UpToDate - Diagnosis of Malaria

11/26/2018 Diagnosis of malaria - UpToDate
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Diagnosis of malaria
Author: Heidi Hopkins, MD

Section Editor: Johanna Daily, MD, MSc
Deputy Editor: Elinor L Baron, MD, DTMH
All topics are updated as new evidence becomes available and our peer review process is
complete.
Literature review current through: Oct 2018. | This topic last updated: Jan 26, 2018.
INTRODUCTION — Prompt and accurate diagnosis of malaria is critical for implementation of

appropriate treatment to reduce associated morbidity and mortality. Accurate detection of malaria is
also important for epidemiological screening and surveillance to inform malaria control strategies,
for research purposes in testing efficacy of antimalarial drugs and vaccines, and for blood bank
screening.
Characteristics of a useful malaria diagnostic tool include the ability to definitively establish
presence or absence of infection, determine which species of malaria is/are present, quantify
parasitemia (ie, parasites per microliter of blood or percent red blood cells infected), detect low-level
parasitemia, and allow monitoring of response to antimalarial therapy (including detection of
recrudescence or relapse). Thus far, there is no single malaria diagnostic tool that meets all of these
criteria. Test characteristics that are important for diagnosis vary depending on the epidemiology of
infection and goals for control in the region where the test is used.
Tools for diagnosis of malaria and the goals of malaria diagnosis in various settings will be reviewed
here. Issues related to epidemiology, pathogenesis, clinical manifestations, treatment, and
prevention of malaria are presented separately. (See separate topic reviews.)
WHEN TO SUSPECT MALARIA — In general, malaria should be suspected in the setting of fever
(temperature ≥37.5°C) and relevant epidemiologic exposure (residence in or travel to an area where
malaria is endemic) [1]. In malaria-endemic areas with stable transmission and during high-
transmission season in areas with seasonal malaria, malaria should also be suspected in children
with palmar pallor or hemoglobin concentration <8 g/dL.
The diagnosis of malaria is established in the setting of symptoms consistent with malaria and a
positive malaria diagnostic test.
Individuals with acquired partial immunity due to repeated exposures in endemic settings may have
asymptomatic parasitemia. There is no diagnostic test capable of distinguishing between
parasitemia causing clinical malaria and febrile illness due to another cause in a patient who also
has asymptomatic parasitemia. (See 'Differential diagnosis' below.)
https://www.uptodate.com/contents/diagnosis-of-malaria/print 1/30
DIAGNOSTIC APPROACHES — Suspected malaria should be confirmed with a parasitologic
diagnosis whenever possible, as discussed in the following sections [1]. (See 'Parasite-based
diagnosis' below.)
If parasite-based diagnostic tools are not readily available and there is clinical suspicion for
Plasmodium falciparum infection, it may be reasonable to make a presumptive diagnosis with
decision to initiate empiric therapy. (See 'Clinical or presumptive diagnosis' below.)
Parasite-based diagnosis — Clinical tools for parasite-based diagnosis include microscopy

(visualization of parasites in stained blood smears) and rapid diagnostic tests (RDTs; which detect
antigen or antibody). Smear examination via light microscopy is the standard tool for diagnosis of
malaria; RDTs should be used if microscopy is not readily available. Molecular techniques for
detection of genetic material are limited to research settings [2].
Light microscopy — Detection of parasites on Giemsa-stained blood smears by light

microscopy is the standard tool for diagnosis of malaria [3]. In expert hands, the sensitivity of
microscopy can be excellent, with detection of malaria parasites at densities as low as 4 to 20
parasites/mcL of blood (approximately 0.0001 to 0.0005 percent parasitemia) [4-7]. Diagnostic
errors occur more commonly in the setting of low-density parasitemia (10 to 100 parasites/mcL of
blood), although errors can also occur with higher densities [8-10]. (See 'Parasite density
monitoring' below.)
Microscopy allows identification of the Plasmodium species as well as quantification of parasitemia.

It also enables diagnosis of hematologic abnormalities and other infectious diseases such as
filariasis, trypanosomiasis, babesiosis, and others.
Drawbacks to microscopy include that it is labor intensive and requires substantial training and
expertise [7,11,12]. The sensitivity and specificity of malaria microscopy in resource-limited settings
is often below levels achievable in reference or research laboratories [9,13-16]. In well-equipped
laboratories outside of endemic areas, variation in techniques used for preparation and
interpretation can influence results [8,17-19], and errors may occur in laboratories with limited
exposure to tropical infections [3,20].
Microscopy cannot reliably detect very low parasitemia (<5 to 10 parasites/mcL) or cases where the
majority of the parasite biomass is sequestered (eg, in the case of placental sequestration during
pregnancy) [11].
Blood smear preparation — Preparation of smears consists of applying a drop of blood to a

