Approach Considerations
In returning travelers from endemic areas, malaria is suggested by the triad of thrombocytopenia, elevated lactate dehydrogenase (LDH) levels, and atypical lymphocytes. These findings should prompt obtaining malarial smears.
In general, blood cultures should be drawn in a febrile patient. Patients from tropical areas may have more than 1 infection; maintaining a high suspicion for additional infections should be considered when patients do not respond to antimalarials.
Assess hemoglobin (decreased in 25% of patients, often profoundly in young children), platelet counts (thrombocytopenia in 50-68% of patients), and liver function (results abnormal in 50% of patients). Also monitor renal function, electrolytes (especially sodium), and parameters suggestive of hemolysis (haptoglobin, LDH, reticulocyte count). Rapid HIV testing may also be indicated in select cases. Importantly, fewer than 5% of patients with malaria have an elevated white blood cell (WBC) count. If leukocytosis is present, the examiner should entertain a broader list of differential diagnoses. The British Committee for Standards in Haematology has guidelines on the laboratory diagnosis of malaria.[8]
If the patient is to be treated with primaquine, a G-6-PD level should be obtained because primaquine can result in severe hemolysis in these patients.
If the patient has cerebral malaria, obtain a blood glucose level to rule out hypoglycemia as a cause of mental-status changes. Note that intravenous (IV) quinine can induce hypoglycemia; therefore, blood glucose should be monitored when IV quinine is used.
Imaging studies
Chest radiography may be helpful if respiratory symptoms are present. If CNS symptoms are present, a computed tomography (CT) scan of the head may be obtained to evaluate evidence of cerebral edema or hemorrhage.
Microhematocrit centrifugation
Using this method with the CBC tube is a more sensitive method of detection of malaria infection. However, microhematocrit centrifugation does not allow the identification of the species of Plasmodium. To determine species, a peripheral blood smear must be examined.
Fluorescent dyes/ultraviolet indicator tests
Several different dyes allow laboratory results to be obtained more quickly. These methods require the use of a fluorescent microscope. Fluorescent /ultraviolet tests may not yield speciation information.
Polymerase chain reaction assay
PCR assay testing is a very specific and sensitive means of determining if species of Plasmodium are present in the blood of an infected individual. PCR assay tests are not available in most clinical situations. However, they are very effective at detecting the Plasmodium species in patients with parasitemias as low as 10 parasites/mL of blood.
Lumbar puncture
If the patient exhibits mental-status changes, and even if the peripheral smear demonstrates P falciparum, a lumbar puncture should be performed to rule out bacterial meningitis.
Blood Smears
A diagnosis of malaria should be supported by the identification of the parasites on a thin or thick blood smear. In rare occasions, P falciparum infection can present without detectable parasitemia. If no alternative diagnosis is found in an at-risk patient with possible cerebral malaria (ie, unrevealing lumbar puncture findings), initiate therapy for presumptive malaria and continue to obtain additional blood smears to confirm the diagnosis.
When reading a smear, 200-300 oil-immersion fields should be examined (more if the patient recently has taken prophylactic medication, because this temporarily may decrease parasitemia). One negative smear does not exclude malaria as a diagnosis; several more smears should be examined over a 36-hour period.
Thick smears
Three thick and thin smears 12-24 hours apart should be obtained. The highest yield of peripheral parasites occurs during or soon after a fever spike; however, smears should not be delayed while awaiting fever spikes.
Thick smears are 20 times more sensitive than thin smears, but speciation may be more difficult. The parasitemia can be calculated based on the number of infected RBCs. This is a quantitative test.
Thin smears
Thin smears are less sensitive than thick smears, but they allow identification of the different species. This should be considered a qualitative test.
Alternatives to Blood Smear Testing
Alternative diagnostic methods typically are used if the laboratory does not have sufficient expertise in detecting parasites in blood smears.
Rapid diagnostic tests (RDT)
Immunochromatographic tests based on antibody to histidine-rich protein-2 (PfHRP2), parasite LDH (pLDH), or Plasmodium aldolase appear to be very sensitive and specific.[9, 10] Some RDTs may be able to detect P falciparum in parasitemias that are below the threshold of reliable microscopic species identification. Only one RDT (BinaxNOW) has been approved to date for the diagnosis of malaria in the United State.[11]
In one study, RDTs were found to perform better than microscopy under routine conditions. RDTs performed by the health facility staff were 91.7% sensitive and 96.7% specific. Microscopy was 52.5% sensitive and 77% specific.[12]
In a study from Tanzania, d'Acremont et al reported that antimalarials could be safely withheld from febrile children (< 5 y) who had negative results from an RDT based on PfHRP2.[13]
RDTs are less effective when parasite levels are below 100 parasites/mL of blood, and, in rare instances, an RDT test is negative in patients with high parasitemias. For these reasons, confirm RDT test results with a second type of screening test when possible. A false-positive result from an RDT may occur up to 2 weeks or more after treatment due to persistence of circulating antigens.
