Case Studies
Received 10.7.05 | Revisions Received 11.27.05 | Accepted 11.28.05
Fever and Coma in a Young Indian Boy
Reeta Thapa, MBBS,1 Naveen Kakkar, MD,1 Mary John, MD2
(Departments of 1Pathology and 2Medicine, Christian Medical College and Hospital, Ludhiana, Punjab, India)
DOI: 10.1309/W4AYK6489BCW824G
Clinical History
Patient
15-year-old Indian boy.
Chief Complaint
High grade fever for 5 days and altered
sensorium 16 hours prior to admission.
Medical/Family History
Unremarkable.
Drug History
History of abuse of dextropropoxyphene, an
opioid derivative.
Physical Exam Findings
The patient was comatose and febrile (102ºF)
with pallor, mild icterus, moderate hepatosplenomegaly, and brisk deep tendon reflexes.
Principal Laboratory Findings
(Table 1 and Image 1)
Questions
1. What is (are) this patient’s most striking clinical and
laboratory findings?
2. How do you explain these findings?
3. What is this patient’s most likely diagnosis?
4. What are the other species of the organism found in this
patient’s blood?
5. What is the geographical distribution of the organisms
found in this patient’s blood?
6. What are the clinical features of the disease caused by the
organism present in this patient’s blood?
7. What causes the clinical effects of the organism found in
this patient’s blood to be more severe compared to other
species of this organism?
8. What is the life cycle of the organism found in this patient’s
blood?
9. How is the diagnosis of the organism found in this patient’s
blood made in the laboratory?
the parasite within the mosquito vector. The Anopheles mosquito
survives at temperatures between 15°C to 38°C; however, optimal
growth of the parasite occurs at 20°C to 30°C and at a minimum
of 60% humidity. Plasmodium falciparum is most common in
Africa, New Guinea, and Haiti and is also seen in South America
and East Asia. Plasmodium vivax occurs in temperate zones and in
large areas of the tropics as well as in Central America and the
Indian subcontinent. Plasmodium malariae and Plasmodium ovale
are common in Africa. In North America, Europe, and other regions of the world where malaria has been eradicated, the disease
is imported by visitors/travelers from endemic areas.
6. In the early phase of malarial infection, clinical symptoms of disease are typically mild and non-specific, similar to
those occurring during an acute viral infection. The classical
Table 1_Principal Laboratory Findings
Test
Possible Answers
1. High-grade fever for several days with altered mental status, icterus, hepatosplenomegaly; severe anemia, mild leukocytosis with left shift, markedly increased LD level, azotemia, mild
hyperbilirubinemia; and the presence of malarial trophozoites
and crescent-shaped gametocytes in several red blood cells on the
peripheral blood smear (PBS) (Table 1 and Image 1).
2. The constellation of this patient’s clinical and laboratory
findings, especially the presence of crescent-shaped gametocytes
in the PBS, are characteristic of a malarial infection with the
protozoan parasite, Plasmodium falciparum.
3. Most likely diagnosis: cerebral malaria due to Plasmodium
falciparum.
4. Plasmodium vivax, Plasmodium ovale, and Plasmodium
malariae. Plasmodia are protozoa belonging to the suborder Hemosporina and the class, Sporozoa, that cause malaria in man.
