Download Review of Cases With the Emerging Fifth Human Malaria Parasite

EMERGING INFECTIONS
INVITED ARTICLE
James M. Hughes and Mary E. Wilson, Section Editors
Review of Cases With the Emerging Fifth Human
Malaria Parasite, Plasmodium knowlesi
Anu Kantele1,2,3 and T. Sakari Jokiranta3
1Division
of Infectious Diseases, Department of Medicine, Helsinki University Central Hospital, 2Department of Medicine, University of Helsinki, and
of Bacteriology and Immunology, Haartman Institute, University of Helsinki, Helsinki, Finland
3Department
Human malaria has been known to be caused by 4 Plasmodium species, with Plasmodium falciparum causing
the most-severe disease. Recently, numerous reports have described human malaria caused by a fifth
Plasmodium species, Plasmodium knowlesi, which usually infects macaque monkeys. Hundreds of human cases
have been reported from Malaysia, several cases have been reported in other Southeast Asian countries, and
a few cases have been reported in travelers visiting these areas. Similarly to P. falciparum, P. knowlesi can cause
severe and even fatal cases of disease that are more severe than those caused by the other Plasmodium species.
Polymerase chain reaction is of value for diagnosis because P. knowlesi infection is easily misdiagnosed as less
dangerous Plasmodium malariae infection with conventional microscopy. P. knowlesi infection should be
suspected in patients who are infected with malaria in Southeast Asia. If human–mosquito–human
transmission were to occur, the disease could spread to new areas where the mosquito vectors live, such as
the popular tourist areas in western India.
More than half of the world population lives in malaria
risk areas in Africa, Central and South America, and
South and Southeast Asia, and the annual malariaassociated mortality approaches 1 million, with 2
children dying from the disease every minute worldwide (World Malaria report 2009, WHO). For the past
80 years, human malaria has been known to be caused
by 4 Plasmodium species—Plasmodium falciparum,
Plasmodium vivax, Plasmodium ovale, and Plasmodium
malariae—with P. falciparum being responsible for the
most-severe cases. Recently, a fifth Plasmodium species
has been recognized as a cause of malaria in humans.
The newcomer is Plasmodium knowlesi, which was formerly known to cause malaria only in macaques.
Received 9 November 2010; accepted 22 February 2011.
Correspondence: Anu Kantele, MD, PhD, Div of Infectious Diseases, Helsinki
University Central Hospital, P.O.Box 348, FIN-00029 HUS, Finland (anu.kantele
@hus.fi).
Clinical Infectious Diseases 2011;52(11):1356–1362
Ó The Author 2011. Published by Oxford University Press on behalf of the Infectious
Diseases Society of America. All rights reserved. For Permissions, please e-mail:
[email protected].
1058-4838/2011/5211-0014$14.00
DOI: 10.1093/cid/cir180
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HISTORY
First described in 1931 in a longtail macaque (Macaca
fascicularis), P. knowlesi was later found to cause naturally acquired malaria in pigtail macaques (Macaca
nemestrina) and the mitred leaf monkey (Presbytis
melalophos), as well. Experimentally, P. knowlesi infects
several other primates, and in 1932, P. knowlesi was
proved to infect humans. Iatrogenic P. knowlesi infection was initially considered to be nonhazardous, and
therefore, the parasite replaced P. vivax as a pyretic agent
in the treatment of neurosyphilis in the early 1930s. This
practice was discontinued, however, as a result of patient
deaths [1].
It was not until 1965 that the first natural infection of
P. knowlesi in humans was reported in an American
traveller returning from Peninsular Malaysia [2]. In
1971, another natural infection was suspected in
Peninsular Malaysia [3]. Despite extensive studies in
Malaysia in the 1960s, no additional reports appeared
until 2004, when Singh et al [4] described 120 cases of
naturally acquired P. knowlesi infection in humans in
Malaysian Borneo. Since then, numerous reports have
been published. By analyzing old blood films, P. knowlesi
has been shown to have caused malaria in a great number of
patients since 1996 [5].