Other tests
In addition to the RDT listed above, new molecular techniques, such as PCR assay testing and nucleic acid sequence-based amplification (NASBA), are also available for diagnosis. They are more sensitive than thick smears but are expensive and unavailable in most developing countries.[14]
The quantitative buffy coat (QBC) is a technique that is as sensitive as thick smears. Because results cannot be used to speciate Plasmodium, a thin smear must be examined.
Malaria is a reportable disease. Identification of parasites by any of the above techniques should prompt notification to the local or state health department.
Histologic Findings
The table below compares histologic findings for P falciparum, P vivax, P ovale, and P malariae.
Table 1. Histologic Variations Among Plasmodium Species (Open Table in a new window)
| Findings | P falciparum | P vivax | P ovale | P malariae |
| Only early forms present in peripheral blood | Yes | No | No | No |
| Multiply-infected RBCs | Often | Occasionally | Rare | Rare |
| Age of infected RBCs | RBCs of all ages | Young RBCs | Young RBCs | Old RBCs |
| Schüffner dots | No | Yes | Yes | No |
| Other features | Cells have thin cytoplasm, 1 or 2 chromatin dots, and applique forms. | Late trophozoites develop pleomorphic cytoplasm. | Infected RBCs become oval, with tufted edges. | Bandlike trophozoites are distinctive. |
Cox-Singh J, Davis TM, Lee KS, Shamsul SS, Matusop A, Ratnam S, et al. Plasmodium knowlesi malaria in humans is widely distributed and potentially life threatening. Clin Infect Dis. Jan 15 2008;46(2):165-71. [Medline]. [Full Text].
Marchand RP, Culleton R, Maeno Y, Quang NT, Nakazawa S. Co-infections of Plasmodium knowlesi, P. falciparum, and P. vivax among Humans and Anopheles dirus Mosquitoes, Southern Vietnam. Emerg Infect Dis. Jul 2011;17(7):1232-9. [Medline].
William T, Menon J, Rajahram G, Chan L, Ma G, Donaldson S, et al. Severe Plasmodium knowlesi malaria in a tertiary care hospital, Sabah, Malaysia. Emerg Infect Dis. Jul 2011;17(7):1248-55. [Medline].
Malaria Surveillance — United States, 2010. Centers for Disease Control and Prevention. Available at http://www.cdc.gov/mmwr/preview/mmwrhtml/ss6102a1.htm?s_cid=ss6102a1_e. Accessed March 1, 2012.
Centers for Disease Control and Prevention. Malaria. Available at http://www.cdc.gov/malaria. Accessed Sep 15, 2011.
McGready R, Lee S, Wiladphaingern J, Ashley E, Rijken M, Boel M, et al. Adverse effects of falciparum and vivax malaria and the safety of antimalarial treatment in early pregnancy: a population-based study. Lancet Infect Dis. Dec 12 2011;[Medline].
Taylor SM, Parobek CM, Fairhurst RM. Haemoglobinopathies and the clinical epidemiology of malaria: a systematic review and meta-analysis. Lancet Infect Dis. Mar 22 2012;[Medline].
[Guideline] Bailey JW, Williams J, Bain BJ, Parker-Williams J, Chiodini P. General Haematology Task Force. Guideline for laboratory diagnosis of malaria. London (UK): British Committee for Standards in Haematology. 2007;19. [Full Text].
Rapid diagnostic tests for malaria ---Haiti, 2010. MMWR Morb Mortal Wkly Rep. Oct 29 2010;59(42):1372-3. [Medline].
Wongsrichanalai C, Barcus MJ, Muth S, Sutamihardja A, Wernsdorfer WH. A review of malaria diagnostic tools: microscopy and rapid diagnostic test (RDT). Am J Trop Med Hyg. Dec 2007;77(6 Suppl):119-27. [Medline].
Centers for Disease Control and Prevention. Notice to Readers: Malaria Rapid Diagnostic Test. Centers for Disease Control and Prevention. Available at http://www.cdc.gov/mmwr/preview/mmwrhtml/mm5627a4.htm. Accessed September 30, 2011.
de Oliveira AM, Skarbinski J, Ouma PO, Kariuki S, Barnwell JW, Otieno K, et al. Performance of malaria rapid diagnostic tests as part of routine malaria case management in Kenya. Am J Trop Med Hyg. Mar 2009;80(3):470-4. [Medline].
d'Acremont V, Malila A, Swai N, Tillya R, Kahama-Maro J, Lengeler C, et al. Withholding antimalarials in febrile children who have a negative result for a rapid diagnostic test. Clin Infect Dis. Sep 1 2010;51(5):506-11. [Medline].
Mens P, Spieker N, Omar S, Heijnen M, Schallig H, Kager PA. Is molecular biology the best alternative for diagnosis of malaria to microscopy? A comparison between microscopy, antigen detection and molecular tests in rural Kenya and urban Tanzania. Trop Med Int Health. Feb 2007;12(2):238-44. [Medline].
Dondorp AM, Fanello CI, Hendriksen IC, Gomes E, Seni A, Chhaganlal KD, et al. Artesunate versus quinine in the treatment of severe falciparum malaria in African children (AQUAMAT): an open-label, randomised trial. Lancet. Nov 13 2010;376(9753):1647-57. [Medline]. [Full Text].