glass microscopy slide, followed by drying and staining procedures. Capillary blood from a
fingerprick (or earlobe or infant heelstick) or anticoagulated venous blood may be used. Smears
should be prepared as soon as possible after blood collection to avoid alteration in parasite
morphology and staining properties.
Two types of blood smears are used in malaria microscopy: thin and thick smears. Thin smear
preparation maintains the integrity and morphology of erythrocytes so that parasites are visible
within red blood cells. Thin smears allow identification of the infecting parasite species and can be
used to measure parasite density. Thick smear preparation involves mechanical lysis of red blood
cells so that malaria parasites can be visualized independent of cell structures. Thick smears allow
the microscopist to review a relatively large quantity of blood and are typically used to screen for
presence or absence of parasites and to estimate parasite density.
The United States Centers for Disease Control and Prevention (CDC) has online guides for
preparation and staining of blood smears.
Blood smear interpretation — Malaria parasites are best seen under 100x magnification
using the oil immersion objective lens; smear evaluation should include examination of at least 200
to 500 fields or examination for 20 to 30 minutes. If malaria is suspected and the initial smear is
negative, additional smears should be prepared and examined over the subsequent 48 to 72 hours
[21]; the CDC recommends repeating a thick and thin smear every 12 to 24 hours for a total of three
sets before ruling out malaria [22,23].
Once a diagnosis of malaria has been established and treatment has been initiated, serial smears
should be examined to monitor the parasitological response and ensure resolution of infection
[21,23,24]. Antimalarial therapy can alter the morphological appearance of parasites and affect their
identification in blood smears, either at the time of initial diagnosis (if presumptive treatment was
administered) or during follow-up [7,25,26].
Species identification — Thin smears allow identification of the malaria species. The
malaria species morphology is variable depending on the stage of infection (figure 1 and figure 2
and table 1 and table 2).
The CDC has bench aids for identification of P. falciparum, P. vivax, P. ovale, and P. malariae. Other
online resources for teaching malaria identification skills include materials available from the World
Health Organization (WHO) [27-30].
Parasite density monitoring — Parasite density often correlates with illness severity; it
should be monitored during and after antimalarial treatment to document resolution of infection.
A standard approach to estimating parasite density in a thick blood smear involves counting asexual
parasite forms and white blood cells in each microscopy field until 200 white blood cells have been
counted. If fewer than 10 asexual parasites are counted per 200 white blood cells, counting should
continue to a total of 500 white blood cells. Subsequently, the measured white blood cell count (in
cells per microL) is divided by the number of white blood cells counted (200 or 500), and the result
is multiplied by the number of parasites counted, giving the parasite density (parasites per microL).
For example, a white blood cell count of 8000/microL divided by 200 white blood cells counted,
times 500 parasites counted, gives a parasite density of 20,000 parasites/microL.
In a thin blood smear, the parasite density can be estimated by examining a monolayer of red blood
cells (RBCs) using the oil immersion objective at 100x. The slide should be examined where the
RBCs are more or less touching (approximately 400 RBCs per field). The parasite density can then
be estimated from the percentage of infected RBCs; at least 500 RBCs should be counted [31].
An alternate expression of parasitemia is the percentage of erythrocytes that are parasitized. Taking
the example above, the percent parasitemia is 20,000 parasites/microL divided by 4,000,000 (the
average number of erythrocytes per microL in human blood), or 0.5 percent. As another example, a
white blood cell count of 5000/microL, divided by 500 white blood cells counted, times 5 parasites
counted, gives a parasite density of 50 parasites/microL. The percent parasitemia is 50 divided by
4,000,000, or 0.001 percent. Variation in white blood cell counts may confound estimates that use
an average rather than a measured white blood count [32].
Only asexual parasite forms are counted in calculating the parasite density. The presence of
gametocytes alone indicates a recent infection (and potential for mosquitoes taking a blood meal to
become infected) but not infection with actively replicating malaria parasites, which may cause
symptoms. Because gametocytes are less susceptible than asexual parasites to many antimalarial
drugs, persistence of gametocytes alone following treatment does not indicate drug resistance [23].
In general, the higher the parasite density, the higher the likelihood of severe malaria; this is
particularly true for individuals who do not have partial immunity (such as travelers from non-
malarious areas and residents of areas with low malaria transmission). However, this association is
not observed in all cases, and the relationship between parasite density, total parasite biomass,
patient immunity, and severity of presenting symptoms remains to be elucidated [33]. The WHO
definition of severe P. falciparum malaria includes hyperparasitemia (>2 percent or 100,000
parasites/microL in low-intensity transmission areas or >5 percent or 250,000 parasites/microL in
areas of high stable malaria transmission intensity) [1]. The CDC definition of severe malaria
includes parasitemia of ≥5 percent [22]. It is important to note that parasites frequently sequester in
capillaries in the setting of severe malaria; therefore, the peripheral blood smear may reflect a low
parasite density relative to the parasite burden present.
P. vivax and P. ovale infect only young erythrocytes, so parasite density for these species is typically
lower; P. falciparum, P. malariae, and P. knowlesi infect mature erythrocytes and can therefore
mount higher parasite densities. A parasitemia of ≥5 percent is very unlikely with any species
except P. falciparum.
P. knowlesi, which may cause severe disease, may be indistinguishable by microscopy from P.
malariae (which generally causes milder illness). Therefore, patients from knowlesi-endemic areas
with microscopic diagnosis of P. malariae should receive parenteral therapy in the setting of
parasitemia >100,000/microL or >20,000/microL if no other testing for severe criteria is available
[34]. (See "Non-falciparum malaria: Plasmodium knowlesi".)
Parasitemia should be monitored during treatment to confirm adequate response to therapy. The
CDC recommends daily repeat blood smear to document declining parasite density until negative or
until treatment day 7 (if discharged prior to complete parasitemia clearance) [23]. During treatment
of severe malaria, parasite density should be monitored every 12 hours during the first two to three
days or until negative; some recommendations suggest switching from parenteral to oral therapy as
tolerated after parasitemia falls below 1 percent [23,34,35]. Parasite density may be expected to fall
by 90 percent over the first 48 hours with quinine or quinidine therapy [23]; clinical trials of
artemisinin combination therapies typically result in median parasite clearance time <72 hours
[36,37], although prolonged parasite clearance times have been observed in areas of Southeast
Asia.
Rapid diagnostic tests — RDTs for detection of malaria parasite antigens are increasingly
important diagnostic tools in resource-limited endemic settings due to their accuracy and ease of
use. They require no electricity or laboratory infrastructure, give results within 15 to 20 minutes, and
can be performed successfully even by health workers with limited training. RDTs provide a
qualitative result but cannot provide quantitative information regarding parasite density. RDTs that
detect antibodies produced by an infected host are also available; however, these are less useful for
diagnosing acute infection.
The approach to RDT selection depends on the epidemiology of infection and goals for control in
the region where the test is used [38]. In regions where infection is primarily caused by P.
falciparum, use of an assay that detects P. falciparum only may be sufficient and cost-effective. In
regions where falciparum and non-falciparum parasites coexist or where P. vivax predominates, use
of an RDT that can detect and distinguish between these species is warranted (table 3).
Antigen-based tests — RDTs detect one or more of the following antigens: histidine-rich
protein 2 (HRP2), Plasmodium lactate dehydrogenase (pLDH), and aldolase. Depending on the
target antigen(s), an RDT may identify Plasmodium genus only or may distinguish P. falciparum
and/or P. vivax infections.
In general, for diagnosis of P. falciparum, RDTs that detect HRP2 are somewhat more sensitive than
those that detect pLDH. For diagnosis of non-falciparum species, RDTs that detect pLDH and
aldolase appear to be comparable.
Most antigen-detecting RDTs are based on immunochromatographic lateral flow technology; they
consist of a nitrocellulose wick packaged as a dipstick, plastic cassette, or paper card (figure 3)
[7,11,12,39,40]. One end of the test strip contains labeled antibodies and an agent to lyse red blood
cells; a blood sample (5 to 20 mcL) and buffer are placed there, and the liquid migrates along the
strip via capillary action, together with the labeled antibodies. The strip also contains a test line
(bound antibody that binds parasite antigen, if present) and a control line (bound antibody that binds
the migrating-labeled antibody to confirm adequate flow). The development time is typically 15 to 20
minutes.
HRP2 — Histidine-rich protein 2 is part of a family of P. falciparum histidine-rich proteins