MONKEY MALARIA
At least 26 Plasmodium species are known to infect primates, yet
natural transmission of a nonhuman Plasmodium species to
humans is rare. The host specificity has been shown to be surprisingly strict: eg, Plasmodium reichenowi causing malaria in
chimpanzees fails to infect humans [6]. Similarly, P. falciparum
causes only mild parasitemia in chimpanzees. These kinds of
differences appear to be caused by species-specific erythrocyte
recognition profiles [6] or different binding of sporozoites to
liver cells [7]. P. knowlesi is clearly not strictly species-specific,
because both experimental monkey-to-human and human-tohuman transmission have proved to be possible [8]. Other
mechanisms of species specificity of plasmodia are attributable
to vector restriction, vector feeding preferences, and vector
species specificity. P. knowlesi transmission is vector restricted in
that the parasite can be transmitted only by certain Anopheles
mosquitoes [1, 9]. At least 2 main vectors in the Anopheles
leucosphyrus group, Anopheles latens and Anopheles cracens,
are known to be forest feeders, biting both humans and macaques at evening or during the night [9, 10]. Taken together,
numerous mechanisms restrict the nonhuman Plasmodium
species from infecting humans, yet P. knowlesi has proved to
make a significant exception to this rule.
In the natural hosts, P. knowlesi causes an asymptomatic lowgrade parasitism or mild disease [4, 10]. It is not known whether
human P. knowlesi infections are obtained only from mosquitoes
fed on macaques or whether natural human-mosquito-human
transmission occurs. The zoonotic nature of the infection is
suggested by the lack of case clustering in Sarawakian human
settlements, where most cases have been described, and by the
fact that most patients have a recent history of working or
dwelling in a forest or forest fringe, which is the environment
characteristic of the vector mosquitoes [10, 11]. During human
infection, gametocytes are formed, but at low levels, which
supports the suggestion that transmission is primarily zoonotic
[12]. Because of the environmental preference of the natural
vector mosquitoes, urban transmission is not likely to occur.
The situation might change if human-mosquito-human transmission occurred, because at least one widely distributed urban
mosquito species (Anopheles stephensi) has experimentally been
shown to be a possible vector for P. knowlesi (reviewed by
Coatney et al [1]).
CASES IN MALAYSIA
In the first study to recognize P. knowlesi as a causative organism
of human malaria in Sarawak, Malaysia, the authors investigated
cases that were identified by microscopic examination as
being due to P. malariae but that had negative polymerase chain
reaction (PCR) results [4]. When new primers were applied,
58% of the cases that originally had PCR results negative for
P. malariae were found to have positive results for P. knowlesi,
resulting in the identification of 120 cases of P. knowlesi
infection in humans.
Thereafter, P. knowlesi was identified in 266 of the samples
from 960 hospitalized Sarawakian patients with malaria [13], in
41 of 49 archived blood-films collected in Sabah [13], and 35 of
47 in Sarawak [5], in Malaysian Borneo, and in a total of 89 cases
in Peninsular Malaysia [9, 13, 14]. In 2009, a prospective report
on P. knowlesi infections in Sarawak was published that contained the clinical picture and the laboratory findings for 107
patients with P. knowlesi infection during 2006–2008 [15]. Since
2004, 5 fatal cases have been reported [13, 16].
CASES IN OTHER SOUTHEAST ASIAN
COUNTRIES
After identifying cases in Malaysia, several patients with
P. knowlesi infection have been documented in other Southeast
Asian countries (Figure 1; Table 2). Diagnosis in all of these cases
was based on PCR analysis, but malaria was detected in practically all of the cases using microscopy. In 2004, P. knowlesi
malaria was described in a patient who lived in a suburb of
Bangkok, Thailand, and who had visited southern Thailand near
the Myanmar border [27]. Subsequently, P. knowlesi has been
identified in 10 patients from southern and southwestern
Figure 1. Plasmodium knowlesi infections reported in humans in
Southeast Asia (modified from Cox-Singh and Singh [10]). The gray
area indicates the geographic distribution of Anopheles leucosphyrus
group mosquitoes, which are the main vectors for P. knowlesi. The figures
represent numbers of patients with a reported infection due to
P. knowlesi. The figures include both local patients and travelers
returning from that area. For 1 traveler, the area in which the infection
was obtained remained unclear, because he had visited several countries
(Thailand, Indonesia, Peninsular Malaysia, and Vietnam) [17].