US Food and Drug Administration FDA Approves Coartem Tablets to Treat Malaria. FDA. Available at http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm149559.htm. Accessed April 8, 2009.
Teuscher F, Gatton ML, Chen N, Peters J, Kyle DE, Cheng Q. Artemisinin-induced dormancy in plasmodium falciparum: duration, recovery rates, and implications in treatment failure. J Infect Dis. Nov 1 2010;202(9):1362-8. [Medline]. [Full Text].
Tozan Y, Klein EY, Darley S, Panicker R, Laxminarayan R, Breman JG. Prereferral rectal artesunate for treatment of severe childhood malaria: a cost-effectiveness analysis. Lancet. Dec 4 2010;376(9756):1910-5. [Medline].
Othoro C, Johnston D, Lee R, Soverow J, Bystryn JC, Nardin E. Enhanced immunogenicity of Plasmodium falciparum peptide vaccines using a topical adjuvant containing a potent synthetic Toll-like receptor 7 agonist, imiquimod. Infect Immun. Feb 2009;77(2):739-48. [Medline]. [Full Text].
Richards JS, Stanisic DI, Fowkes FJ, Tavul L, Dabod E, Thompson JK, et al. Association between naturally acquired antibodies to erythrocyte-binding antigens of Plasmodium falciparum and protection from malaria and high-density parasitemia. Clin Infect Dis. Oct 15 2010;51(8):e50-60. [Medline].
Olotu A, Lusingu J, Leach A, Lievens M, Vekemans J, Msham S, et al. Efficacy of RTS,S/AS01E malaria vaccine and exploratory analysis on anti-circumsporozoite antibody titres and protection in children aged 5-17 months in Kenya and Tanzania: a randomised controlled trial. Lancet Infect Dis. Feb 2011;11(2):102-9. [Medline].
[Best Evidence] Briand V, Bottero J, Noël H, Masse V, Cordel H, Guerra J, et al. Intermittent treatment for the prevention of malaria during pregnancy in Benin: a randomized, open-label equivalence trial comparing sulfadoxine-pyrimethamine with mefloquine. J Infect Dis. Sep 15 2009;200(6):991-1001. [Medline].
Briand V, Cottrell G, Massougbodji A, Cot M. Intermittent preventive treatment for the prevention of malaria during pregnancy in high transmission areas. Malar J. Dec 4 2007;6:160. [Medline]. [Full Text].
Piola P, Nabasumba C, Turyakira E, Dhorda M, Lindegardh N, Nyehangane D, et al. Efficacy and safety of artemether-lumefantrine compared with quinine in pregnant women with uncomplicated Plasmodium falciparum malaria: an open-label, randomised, non-inferiority trial. Lancet Infect Dis. Nov 2010;10(11):762-9. [Medline].
Trape JF, Tall A, Diagne N, Ndiath O, Ly AB, Faye J, et al. Malaria morbidity and pyrethroid resistance after the introduction of insecticide-treated bednets and artemisinin-based combination therapies: a longitudinal study. Lancet Infect Dis. Dec 2011;11(12):925-32. [Medline].
Centers for Disease Control and Prevention. Atlanta, GA: DHHS; 2009. Malaria and Travelers. Available at http://www.cdc.gov/malaria/travelers/index.html. Accessed Sep 15, 2011.
The RTS,S Clinical Trials Partnership. First results of phase 3 trial of RTS,S/AS01 malaria vaccine in African children. N Engl J Med. 2011/Oct;365:[Full Text].
White NJ. A vaccine for malaria (editorial). N Engl J Med. 2011/Oct;365:[Full Text].
Centers for Disease Control and Prevention. Malaria Diagnosis and Treatment in the United States. Available at http://www.cdc.gov/malaria/diagnosis_treatment/index.html. Accessed Sep 15, 2011.
Poespoprodjo JR, Fobia W, Kenangalem E, Lampah DA, Warikar N, Seal A, et al. Adverse pregnancy outcomes in an area where multidrug-resistant plasmodium vivax and Plasmodium falciparum infections are endemic. Clin Infect Dis. May 1 2008;46(9):1374-81. [Medline]. [Full Text].
Carmona-Fonseca J, Alvarez G, Maestre A. Methemoglobinemia and adverse events in Plasmodium vivax malaria patients associated with high doses of primaquine treatment. Am J Trop Med Hyg. Feb 2009;80(2):188-93. [Medline].
| Findings | P falciparum | P vivax | P ovale | P malariae |
| Only early forms present in peripheral blood | Yes | No | No | No |
| Multiply-infected RBCs | Often | Occasionally | Rare | Rare |
| Age of infected RBCs | RBCs of all ages | Young RBCs | Young RBCs | Old RBCs |
| Schüffner dots | No | Yes | Yes | No |
| Other features | Cells have thin cytoplasm, 1 or 2 chromatin dots, and applique forms. | Late trophozoites develop pleomorphic cytoplasm. | Infected RBCs become oval, with tufted edges. | Bandlike trophozoites are distinctive. |
Print