[41]. It is only produced by P. falciparum; therefore, use of HRP2-based RDTs is appropriate in
regions where P. falciparum is the predominant species (eg, much of sub-Saharan Africa).
Combination tests may be useful in areas endemic for multiple Plasmodium species.
HRP2-based RDTs can detect lower levels of parasitemia than RDTs based on other target antigens
[42-47]. However, detectable HRP2 antigen may persist in the bloodstream for anywhere from a few
days to several weeks after parasitemia is no longer present. In the absence of good quality
confirmatory microscopy, there is currently no way to distinguish HRP2 antigenemia resulting from a
new infection or persistent infection (ie, resulting from treatment failure) from antigenemia persisting
from a recently treated infection. Some endemic countries' national guidelines therefore advise that
a positive HRP2 result should be considered to represent a new infection only if the specimen was
drawn 7 to 14 days or longer following a previously treated infection; however, it is recognized that
this provides general guidance only and the duration of persistent antigenemia varies considerably
among individual cases. Therefore, the usefulness of HRP2-based assays may be limited in areas
of intense malaria transmission where positive results may occur as a result of prior infection. For
the same reason, HRP2-based assays are not useful for monitoring following treatment [48-52].
Variability in HRP2 gene sequence may affect test performance in some circumstances [53-55];
HRP2 diversity is not known to be a major cause of variation in RDT sensitivity but is a subject of
ongoing study [56,57]. HRP2 gene deletions leading to false-negative RDT results have been
identified in P. falciparum parasites from the Peruvian Amazon [58,59]; therefore, HRP2-based tests
are not reliable for infections contracted in this area.
Reports have emerged of pfhrp2 and pfhrp3 mutations or deletions in Africa and India leading to
false-negative RDT results in some cases [60-64]. One report noted in Eritrea microscopically
confirmed positive samples were negative by HRP2-based RDT, a finding attributed to deletion of
the pfhrp2 gene [65]. The global distribution, frequency, and operational implications of these
deletions are not yet fully understood. The WHO has issued epidemiologic and laboratory guidance
for assessment of mutations, and a global action plan for surveillance and response is in
preparation [57,66,67].
Rarely, false-negative HRP2 results may occur at very high levels of antigenemia or parasitemia
due to a prozone-like effect [68-70].
pLDH — Plasmodium lactate dehydrogenase is the terminal enzyme in the malaria

parasite glycolytic pathway and is produced by asexual and sexual forms of all Plasmodium species
[71]. Plasmodium LDH can be distinguished from human LDH on the basis of unique epitopes and
enzymatic characteristics [72,73].
Two types of pLDH-based RDTs are available: those that target a conserved pLDH element in all
human malaria species and those that target species-specific regions that distinguish P. falciparum
or P. vivax. pLDH antibodies specific for P. ovale and P. malariae have been described but are not
yet commercially available [40].
Serum pLDH levels correlate with parasite density and become undetectable at the same time
blood smears become negative following antimalarial therapy [73] so that pLDH-based assays may
be used for monitoring following treatment and to diagnose treatment failure [52,74-77].
pLDH-based RDTs are less sensitive than HRP2-based tests for detection of P. falciparum infection,
especially at relatively low parasite densities (<500 parasites/mcL) [42,45,78,79]. In highly endemic
areas, this may have little clinical significance since patients with relatively low parasite densities
are often asymptomatic.
Antigenic variation does not appear to significantly affect pLDH-based detection of most parasite
species [80].
Aldolase — Aldolase is an enzyme in the malaria parasite glycolytic pathway that is