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Thailand [28]; 33 patients from Myanmar [29, 30]; 5 patients, including 2 patients with a history of staying in forest
areas, from the Philippines [32]; 2 soldiers and 4 other patients
from northwestern Singapore [24–26]; 5 patients from central
Vietnam [31]; and 1 patient, a gold miner from southern
Borneo, in Indonesia [21]. As Sulistyaningsih et al [21] have
concluded, it appears to be possible that the parasite is widely
distributed throughout Borneo.
CASES IN TRAVELERS
After the first reported case of P. knowlesi infection in a traveler
(Table 2) in 1965 [2], the next case was reported 42 years later. In
2007, a Finnish man was infected during a 4-week visit to
Peninsular Malaysia, where he stayed in a jungle area for 5 days
[23]. He did not take any malaria prophylaxis, and his illness
was originally diagnosed by microscopy as coinfection due to
P. falciparum and P. malariae. This and the next few cases were
confirmed using PCR and sequencing or P. knowlesi–specific
nested PCR. The third reported case was in a Swedish man who
had been travelling in Malaysian Borneo for 2 weeks and stayed
in a jungle for 1 week. Rapid diagnostic test results for malaria
was negative, but microscopic examination revealed low parasitemia with a suspicion of P. malariae infection [18]. The
fourth report described a woman from the United States who
had visited the Philippines, her native country [33]. The fifth
case was in a Malaysian immigrant in the Netherlands [19]. The
sixth traveller documented with P. knowlesi infection was an
Australian man working 10 days a month near woodlands in
Indonesian Borneo in the province located farthest from the
Malaysian border [22]. The seventh case was in a Spanish man
who had returned from a long tour in Southeast Asia [17]. In
addition to these reports, the British health statistics list 1 case
of P. knowlesi infection in 2006 in a patient who had visited
Brunei [20].
CLINICAL PICTURE AND OUTCOME
The clinical picture and outcome of P. knowlesi infection is
described in a prospective study involving 107 patients in theSarawak hospital in Malaysia during the period 2006–2008
[15]. The clinical and laboratory profiles of these patients
resembled those of patients infected with other Plasmodium
species. A Vietnamese report suggests that asymptomatic infections may also occur [34]. In Malaysia, the patients with
P. knowlesi infection typically presented with a nonspecific
febrile illness with daily fever and chills. Other frequent symptoms included headache, rigors, malaise, myalgia, abdominal
pain, breathlessness, and productive cough. Tachypnea, pyrexia,
and tachycardia were common clinical signs. All patients had
thrombocytopenia at hospital admission or on the following
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day, yet none of the patients had clinical coagulopathy.
At hospital admission, only a few of the patients had anemia,
whereas mild hepatic dysfunction was relatively common.
The great majority of patients (94%) experienced no complications, and the infection responded well to chloroquine and
primaquine treatment [15].
Applying the World Health Organization criteria for
P. falciparum infection, P. knowlesi infection was evaluated
as severe in 7% of the cases, with the most frequent complication being respiratory distress with pulmonary rather than
metabolic etiology. A strong correlation was found between
parasite density and the development of respiratory distress.
Parasite density was also strongly and independently associated
with renal dysfunction. Two of the patients died, representing
a case fatality rate of 1.8% [15]. Phylogenically, P. knowlesi
is relatively closely related with P. vivax; therefore, it is not
surprising that infections with these 2 species share some common features, such as occasional severity and marked thrombocytopenia [35]. However, disease caused by P. knowlesi is
somewhat more severe than disease caused by P. vivax, although
also vivax malaria can be severe in a significant number of cases,
at least in certain regions (severe malaria in 3%, compared
with 7% in individuals with P. knowlesi malaria) [15, 35].
In P. knowlesi infections, neurological symptoms are rare,
and no cases of cerebral malaria have been reported [15]. A
post-mortem study of a lethal P. knowlesi case suggests, however,
that P. knowlesi–infected red cells can sequester in capillaries
of the brain, heart, and kidneys [16].