5. Malaria is more prevalent in the tropics and subtropics
where optimal conditions exist for the development and growth of
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Result
Hematology
WBC count
Hemoglobin
Hematocrit
Platelet count
Reticulocyte count
Differential: Myelocytes
Metamyelocytes
Neutrophils
Lymphocytes
Eosinophils
PBS findings
Chemistry
Blood urea nitrogen
Serum creatinine
Total bilirubin
Direct bilirubin
ALT
AST
ALP
LD
“Normal” Reference
Range
15.9
4.0-11.0 x 103/L
4.1
12.0-16.0 g/dL
11.4
38-47%
75
150-400 x 103/L
3.4
0.2-2%
22
0%
14
0%
20
40-80%
42
20-40%
2
0-6%
Many RBCs with malarial trophozoites and
crescent-shaped gametocytes (Parasitic
Index = 80%) (Image 1)
198
3.1
3.7
2.5
80
310
351
4480
15-45 mg/dL
0.7-1.5 mg/dL
0.5-1.4 mg/dL
0-0.4 mg/dL
5-50 U/L
5-50 U/L
70-230 U/L
230-460 U/L
WBC, white blood cell; PBS, peripheral blood smear; ALT, alanine aminotransferase;, AST,
aspartate aminotransferase; ALP, alkaline phosphatase; LD, lactate dehydrogenase
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Case Studies
of this phase correlates with the interval between clinical
paroxysms of fever. The merozoites infect other RBCs to repeat the cycle while some develop into the sexual forms, the
male and female gametocytes which, in the case of
Plasmoidum falciparum, are large and crescent-shaped. Once a
mosquito ingests a blood meal from an individual whose
RBCs contain gametocytes, they fuse to form a zygote, followed by development of an ookinete and an oocyst. The mature oocyst releases 50 to 100 sporozoites into the salivary
apparatus of the mosquito and this permits the cycle to continue in the human host during its next human blood meal.
Unlike other malarial species, exo-erythrocytic schizogony
does not occur in Plasmodium falciparum infection and therefore, relapses do not occur in individuals infected with this
malarial species.
Image 1_Patient’s peripheral blood smear, illustrating the presence of
trophozoites (arrows) and a crescent-shaped gametocyte (inset) of
Plasmodium falciparum (1,000x magnification).
paroxysms of chills and fever occurring at regular periodic intervals for Plasmodium vivax (48 h), Plasmodium ovale (48 h), and
Plasmodium malariae (72 h) are absent in infections with Plasmodium falciparum in which the pattern of fever is irregular and
occurs at 24 to 48 hours. Associated clinical findings with malarial infection include: anemia, mild jaundice, and
hepatosplenomegaly. The clinical complications of malarial infection are seen more frequently and are more significant,
including life-threatening, in falciparum malaria than other
malarial species and include: cerebral malaria, hypotension, hypothermia, acute renal failure, lactic acidosis, acute respiratory
distress syndrome (ARDS), and intravascular hemolysis leading
to hemoglobinuria.1
7. The increased severity of disease symptoms associated
with malarial infection by Plasmodium falciparum is due to the
larger parasitic load (ie, more red blood cells are parasitized)
caused by this malarial parasite compared to other malarial
species. In addition, parasitized RBCs are rendered sticky by a
protein, Plasmodium falciparum erythrocyte membrane protein
(PfEMP), that causes knob-like structures on RBC membranes
and increases their adherance to the endothelium of capillaries
and venules. This leads to vascular occlusion and tissue anoxia
which causes increased capillary permeability and edema, the
primary cause of the cerebral symptoms associated with Plasmodium falciparum infection.2
8. The definitive host for plasmodium species is the mosquito vector, the female anopheles mosquito. Man is the intermediate host. In the human host, sporozoites inoculated
during the mosquito bite enter the liver where pre-erythrocytic schizogony occurs within the hepatocytes to liberate
daughter merozoites into the peripheral circulation. Released
merozoites which may be 10,000 to 30,000 in number attach
to red blood cell (RBC) membranes and enter these cells for
the next phase of the life-cycle, erythrocytic schizogony. In
this phase of the life-cycle, the trophozoites grow by feeding
on the hemoglobin of the host RBCs until schizogony occurs
with discharge of merozoites into the blood stream. The duration
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LABMEDICINE 䊏 Volume 37 Number 3 䊏 March 2006
9. The diagnosis of malaria in the laboratory can be made
by direct methods which involve visualization of the parasite or
by indirect methods that identify the presence of malarial enzymes or antigen:
Direct methods:
a. Thin-smear examination: the malarial parasite is directly
visualized by microscopic examination of a thin film of
peripheral blood stained with Romanowsky, Giemsa,
Leishman, Wright’s or Field’s stain. Malarial ring forms
(trophozoites), crescent-shaped gametocytes, or both may be
seen in the peripheral blood smear.