conserved across all human malaria species. Serum aldolase levels correlate with parasite density
and become undetectable with clearance of parasitemia.
For detection of P. falciparum, the sensitivity of aldolase-based assays is generally somewhat lower
than that of HRP2-based assays [40,78,81,82]. For detection of non-falciparum infections, the
sensitivity of aldolase and pLDH assays is comparable.
Genetic diversity does not appear to be a factor in aldolase-based RDT accuracy [83,84].
Accuracy — There are many different commercial RDT products available. The WHO-FIND
global RDT testing program conducts standardized laboratory evaluations of RDTs, including testing
against well-characterized panels of parasites and antigens. Periodic reports from this program are
available online and provide the most systematic and reliable information on accuracy of available
malaria RDTs at any given time [47,85].
The validity of individual reports on RDT accuracy must be considered in light of the parasite
antigen(s) targeted, the comparison standard(s) used (routine microscopy, expert microscopy,
polymerase chain reaction [PCR]), malaria epidemiology in the study area (including presence of
Plasmodium species and level of transmission), the population in which the RDTs were evaluated,
and the personnel performing the RDTs. Other factors influencing RDT accuracy include the type of
antibody used (monoclonal versus polyclonal), the source of antigen used to induce the test
antibodies, and the epitope targeted by test antibodies [11,40].
Given the volume and variety of data, any statement of RDT accuracy must include a number of
caveats. A meta-analysis of RDT diagnosis for uncomplicated P. falciparum malaria in endemic
countries (in comparison with microscopy) noted sensitivity and specificity of 93 to 98 percent for
assays targeting HRP2 and pLDH [86]. A separate meta-analysis of RDT diagnosis for travelers
returning from endemic areas noted that for P. falciparum, tests utilizing HRP2 were more accurate
than those utilizing pLDH (negative likelihood ratios 0.08 and 0.13, respectively) [87]. Three-band
HRP2 tests had similar negative likelihood ratios but higher positive likelihood ratios compared with
two-band tests (34.7 versus 98.5; p = 0.003). Evidence was limited for species other than P.
falciparum.
Use in endemic areas — Use of RDTs in endemic areas has increased rapidly [88].
Globally, the proportion of suspected malaria cases in the public health care sector who receive a
parasitologic test has increased in most endemic regions since 2010; the greatest estimated rise, in
Africa, was from 36 to 87 percent between 2010 and 2016, mostly due to an increase in RDT use
[67].
However, the safety and acceptability of withholding antimalarial treatment from patients with
negative RDT results remains an important concern [1,89-91]; administration of presumptive
antimalarial treatment for fever has long been a recommended standard of care in many endemic
areas [92-94]. Favorable outcomes for management for uncomplicated febrile illness in children
based on RDT results have been observed in a number of endemic settings, including Benin [95],
Ghana [96], Papua New Guinea [97], Tanzania [98,99], and Zambia [100]. However, RDTs do not
have adequate negative predictive value to justify withholding treatment in the setting of severe
illness [45,101,102].
The sensitivity of light microscopy for detecting placental infection is low [103], and submicroscopic
malaria infections in pregnancy may be associated with adverse clinical outcomes including
maternal anemia [103,104] and low birth weight [105]. Use of RDTs for diagnosis of asymptomatic
malaria in pregnancy is the subject of ongoing study [106-109]. (See "Malaria in pregnancy:
Prevention and treatment".)
Use outside endemic areas — Use of RDTs by travelers for self-diagnosis may be an
acceptable first step if expert diagnosis is not immediately available, but the diagnosis should be
confirmed as soon as possible by more a reliable method [87,110-114]. Among 153 symptomatic
British travelers, 9 percent failed to successfully perform a valid RDT for self-diagnosis; among
those who did, the sensitivity and specificity were 97 and 95 percent, respectively (compared with
microscopy) [115].
One RDT has been approved by the US Food and Drug Administration (FDA): BinaxNOW Malaria.
The test is a combination assay with antibodies for detection of HRP2 and aldolase. Among 256
febrile returned travelers, the sensitivity of BinaxNOW for the detection of P. falciparum and non–P.
falciparum infection was 94 and 84 percent, respectively [112]. Subsequent experience has
confirmed excellent but not perfect performance. Both false-positive and false-negative test results
have been described, the latter especially in cases with low parasite density and/or non-falciparum
infections [11,116-119]. The CDC advises that RDTs should be used with a positive control (stored
blood containing P. falciparum), and both negative and positive results should be confirmed with
microscopy [120].
RDTs should not be used for screening donated blood, since the thresholds of detection are not
sufficiently sensitive to detect low parasite density [11,121].
Molecular tests — Use of molecular tests for malaria detection is generally limited to reference
laboratories and is primarily for research and epidemiologic purposes [122]. The CDC offers PCR
confirmation of species and identification of drug resistance mutations for malaria cases diagnosed
in the United States [123].
Nucleic acid tests (eg, PCR) are typically used as a gold standard in efficacy studies for antimalarial
drugs, vaccines, and evaluation of other diagnostic agents [38,124,125]. The theoretical limit of
detection for PCR has been estimated at 0.02 to 1 parasite/microL [126]. Nested PCR is the most
sensitive nucleic acid amplification technology; its sensitivity is 400 parasites/mL [127,128]. Parasite
DNA may be amplified after extraction from small volumes (typically 50 to 200 mcL) of whole blood
from dried blood spots stored on filter paper following extraction [129,130]. Commonly used PCR
assays target genus-specific and species-specific sequences of the 18S small-subunit ribosomal
RNA, circumsporozoite surface protein (a nuclear gene encoding a cysteine protease), and the
cytochrome b gene [7,131-134].
Low-density malaria infections that are detectable by PCR but below the detection threshold of
microscopy or RDTs can contribute to transmission [10,135-142]. Accurate detection of low-density
malaria infection is of increasing importance as some malaria-endemic areas move toward
elimination [143,144], with surveillance and screening playing larger roles in program management
[145-147]. However, the infrastructure and training required for use of PCR limits its utility for these
applications.
Loop-mediated isothermal amplification (LAMP) assays for detection of malaria parasite DNA are
being developed to facilitate use of molecular technology in endemic areas [148-153]. Use of LAMP
for amplification of DNA occurs at a single temperature so does not require the thermocycler
instrumentation necessary for PCR. LAMP generates 109 to 1010 replicates in 15 to 60 minutes, and
the resultant turbidity can be detected visually or by turbidimetry, without need for further
manipulation. Use of LAMP assays with a variety of target sequences and processing methods has
demonstrated variable sensitivity and specificity [154-160].
Clinical or presumptive diagnosis — There are no pathognomonic clinical signs or symptoms for
diagnosis of malaria [161-164], and accurate diagnosis requires detection of malaria parasites. (See
'Parasite-based diagnosis' above.)
If parasite-based diagnosis is not immediately available and there is clinical suspicion for P.
falciparum infection, it is reasonable to begin antimalarial therapy to prevent progression to severe
disease with plans to obtain diagnostic confirmation as soon as possible, recognizing that treatment
may influence the accuracy of subsequent diagnostic testing. Making a presumptive diagnosis
depends on individual patient circumstances including relevant malaria exposure, clinical
manifestations such as fever, and suggestive laboratory findings including anemia, in the absence
of a clear alternative diagnosis.
Typical symptoms and signs in uncomplicated malaria (including fever, malaise, myalgia, arthralgia,
headache) are not distinguishable from those caused by other etiologies and may overlap with other
clinical presentations (including self-limited illnesses as well as other viral, bacterial, and
parasitological infections that require specific treatment). (See "Clinical manifestations of malaria in
nonpregnant adults and children".)
There are no routine laboratory test results that are specific for malaria. Anemia is usually mild to
moderate, though severe anemia may occur in the setting of P. falciparum malaria. In a series of
Canadian travelers, patients with malaria presented with anemia in 41 percent of cases [20]. White
blood cell counts were elevated above 9.8 x 109/L in 3 percent of patients but were less than 5.0 x
109/L in 48 percent. Platelets were low in 83 percent of P. vivax–infected patients (mean 102 x
109/L) and in 62 percent of P. falciparum–infected patients (mean 137 x 109/L). A retrospective
review of refugee children arriving to the United States from Liberia compared clinical signs with
malaria parasites seen on blood smear; the presence of fever, thrombocytopenia, and
splenomegaly had a sensitivity and specificity of 71 and 88 percent, respectively [165].
Even in endemic areas, clinical diagnosis of malaria is frequently incorrect [92,93,166-171]. In sub-
Saharan Africa, which has the greatest burden of malarial disease, the prevalence of confirmed
malaria parasitemia among febrile patients varies widely, with most reports well under 50 percent
[42,172]. For example, in urban Niger during the high-transmission season, nearly half (46 percent)
of presumptive malaria diagnoses were erroneous, while the proportion rose to 96 percent during
the low-transmission season [166].
A systematic review sought to determine the predictive value of clinical findings for diagnosis of
malaria in patients in endemic areas and in returning travelers [173]. Data synthesis showed that, in
endemic areas, splenomegaly and hepatomegaly increase the likelihood of malaria (summary
likelihood ratios [LRs] 3.3, 95% CI 2.0-4.7 and 2.4, 95% CI 1.6-3.6, respectively), but individual
findings could not reliably exclude malaria. Combinations of findings were useful to stratify patient
risk but were not adequate to reliably exclude malaria. In returning travelers, the presence of
splenomegaly (LR 6.5, 95% CI 3.9-11.0), jaundice or icterus (LR 4.5, 95% CI 1.7-12.0), or pallor (LR
2.8, 95% CI 1.7-4.6) increase the likelihood of malaria. Malaria was more likely in the setting of
thrombocytopenia and hyperbilirubinemia (diagnostic odds ratios 74.0, 95% CI 9.2-601.0 and 11,
95% CI 8-15), while normal platelet counts and total bilirubin levels made malaria less likely but did
not exclude the diagnosis.
DIFFERENTIAL DIAGNOSIS — The differential diagnosis of malaria is discussed separately. (See