Similarly to P. falciparum, P. knowlesi can cause severe or even
fatal disease. It has a short lifecycle of 24 h [1], enabling a rapid
progression of the disease (Table 1). The erythrocyte invasion by
P. knowlesi is not restricted to young or old cells, which allows
high parasitemia, and development of the parasite in erythrocytes is asynchronous. The threshold for hyperparasitemia in
P. knowlesi infections is lower than in P. falciparum malaria
and, at least theoretically, hyperparasitemia, together with the
shorter asexual cycling time, may even render P. knowlesi more
virulent in its severe form. In 3 of the 5 reported lethal cases,
a high parasitemia was seen (15%, .10%, and .10 parasites per
high-power microscope field) [13, 16]. Clinicians treating these
patients should be aware of the potential lethal outcome of the
infection.
TREATMENT
As malaria due to P. knowlesi might progress rapidly into severe
disease, it should be treated like P. falciparum malaria if the
species identification is based on microscopic examination alone
or if coinfection with P. falciparum cannot be excluded with
certainty using PCR. P. knowlesi itself appears to be susceptible
to numerous alternative treatments (Table 1). The majority of
Table 1. The 5 Plasmodium-Species Causing Malaria in Humans
Plasmodium
falciparum
Variable
Plasmodium
knowlesi
Plasmodium
vivax
Plasmodium
ovale
Plasmodium
malariae
Main site of
distribution,
proportion in
the endemic
area (%)
Global,
most common
in Africa,
80–90 (Africa)
Malaysia (and
neighboring
areas), 1–60
Mostly in Asia, 50–80
Africa, 5–8
Global, 0.5–3
Life threatening
yes
yes
yes
no
no
Red cells
and fever
cycle, days
Infected
red cells
Parasitemia
2
1
2
2
3
All
All
Young cells
Young cells
Old cells
Can be high
Can be high
,2%
,2%
,2%
Liver
hypnozoites
No
Probably no
Yes
Yes
No
Treatmenta
Combinations with
arthemisinine
derivatives
Probably all
the medications
listed for the
other plasmodia
Chloroquine
followed by
primaquine
Chloroquine
followed by
primaquine
Chloroquine
Atovaquone
plus proguanil
Not known,
probably
Atovaquone
plus proguanil
Atovaquone
plus proguanil
Atovaquone
plus proguanil
Doxycycline
Mefloquine
Atovaquone
plus proguanil
Chloroquine
(resistance rare)
Chloroquine
Chloroquine
Doxycycline
Doxycycline
Chloroquine
Doxycycline
Mefloquine
Mefloquine
Doxycycline
Mefloquine
Mefloquine
No preventing
medication
can prevent
liver hypnozoites
Atovaquone
plus proguanil
Mefloquine
Quinine 6 doxycycline
Medical
prevention
No preventing
medication
can prevent
liver hypnozoites
a
If a patient with a P. falciparum infection has high parasitemia, poor condition, and/or complications, intravenous medication (artesunate or quinine with or
without doxycycline) is recommended. This probably applies also to P. knowlesi infections requiring intravenous medication. Possible use of chloroquine has been
suggested as well [36], but this needs to be further explored before a recommendation can be made.
Malaysian patients were primarily treated with chloroquine
[4, 15, 36], the Finnish patient was treated with quinine
and doxycycline [23], the Swedish patient was treated with
mefloquine [18], and the American patient was treated with
the combination of atovaquone and proguanil [33]. This suggests that P. knowlesi malaria can be treated with all of these
agents (Table 1). In general, antimalarial medication should
be commenced at once after patients are found to have positive
blood smear results, and the species can be identified or confirmed later. In P. knowlesi infection, commencing medication
immediately is as important as it is in P. falciparum infection
because of the potentially severe nature of both infections and
because of the difficulty in distinguishing between these 2 species
or determining whether there is a mixed infection on the basis
of microscopic examination alone.