b. Thick-smear examination: dehemoglobinized thick smears
are used for screening blood for the presence of malarial
parasites. However, artifacts and distortion of morphology
do not always permit correct identification of the malarial
species present. For this reason, examination of a thin- and
thick-smear should always be performed simultaneously
when screening a PBS for the presence of malarial
parasites. Both smears are examined using the oil
immersion lens and the number of parasitized RBCs and
parasites are counted in the thin- and thick-smears,
respectively. A minimum of 100 oil immersion fields of
the thick-smear should be examined before a negative
report is released. Thick smears are extremely helpful in
cases of low parasite load in which thin-smear examination
may be negative.
c. Concentration smears: useful in identifying the presence of a
malarial parasite when the degree of parasitemia is low. Thin
smears should be visualized simultaneously for identification
of the species of malarial parasite present because speciation
is difficult using concentration smears.
Indirect methods:
a. Staining the blood smear with fluorescent dyes, especially
acridine orange, has been shown to be a sensitive test in the
diagnosis of malaria. Compared to Giemsa-stained PBSs,
acridine orange-stained PBSs provide higher sensitivity in
detecting malarial organisms when the level of parasitemia
is low (<1,000 organisms/µL). Rapid results is the major
advantage of this method.3
b. The plasmodial lactate dehydrogenase (pLD) assay provides
better sensitivity in detecting Plasmodium falciparum than
blood smear examination.4 Moreover, because this assay can
be performed rapidly and is positive only during active
infection, it is being used increasingly to identify individuals
infected with Plasmodium falciparum.
c. The detection of histidine rich receptor-2 (HRP-2) antigen
using monoclonal antibodies can be used to identify
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Case Studies
plasmodium infection; however, this test can be positive
even after the active infection has subsided.
d. Polymerase chain reaction (PCR) assays have been used
recently to diagnose malarial infection and also during
vaccine trials.5 Although such assays are more sensitive than
the gold standard (ie, microscopic examination by thinand/or thick-smear) in the detection and identification of
malarial parasites, the high cost of these assays can be
prohibitive to the economies of developing countries where
malaria is rampant.
e. Other serological methods for the detection of malarial
organisms include enzyme-linked immunosorbent assays
(ELISAs), indirect hemagglutination assays, and
immunoprecipitation assays; however, these assays are
generally cumbersome and not used routinely by most
clinical laboratories. LM
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Keywords: Plasmodia, parasitemia, cerebral malaria, trophozoite,
crescent-shaped gametocyte, schizogony
1. Mackintosh CL, Beeson JG, Marsh K. Clinical features and pathogenesis of
severe malaria. Trends Parasitol. 2004; 20:597-603.
2. Russell C, Mercereau-Puijalon O, Le Scanf C, et al. Further definition of
PfEMP-1 DBL-1alpha domains mediating resetting adhesion of Plasmodium
falciparum. Mol Biochem Parasitol. 2005;144:109-113.
3. Keiser J, Utzinger J, Premji Z, et al. Acridine Orange for malaria diagnosis: its
diagnostic performance, its promotion and implementation in Tanzania, and
the implications for malaria control. Ann Trop Med Parasitol. 2002;96:643654.
4. Odhiambo RA, Odulaja A. New enzymatic assay, parasite lactate dehydrogenase,
in diagnosis of malaria in Kenya. East Afr Med J. 2005;82:111-117.
5. Ndao M, Bandyayera E, Kokoskin E, et al. Comparison of blood smear,
antigen detection, and nested-PCR methods for screening refugees from
regions where malaria is endemic after a malaria outbreak in Quebec, Canada.
J Clin Microbiol. 2004;42:2694-2700.
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