"Clinical manifestations of malaria in nonpregnant adults and children", section on 'Differential
diagnosis'.)
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from

selected countries and regions around the world are provided separately. (See "Society guideline
links: Malaria".)
SUMMARY
● The approach to diagnosis of malaria consists of clinical diagnosis and parasite diagnosis.
Parasite-based confirmation should be pursued whenever malaria is suspected clinically.
Forms of parasite diagnosis include light microscopy (visualization of parasites in stained blood
samples), rapid diagnostic tests (RDTs; detecting antigen or antibody), and molecular
techniques detecting parasite genetic material. (See 'Introduction' above.)
● Detection of parasites on Giemsa-stained blood smears by light microscopy is the standard tool
for diagnosis of malaria; it allows identification of the Plasmodium species as well as
quantification of parasitemia. However, microscopy cannot reliably detect very low parasitemia
(<5 to 10 parasites/mcL); it is also labor intensive and requires substantial training and
expertise. Issues related to smear preparation and interpretation are discussed in detail above.
(See 'Light microscopy' above.)
● Rapid diagnostic tests for detection of malaria parasite antigens are becoming increasingly
important diagnostic tools in resource-limited endemic settings due to their accuracy and ease
of use. They require no electricity or laboratory infrastructure, give results within 15 to 20
minutes, and can be performed successfully even by health workers with limited training. RDTs
provide a qualitative result but cannot provide quantitative information regarding parasite
density. (See 'Rapid diagnostic tests' above.)
● The approach to RDT selection depends on the epidemiology of infection and goals for control
in the region where the test is used. In regions where infection is primarily caused by P.
falciparum, use of an assay that detects P. falciparum only may be sufficient and cost-effective.
In regions where falciparum and non-falciparum parasites coexist or where P. vivax
predominates, use of an RDT that can detect and distinguish between these species is
warranted (table 3). (See 'Rapid diagnostic tests' above.)
● RDTs detect one or more of the following antigens: histidine-rich protein 2 (HRP2), Plasmodium
lactate dehydrogenase (pLDH), and aldolase. In general, for diagnosis of P. falciparum, RDTs
that detect HRP2 are more sensitive than those that detect pLDH. For diagnosis of non-
falciparum species, RDTs that detect pLDH and aldolase appear to be comparable. (See
'Antigen-based tests' above.)
● Use of molecular tests for malaria detection is generally limited to reference laboratories and is
primarily for research and epidemiologic purposes. Nucleic acid tests (eg, polymerase chain
reaction) are typically used as a gold standard in efficacy studies for antimalarial drugs,
vaccines, and evaluation of other diagnostic agents. Loop-mediated isothermal amplification for
detection of malaria parasite DNA is being developed as a field assay to facilitate use of
molecular technology in endemic areas. (See 'Molecular tests' above.)
ACKNOWLEDGMENT — The editorial staff at UpToDate would like to acknowledge Dr. Clinton
Murray, who contributed to an earlier version of this topic review.
Use of UpToDate is subject to the Subscription and License Agreement.
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150. Hopkins H, González IJ, Polley SD, et al. Highly sensitive detection of malaria parasitemia in a
malaria-endemic setting: performance of a new loop-mediated isothermal amplification kit in a
remote clinic in Uganda. J Infect Dis 2013; 208:645.
151. Patel JC, Lucchi NW, Srivastava P, et al. Field evaluation of a real-time fluorescence loop-
mediated isothermal amplification assay, RealAmp, for the diagnosis of malaria in Thailand
and India. J Infect Dis 2014; 210:1180.
152. Perera RS, Ding XC, Tully F, et al. Development and clinical performance of high throughput
loop-mediated isothermal amplification for detection of malaria. PLoS One 2017; 12:e0171126.
153. Serra-Casas E, Manrique P, Ding XC, et al. Loop-mediated isothermal DNA amplification for
asymptomatic malaria detection in challenging field settings: Technical performance and pilot
implementation in the Peruvian Amazon. PLoS One 2017; 12:e0185742.
154. Paris DH, Imwong M, Faiz AM, et al. Loop-mediated isothermal PCR (LAMP) for the diagnosis
of falciparum malaria. Am J Trop Med Hyg 2007; 77:972.
155. Pöschl B, Waneesorn J, Thekisoe O, et al. Comparative diagnosis of malaria infections by
microscopy, nested PCR, and LAMP in northern Thailand. Am J Trop Med Hyg 2010; 83:56.
156. Sirichaisinthop J, Buates S, Watanabe R, et al. Evaluation of loop-mediated isothermal
amplification (LAMP) for malaria diagnosis in a field setting. Am J Trop Med Hyg 2011; 85:594.
157. Polley SD, Mori Y, Watson J, et al. Mitochondrial DNA targets increase sensitivity of malaria
detection using loop-mediated isothermal amplification. J Clin Microbiol 2010; 48:2866.
158. Polley SD, González IJ, Mohamed D, et al. Clinical evaluation of a loop-mediated amplification
kit for diagnosis of imported malaria. J Infect Dis 2013; 208:637.
159. Piera KA, Aziz A, William T, et al. Detection of Plasmodium knowlesi, Plasmodium falciparum
and Plasmodium vivax using loop-mediated isothermal amplification (LAMP) in a co-endemic
area in Malaysia. Malar J 2017; 16:29.
160. Katrak S, Murphy M, Nayebare P, et al. Performance of Loop-Mediated Isothermal