Two plasmodium species, P. vivax and P. ovale, may become
dormant as liver hypnozoites and can cause one or more relapses of disease even years after the original infection if
primaquine is not given to eradicate this form of the parasite
(Table 1). After the primary treatment, Malaysian patients
have been treated with primaquine to eliminate possible hypnozoites [15, 36]; however, there is no evidence from either
macaque or human infections on relapses or indicating that that
hypnozoites exist in P. knowlesi infection. Therefore, it appears
to be unlikely that primaquine administration is beneficial or
necessary in P. knowlesi infection.
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Figure 2. Examples of challenges in species identification using
microscopy. On the left are photos from thin smears from a Finnish tourist
with a Plasmodium knowlesi infection after a visit to western Peninsular
Malaysia. In the middle are thin smears from patients with Plasmodium
falciparum infection, and on the right are thin smears from patients with
Plasmodium malariae infection (Giemsa or May-Grünwald-Giemsastaining; original magnification, 31000).
DIAGNOSIS
Malaria diagnosis is traditionally based on light microscopy
of thin and thick blood smears. In experienced laboratories,
microscopy is reliable, but even in such laboratories, its sensitivity is always not optimal [37]. In P. knowlesi infections,
microscopic examination has been used to identify plasmodia
in the samples and to determine the level of parasitemia.
Microscopic examination, however, fails to correctly identify
the species of P. knowlesi, because its early trophozoites resemble
the ring forms of P. falciparum, and its later stages mimic those
of P. malariae (Figure 2) [8]. This explains why P. knowlesi
infection is usually misidentified as P. falciparum and/or
P. malariae infection [2, 5, 12, 13, 23, 25, 28]. Because
P. knowlesi malaria is life threatening, this parasite should
always be suspected in cases in which microscopic examination
suggests P. malariae, but in which the patient has either severe
disease, considerable parasitemia (.0.1%; ie, a parasite count
of .5000 parasites/lL), or a recent history of visiting woods
or their vicinity in Southeast Asia [5].
The PCR techniques that are used for the diagnosis of malaria
and are not specifically designed for detection of P. knowlesi
fail to detect it [17, 22, 38]. This parasite has been detected only
with P. knowlesi–specific PCR assays that use nested PCR [4, 28],
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real-time PCR [38], or PCR combined with sequencing [23].
The widely used nested PCR assay (using the primers Pmk8 and
Pmk9r), however, occasionally gives false-positive results in either uninfected or P. vivax–infected individuals [21, 31, 39],
indicating that a molecular method to test all 5 human malaria
species or verification of identification by sequencing of the PCR
product is needed [21, 28, 31]. A more specific set of primers has
also been suggested [38, 39]. Although PCR analyses can be
done by scraping material from microscopy slides, ethylenediaminetetraacetic acid-anticoagulated blood samples should
be used to minimize contamination.
In several countries, traditional microscopy-based malaria
diagnostics have recently been combined with, or at least partially replaced by, the use of malaria rapid diagnostic tests
(RDTs). Some of the kits available are based on detection of
plasmodium-specific lactate dehydrogenase, whereas others
detect histidine-rich protein II (HRP-2) of P. falciparum either
alone or in combination with a pan-malarial antigen, aldolase.
Currently, no commercially available RDTs are designed
to specifically detect P. knowlesi. Performance of these mainly
P. falciparum– and P. vivax–targeted RDTs in P. knowlesi infection has been reported in a few cases [18, 25], which suggests
that anti-HRP-2 antibodies do not always recognize P. knowlesi
[18], whereas anti-aldolase and anti-LDH antibodies are more
reliable [19, 40]. In conclusion, these tests are not recommended
because of the unreliable results and low sensitivity in detecting
P. knowlesi. Because knowlesi malaria can be symptomatic in
patients with low parasitaemia, RDTs should detect it with
sensitivity of 1 or even ,1 parasite/lL of blood.
PREVENTION OF P. KNOWLESI–INFECTION
As with the other types of human malaria, prevention of
P. knowlesi infection is based on avoiding mosquito bites and
taking preventive medication when indicated. The efficacy of
these measures against P. knowlesi has not been shown, but it
can be assumed that its vector behaves like the vectors of
other Anopheles species, and general precautions for avoiding
the bites of Anopheles mosquitoes probably apply. Current
indoor control measures for malaria do not, however, prevent
zoonotic transmission of malaria by vectors that mainly feed in
the forest [9, 10]. Zoonotic P. knowlesi infection can, accordingly, continue to be a problem for malaria control, and also
poses a significant threat to the renewed efforts aimed at fully
eradicating malaria.
