a pHRP2 concentration-based test to
identify true cerebral malaria in children
and adults with P. falciparum parasite-
mia and coma? Not quite yet. First,
other studies are needed to replicate the
ndings reported here by Seydel et al. In
particular, it will be important to assess
whether ndings are similar in older
children and adults in Southeast Asia
who develop cerebral malaria. Second,
uniform protocols for measurement of
Received 6 March 2012; accepted 17 May 2012.
Correspondence: Chandy C. John, MD, Division of Global
Pediatrics, University of Minnesota Medical School, 717 Del-
aware St SE, Rm 366, Minneapolis, MN 55414 (ccj@umn.
edu).
The Journal of Infectious Diseases
The Author 2012. Published by Oxford University Press
on behalf of the Infectious Diseases Society of America. All
rights reserved. For Permissions, please e-mail: journals.
permissions@oup.com.
DOI: 10.1093/infdis/jis373
EDITORIAL COMMENTARY JID 1
Journal of Infectious Diseases Advance Access published June 11, 2012

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pHRP2 will need to be agreed upon, as
multiple testing methods and protocols
currently exist. The cutoff of 1700 ng/mL
proposed might not be appropriate for a
test using different pHRP2 standards or
antibodies. Ideally, identical or highly
similar testing kits and protocols should
be used in the comparator studies. Third,
the presence of pHRP2 deletions must be
sought in areas where testing is conduct-
ed or proposed. Parasite populations that
lack pHRP2 have been documented in
the Amazon [7], and populations with
deletions in the histidine-rich repeat
region of the hrp2 gene have been report-
ed in Mali [8]. In these areas, pHRP2
concentrations may be low or unmeasur-
able, and a test of pHRP2 concentration
would be useless. This potential obstacle
underscores the importance of conrma-
tory studies in other malaria-endemic
areas. Furthermore, in areas of high
malaria transmission, pHRP2 concentra-
tion may reect recent as well as current
infections and may not predict disease
severity [9]. Thus, in areas of high trans-
mission, assessment of pHRP2 concen-
tration may have little utility in the
diagnosis of cerebral malaria. However,
because most cerebral malaria occurs in
areas of low to moderate and unstable
transmission, this possibility is not a
major concern. Finally, the study by
Seydel et al was designed specically to
differentiate in children with P. falcipa-
rum parasitemia and coma those who
were retinopathy positive ( presumed
true cerebral malaria) from those who
were retinopathy negative ( presumed to
have another cause of coma). Children
with other forms of severe malaria may
have signicant parasite sequestration
and high pHRP2 concentrations. The
ndings of the study by Seydel et al do
not support the use of a high pHRP2
concentration to differentiate cerebral
malaria from other forms of severe
malariathat is a clinical decisionbut
rather support its use to improve accura-
cy of the diagnosis of cerebral malaria in
the child with P. falciparum parasitemia
and coma. With all of these caveats,
high-concentration pHRP2 is a great
candidate for a rapid diagnostic test
(RDT), because pHRP2 is already the
basis of RDTs widely used in low-
income countries for diagnosis of clinical
P. falciparum malaria [10]. If current
pHRP2 RDTs can be modied to detect
pHRP2 above a specic concentration, a
high-concentration pHRP2 RDT could
be available for practical use in hospitals
in low-income country in a relatively
short period of time.
It will take a few years and several more
studies to know whether a point-of-care
test based on a cutoff concentration of
pHRP2 can improve the diagnosis of cere-
bral malaria in the eld. It is likely that
this test will not be useful in all areas
where P. falciparum malaria is endemic.
But to date no other biomarker for cere-
bral malaria has demonstrated the high
positive and negative predictive values
seen for pHRP2 in the study by Seydel
et al. A test of pHRP2 concentration could
be the rst eld-based test since microsco-
py to improve the diagnosis of cerebral
malaria. That potential makes this study
an exciting new contribution to research
on severe malaria.
Notes
Financial support. The author receives
funding from the National Institute of Neuro-
logic Disorders and Stroke, the National Insti-
tute of Child Health and Development, and
the Fogarty International Center for malaria
research and training.
Potential conicts of interest. The author
was one of multiple collaborators in a 1-year,
multisite project of which Dr Terrie E. Taylor
was principal investigator (20102011). He re-
ceived no compensation for this project and has
not published with Dr Taylor.
All authors have submitted the ICMJE Form
for Disclosure of Potential Conicts of Interest.
Conicts that the editors consider relevant
to the content of the manuscript have been
disclosed.
References
1. World Health Organization. Severe falcipa-
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2. Taylor TE, Fu WJ, Carr RA, et al. Differen-
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3. Desakorn V, Dondorp AM, Silamut K, et al.
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4. Parra ME, Evans CB, Taylor DW. Identica-
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6. Seydel KB, Fox LL, Glover SJ, et al. Plasma
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nostic tests. PloS One 2010; 5:e8091.
8. Koita OA, Doumbo OK, Ouattara A, et al.
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9. Manning L, Laman M, Stanisic D, et al.
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2 JID EDITORIAL COMMENTARY

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