Amplification for the Identification of Submicroscopic Plasmodium falciparum Infection in
Uganda. Am J Trop Med Hyg 2017; 97:1777.
161. Chandramohan D, Jaffar S, Greenwood B. Use of clinical algorithms for diagnosing malaria.
Trop Med Int Health 2002; 7:45.
162. Dorsey G, Gandhi M, Oyugi JH, Rosenthal PJ. Difficulties in the prevention, diagnosis, and
treatment of imported malaria. Arch Intern Med 2000; 160:2505.
163. Kockaerts Y, Vanhees S, Knockaert DC, et al. Imported malaria in the 1990s: a review of 101
patients. Eur J Emerg Med 2001; 8:287.
164. Casalino E, Le Bras J, Chaussin F, et al. Predictive factors of malaria in travelers to areas
where malaria is endemic. Arch Intern Med 2002; 162:1625.
165. Maroushek SR, Aguilar EF, Stauffer W, Abd-Alla MD. Malaria among refugee children at
arrival in the United States. Pediatr Infect Dis J 2005; 24:450.
166. Olivar M, Develoux M, Chegou Abari A, Loutan L. Presumptive diagnosis of malaria results in
a significant risk of mistreatment of children in urban Sahel. Trans R Soc Trop Med Hyg 1991;
85:729.
167. Sowunmi A, Akindele JA. Presumptive diagnosis of malaria in infants in an endemic area.
Trans R Soc Trop Med Hyg 1993; 87:422.
168. Luxemburger C, Nosten F, Kyle DE, et al. Clinical features cannot predict a diagnosis of
malaria or differentiate the infecting species in children living in an area of low transmission.
Trans R Soc Trop Med Hyg 1998; 92:45.
169. Chandramohan D, Carneiro I, Kavishwar A, et al. A clinical algorithm for the diagnosis of
malaria: results of an evaluation in an area of low endemicity. Trop Med Int Health 2001;
6:505.
170. Mwangi TW, Mohammed M, Dayo H, et al. Clinical algorithms for malaria diagnosis lack utility
among people of different age groups. Trop Med Int Health 2005; 10:530.
171. Vinnemeier CD, Schwarz NG, Sarpong N, et al. Predictive value of fever and palmar pallor for
P. falciparum parasitaemia in children from an endemic area. PLoS One 2012; 7:e36678.
172. Patrick Kachur S, Schulden J, Goodman CA, et al. Prevalence of malaria parasitemia among
clients seeking treatment for fever or malaria at drug stores in rural Tanzania 2004. Trop Med
Int Health 2006; 11:441.
173. Taylor SM, Molyneux ME, Simel DL, et al. Does this patient have malaria? JAMA 2010;
304:2048.
Topic 5707 Version 36.0
GRAPHICS
Life cycle of Plasmodium*
(1) Plasmodium-infected Anopheles mosquito bites a human and transmits sporozoites into the
bloodstream.
(2) Sporozoites migrate through the blood to the liver where they invade hepatocytes and divide to form
multinucleated schizonts (pre-erythrocytic stage). Atovaquone-proguanil and primaquine have activity
against hepatic-stage schizonts.
(3) Hypnozoites are a quiescent stage in the liver that exist only in the setting of P. vivax and P. ovale
infection. This liver stage does not cause clinical symptoms, but with reactivation and release into the
circulation, late-onset or relapsed disease can occur up to many months after initial infection. Primaquine is
active against the quiescent hypnozoites of P. vivax and P. ovale.
(4) The schizonts rupture and release merozoites into the circulation where they invade red blood cells.
Within red cells, merozoites mature from ring forms to trophozoites to multinucleated schizonts
(erythrocytic stage). Blood-stage schizonticides such as artemisinins, atovaquone-proguanil, doxycycline,
mefloquine, and chloroquine interrupt schizogony within red cells.
(5) Some merozoites differentiate into male or female gametocytes. These cells are ingested by the
Anopheles mosquito and mature in the midgut, where sporozoites develop and migrate to the salivary
glands of the mosquito. The mosquito completes the cycle of transmission by biting another host.
* There is strong evidence that drugs listed in parentheses are active against designated stage of parasitic life
cycle.
¶ Primaquine is a blood-stage schizonticide with activity against schizonts of P. vivax but not those of P. falciparum.
Graphic 70176 Version 8.0
Red blood cell morphology in various forms of Plasmodium infections
* Identification of a schizont with >12 merozoites in the peripheral circulation is an important diagnostic
clue for P. vivax. In general, schizonts of P. falciparum are very rarely seen in blood films; they are
generally absent from the peripheral circulation except in cases of severe infection with overwhelming
parasitemia.
Comparing the malaria species
Plasmodium
Plasmodium Plasmodium Plasmodium Plasmodium
knowlesi [1-
falciparum vivax ovale malariae 7]
Geography Tropical, Tropical, Tropical, Tropical, isolated Southeast Asia