None of the tourists with reported P. knowlesi infection used
preventive medication [18, 19, 22, 23, 33]. Because chloroquine
[4, 15], doxycycline [23], mefloquine [18], or atovaquoneproguanil in combination [22] have been successfully used in
treatment of the disease, all of these agents could probably be
used as preventive medicines against P. knowlesi, as well.
Table 2. Reported Human Plasmodium knowlesi Infections
Country/area
Malaysia/Borneo
Local
cases
Cases in
travelers
Reference(s)
570
3
[3, 4, 5, 13, 15]; [2, 18, 19]
1
[20]
1
89
1
1
[21, 22]
[9, 13, 14, 23]
Brunei/Borneo
Indonesia/Borneo
Malaysia/Peninsular
Singapore
6
[24–26]
Thailand
11
[27, 28]
Myanmar
33
[29, 30]
Vietnam
5
Philippines
5
Total
720
[31]
1
[32, 33]
8a
a
Area of infection in 1 case was unclear (Thailand, Indonesia, Peninsular
Malaysia, or Vietnam) [17].
not necessarily linked to the actual spread of the parasite but
to the use of more-accurate diagnostic methods.
The high number of human cases (Table 2) suggests that
P. knowlesi may be more capable of infecting humans than are
the other species that cause nonhuman primate malaria. To
date, only experimental, and not natural, human-mosquitohuman transmission has been reported [8]. If natural humanmosquito-human transmission occurred, P. knowlesi could
spread more widely in Asia. This is made possible by the wide
distribution of at least one vector species, Anopheles latens, in
Southeast Asia and in the southern parts of the Indian subcontinent, including the popular tourist areas in western India
[10] (Figure 1). It remains to be seen whether this kind
of spreading has occurred in the past or will occur in the future,
but to date, neither human-mosquito-human transmission nor
spreading of P. knowlesi has been documented.
SIGNIFICANCE AND FUTURE PROSPECTS
Acknowledgments
As the number of human P. knowlesi cases increases, clinicians
and laboratory personnel should be alerted to this emerging—
and potentially lethal—cause of malaria [13, 16]. Laboratory
personnel have thus far only been trained to identify the 4
traditional Plasmodium species. Numerous cases in several
countries may have been misidentified as being due to P. malariae.
Moreover, some malaria RDTs have failed to detect P. knowlesi,
and all RDTs fail to identify the species [18,19]. Therefore,
if rapid and reliable molecular diagnostic methods are not available to establish the diagnosis of P. knowlesi infection, either ordinary malaria microscopic examination or at least
superficial microscopic examination together with RDTs appears
to be necessary to diagnose malaria in general in patients infected
with P. knowlesi.
So far, human P. knowlesi infections have been described in
high numbers only in Malaysia. The great majority are from
Malaysian Borneo [3, 4, 13, 15], yet numerous cases have also
been described in Peninsular Malaysia [9, 13, 14, 23]. Due to the
reports of P. knowlesi malaria obtained in the neighboring
countries, Thailand [27, 28], Singapore [24–26], Brunei [20],
Indonesia [21, 22], Myanmar [29, 30], Vietnam [31], and the
Philippines [32, 33], it appears that P. knowlesi is a natural
parasite of macaques throughout the Southeast Asian region.
The wide distribution of human cases shows that P. knowlesi is
generally able to infect humans, which is also suggested by the
genetic polymorphism of the P. knowlesi identified from human
samples [28]. The fact that P. knowlesi is being identified in
increasing numbers now may be attributable in some areas to
the reduction of cases of P. falciparum and P. vivax infection,
whereas the number of cases of P. knowlesi infection remains
constant. The availability and use of specific PCR methods to
detect P. knowlesi may generate more reports of P. knowlesi
infection, and therefore, the increase in the number of reports is
Potential conflicts of interest. All authors: no conflicts.
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