temperate zones temperate endemic in West pockets
zones, absent Africa, present
from West Africa in Philippines,
Indonesia, and
Papua New
Guinea
RBC RBCs of all ages Young RBCs Young RBCs Older RBCs RBCs of all ages
preference (reticulocytes) (reticulocytes)
Infected Normal Larger than Larger than Normal or Normal

RBC normal normal smaller than
diameter normal
Ameboid No Yes Yes No No

trophozoites
Band forms No No No Yes Yes
Schizont* 16 to 20 20 to 24 4 to 16 6 to 12 8 to 16
merozoites; very merozoites merozoites (8 merozoites (8 or merozoites (10
rare in typical) 10 typical) typical)
peripheral
circulation
Parasitemia Can be very Usually <2% Usually <2% Usually very low Can be high
high
Disease End organ End organ Severe disease Severe disease Severe disease
severity damage and damage and uncommon rare can occur
death can occur death less
common than P.
falciparum but
can occur
Chloroquine Yes Yes No Rare No

resistance
Relapses No Yes Yes No No

from liver
Incubation 12 days (8 to 14 days (10 to 15 days (10 to 18 days (15 to 11 days (9 to

period 25) 30; occasionally 20) 35; occasionally 12)
months) months to
years)
Prepatent 11 days 12 days Δ 12 days 32 days Uncertain in

period
¶ naturally
infected humans
Cycle in red 48 hours 48 hours 48 hours 72 hours 24 hours

cell
RBC: red blood cell.

* Identification of a schizont with >12 merozoites in the peripheral circulation is an important diagnostic clue
for P. vivax. In general, schizonts of P. falciparum are very rarely seen in blood films; they occur only in the
setting of severe disease with hyperparasitemia.
¶ The prepatent period is the time from mosquito bite to the first appearance of parasites in the peripheral
blood (as detected by microscopy).
Δ The latency period of vivax is typically longer than falciparum (refer to UpToDate table summarizing time to
symptoms for each species).
References:
1. Shearer FM, Huang Z, Weiss DJ, et al. Estimating geographical variation in the risk of zoonotic
Plasmodium knowlesi infection in countries eliminating malaria. PLoS Negl Trop Dis 2016; 10:e0004915.
2. Lim C, Hansen E, DeSimone TM, et al. Expansion of host cellular niche can drive adaptation of a
zoonotic malaria parasite to humans. Nat Commun 2013; 4:1638.
3. Lee KS, Cox-Singh J, Singh B. Morphological features and differential counts of Plasmodium knowlesi
parasites in naturally acquired human infections. Malar J 2009; 8:73.
4. William T, Menon J, Rajahram G, et al. Severe Plasmodium knowlesi malaria in a tertiary care hospital,
Sabah, Malaysia. Emerg Infect Dis 2011; 17:1248.
5. Grigg MJ, William T, Menon J, et al. Artesunate-mefloquine versus chloroquine for treatment of
uncomplicated Plasmodium knowlesi malaria in Malaysia (ACT KNOW): An open-label, randomised
controlled trial. Lancet Infect Dis 2016; 16:180.
6. Chin W, Contacos PG, Collins WE, et al. Experimental mosquito-transmission of Plasmodium knowlesi to
man and monkey. Am J Trop Med Hyg 1968; 17:355.
7. Coatney GR, Collins WE, Contacos PG. The Primate malarias. Division of Parasitic Diseases, Atlanta, GA
1971.
Clues to species diagnosis via thin smear
P.
P. falciparum P. vivax P. ovale
malariae
Size of RBCs Normal size (sometimes Enlarged Enlarged and usually Normal size
distorted and crenated) oval in shape (with
fimbriated ends)
Number of May be multiple Usually one Usually one Usually one

parasites per
RBC
Typical form Rings Amoeboid, often Compact and regular Compact

of trophozoite fragmented
Other Banana-shaped Schuffner's granules; Schuffner's granules; Often see

characteristics gametocytes; black often see often see gametocytes
pigment in RBCs; gametocytes and gametocytes and and
schizonts rare schizonts schizonts schizonts
RBC: red blood cell.
Target antigens of commercially available RDTs*
RDT type Target antigens of test Possible results
I 1. HRP2 (P. falciparum specific) No Pf

Pf ¶
Invalid
II 1. HRP2 (P. falciparum specific) No malaria

2. Aldolase (pan-specific) Pf or mixed Δ
Pv, Po, and/or Pm ◊
Invalid
III 1. HRP2 (P. falciparum specific) No malaria

2. pLDH (pan-specific) Pf or mixed Δ
Pv, Po, and/or Pm ◊
Invalid
IV 1. pLDH (P. falciparum specific) No malaria

2. pLDH (pan-specific) Pf or mixed Δ
Invalid
V 1. pLDH (P. falciparum specific) No malaria

2. pLDH (P. vivax specific) Pf ¶
Pv
Pf and Pv
Invalid
VI 1. HRP2 (P. falciparum specific) No malaria

2. pLDH (pan-specific) Pf and Pv +/– Po and/or Pm Δ
3. pLDH (P. vivax specific) Pf +/– Po and/or Pm
Pv +/– Po and/or Pm ◊
Po and/or Pm
Invalid
VII 1. Aldolase No malaria

Pf, Pv, Po, and/or Pm ◊
Invalid
RDT: rapid diagnostic test; HRP2: histidine-rich protein 2; pLDH: Plasmodium lactate dehydrogenase; Pf:
Plasmodium falciparum; Pm: Plasmodium malariae; Po: Plasmodium ovale; Pv: Plasmodium vivax; invalid: an
absent control line.
* Most combinations are available in cassette or dipstick format. All RDTs include a control line in addition to
test line(s).
¶ Indicates that Pf is present. There could be other species present as coinfection.
Δ RDT cannot distinguish Pf from mixed infections (Pf with Pv, Po, or Pm). A positive HRP2 line alone could be
present in low-density Pf infection, as an anti-aldolase test line is commonly less sensitive than an anti-HRP2
line, but low-density non-falciparum coinfection can equally be missed.
◊ Pf is excluded, other species are present as single species or as a coinfection.
Reprinted by permission from Macmillan Publishers Ltd: Nature Reviews Microbiology. Bell D, Wongsrichanalai
C, Barnwell JW. Ensuring quality and access for malaria diagnosis: how can it be achieved? Nat Rev Microbiol
2006; 4:682. Copyright © 2006. www.nature.com/nrmicro.
Mode of action of antigen-detecting malaria rapid diagnostic tests
A malaria rapid diagnostic test (RDT) is a lateral flow immunochromatographic device that detects
protein (antigen [Ag]) derived from the blood stage of malaria parasites. Blood is usually obtained
from a finger prick, in a similar way to that usually used for malaria microscopy. A small sample of
blood, usually 5 to 20 microL, is placed on the RDT strip, or in a well of the cassette or card test
device, and lysed to release the Ag from within red blood cells and parasites from within these cells
(a variable amount of Ag is also present in the serum). After several minutes, the test produces a
series of visible lines to signal the presence or absence of Ag in the blood sample by the mechanism
outlined below:
(A) Dye-labeled antibody (Ab), specific for the target Ag, is present on the lower end of the
nitrocellulose strip or in a well provided by a casing covering the strip. Ab, specific for another epitope
on the target Ag, is bound to the strip in a thin (test) line, and Ab specific for the labeled Ab is bound
at the control line.
(B) Blood and buffer, which have been placed on the strip or in the well, are mixed with labeled Ab
and are drawn up the strip across the lines of bound Ab.
(C) If Ag is present, labeled Ab will be trapped on the test line. Other labeled Ab is trapped on the
control line. If sufficient labeled Ab accumulates, the dye labels will become visible to the naked eye
as a narrow line.
* Not normally visible.
Reprinted by permission from: Macmillan Publishers Ltd: Nature Reviews Microbiology. Bell D,
Wongsrichanalai C, Barnwell JW. Ensuring quality and access for malaria diagnosis: how can it be achieved?
Nat Rev Microbiol 2006; 4:682. Copyright © 2006. www.nature.com/nrmicro.
Contributor Disclosures
Heidi Hopkins, MD Nothing to disclose Johanna Daily, MD, MSc Nothing to disclose Elinor L
Baron, MD, DTMH Nothing to disclose
Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found,
these are addressed by vetting through a multi-level review process, and through requirements for
references to be provided to support the content. Appropriately referenced content is required of all
authors and must conform to UpToDate standards of evidence.
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11/26/2018 Diagnosis of malaria - UpToDate

Official reprint from UpToDate®

Author: Heidi Hopkins, MD

INTRODUCTION — Prompt and accurate diagnosis of malaria is critical for implementation of

Parasite-based diagnosis — Clinical tools for parasite-based diagnosis include microscopy

Light microscopy — Detection of parasites on Giemsa-stained blood smears by light

Microscopy allows identification of the Plasmodium species as well as quantification of parasitemia.

Blood smear preparation — Preparation of smears consists of applying a drop of blood to a

HRP2 — Histidine-rich protein 2 is part of a family of P. falciparum histidine-rich proteins

pLDH — Plasmodium lactate dehydrogenase is the terminal enzyme in the malaria

Aldolase — Aldolase is an enzyme in the malaria parasite glycolytic pathway that is

DIFFERENTIAL DIAGNOSIS — The differential diagnosis of malaria is discussed separately. (See

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from

Use of UpToDate is subject to the Subscription and License Agreement.

92. Ndyomugyenyi R, Magnussen P, Clarke S. Diagnosis and treatment of malaria in peripheral

141. Ouédraogo AL, Bousema T, Schneider P, et al. Substantial contribution of submicroscopical

160. Katrak S, Murphy M, Nayebare P, et al. Performance of Loop-Mediated Isothermal

Topic 5707 Version 36.0

Life cycle of Plasmodium*

Graphic 70176 Version 8.0

Red blood cell morphology in various forms of Plasmodium infections

Graphic 80296 Version 8.0

Comparing the malaria species

Geography Tropical, Tropical, Tropical, Tropical, isolated Southeast Asia

Infected Normal Larger than Larger than Normal or Normal

Ameboid No Yes Yes No No

Band forms No No No Yes Yes

Chloroquine Yes Yes No Rare No

Relapses No Yes Yes No No

Incubation 12 days (8 to 14 days (10 to 15 days (10 to 18 days (15 to 11 days (9 to

Prepatent 11 days 12 days Δ 12 days 32 days Uncertain in

Cycle in red 48 hours 48 hours 48 hours 72 hours 24 hours

RBC: red blood cell.

Graphic 53291 Version 10.0

Clues to species diagnosis via thin smear

Number of May be multiple Usually one Usually one Usually one

Typical form Rings Amoeboid, often Compact and regular Compact

Other Banana-shaped Schuffner's granules; Schuffner's granules; Often see

RBC: red blood cell.

Graphic 77935 Version 2.0

Target antigens of commercially available RDTs*

RDT type Target antigens of test Possible results

I 1. HRP2 (P. falciparum specific) No Pf

II 1. HRP2 (P. falciparum specific) No malaria

III 1. HRP2 (P. falciparum specific) No malaria

IV 1. pLDH (P. falciparum specific) No malaria

V 1. pLDH (P. falciparum specific) No malaria

VI 1. HRP2 (P. falciparum specific) No malaria

VII 1. Aldolase No malaria

Graphic 88872 Version 5.0

Mode of action of antigen-detecting malaria rapid diagnostic tests

* Not normally visible.

Graphic 88871 Version 1.0

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