BRIEF REPORT CID 2008:47 (15 August) e39

B R I E F R E P O R T
Febrile Plasmodium falciparum Malaria
4 Years after Exposure in a Man with
Sickle Cell Disease
Tatiana Greenwood,
1
Tomas Vikerfors,
2
Maria Sjo berg,
2
Gunnar Skeppner,
1
and Anna Fa rnert
3
Departments of
1
Pediatrics and
2
Infectious Diseases, O

rebro University Hospital,

O

rebro, and
3
Infectious Diseases Unit, Department of Medicine Solna,
Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden
We report a case of symptomatic Plasmodium falciparum
malaria that manifested 4 years after a visit to an area of
endemicity in an 18-year-old male patient with sickle cell
disease. The exceptionally long incubation time raises the
questions of howand where P. falciparumparasites canreside
for several years before suddenly causing disease.
Plasmodium falciparum malaria is an acute and potentially fatal
infection that accounts for the main global burden of malaria.
After inoculation by the Anopheles mosquito, the parasites ma-
ture in the liver for at least 1 week before multiplying in the
blood to levels that cause fever and a wide variety of symptoms.
The incubation time is generally !2 months [1, 2]. Chemo-
prophylaxis and partial immunity may prolong the prepatent
period. However, in contrast to infections caused by the other
Plasmodium species, delayed onset of P. falciparum malaria oc-
curs very rarely [1, 2].
We describe a case of clinical P. falciparum malaria that de-
veloped 4 years after exposure. This exceptional case raises
several issues about the chronicity and activation of P. falci-
parum infection.
Case report. The patient was an 18-year-old man who was
admitted to O

rebro Hospital (O

rebro, Sweden) with a 3-day

history of chest, stomach, and back pain and recurrent episodes
of sweating and fever. He was known to have sickle cell disease
with splenomegaly but few other complications. At hospital
admission, the patient had a temperature of 39C, a slight tach-
ycardia, paraesthesia of the lower lip, and splenomegaly. The
Received 18 February 2008; accepted 21 March 2008; electronically published 10 July
2008.
Reprints or correspondence: Dr. Tatiana Greenwood, Dept. of Pediatrics, O

rebro University
Hospital, SE-70185 O

rebro, Sweden (tatiana.greenwood@orebroll.se).

Clinical Infectious Diseases 2008; 47:e3941
2008 by the Infectious Diseases Society of America. All rights reserved.
1058-4838/2008/4704-00E1$15.00
DOI: 10.1086/590250
rest of the ndings of the examination were normal, without
focal signs of infection. Blood test results revealed a C-reactive
protein level of 263 mg/L, an erythrocyte sedimentation rate
of 50 mm/h, a hemoglobin level of 118 g/L, a WBC count of
cells/L, a platelet count of platelets/L,
9 9
14.2 10 110 10
slightly elevated liver enzyme levels (lactate dehydrogenase level,
28 mkat/L; alanine aminotransferase level, 2.3 mkat/L; aspartate
aminotransferase level, 3.5 mkat/L; alkaline phosphatase level,
4.6 mkat/L), and signs of coagulopathy, with d-dimer 120 mg/
L and brinogen level of 8.7 g/L. Chest radiograph and elec-
trocardiograph ndings were normal.
The patient received a clinical diagnosis of acute chest syn-
drome (related to his sickle cell disease), with suspected infec-
tion. He was treated with intravenous cefotaxime, uids, an-
algesics, and oxygen. He improved after 2 days; however, the
recurring episodes of fever and sweating persisted. Results of
bacterial culture of blood, nasopharynx, urine, and stool spec-
imens were normal, as were the results of serological tests for
ongoing Epstein-Barr virus and cytomegalovirus.
The patient was born in Togo, where he lived until he was
4 years of age. During his 14 years in Sweden, he had visited
his country of origin on only a few occasions, and his last visit
was 4 years before hospital admission. The suspicion of a ma-
larial infection was, therefore, low. However, to exclude the
benign forms of malaria, which have longer incubation times
(Plasmodium ovale, Plasmodium vivax, and Plasmodium ma-
lariae), a screening test (MalaQuick; ICT) was performed. Sur-
prisingly, the result of the test was positive for P. falciparum.
Light microscopic examination of Giemsa-stained blood smears
detected P. falciparum in !0.01% of erythrocytes, with mainly
rings but also with a few trophozoites, schizonts, and game-
tocytes, as well as crescent-shaped erythrocytes (gure 1). The
patient was treated with atovaquone and proguanil (Malarone
R) for 3 days and was afebrile after 2 days. The unexpected
diagnosis was further conrmed by 2 separate PCR methods:
a species-specic PCR [3], which detected only P. falciparum,
and a P. falciparum genotyping method, which identied 1
parasite clone. At follow-up, the patient was fully recovered,
and results of another microscopic examination and PCR were
negative.
During his visit to Togo, which lasted for 1 month, the patient
had taken meoquine prophylaxis weekly, with uncertain com-
pliance. He recalled having had an episode of fever, which he
believed was treated with antimalarial tablets. He denied having
any episodes of fever after that. The patient had no history of
travel to other areas where malaria is endemic, he had not

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e40 CID 2008:47 (15 August) BRIEF REPORT
Figure 1. Erythrocytes infected with Plasmodium falciparum tropho-
zoites (A) and schizonts (B) and crescent-shaped erythrocytes (i.e., sickle
cells; C) in Giemsa-stained thin smears of peripheral blood specimens
obtained from the patient. Smears are from the time of diagnosis.
received blood transfusions, he had not visited an airport, and
he had not had close contact with a person with malaria. There-
fore, it was concluded that he most likely was infected during
his last visit to Togo, in June 2002.
Blood smear specimens saved for routine hematological con-
trol in May 2002 (i.e., before the visit to Togo) were reanalyzed
and found to be parasite-free by microscopic examination. No
additional microscopic smear or blood specimens were avail-
able for analysis for the presence of parasites during the sub-
patent period (20022006).
Discussion. P. falciparum is considered to have an incu-
bation time of 1 week to a few months. In our case, a clinical
episode with fever developed 4 years after exposure. In contrast
to P. vivax and P. ovale infections, P. falciparum and P. malariae
infections do not have any dormant liver stages (i.e., hypno-
zoites that cause relapses after several years). P. malariae in-
fection may have a very long incubation period (as long as
several decades), but it is not known where the parasites reside.
P. falciparum infection has a more acute onset, with 195% of
infections occurring within 2 months after exposure [1].
Persistent P. falciparum parasitemia is, however, often found
in individuals in areas of high transmission who have developed
antimalarial immunity as a result of repeated infections. This
immunity protects from disease but is not considered to be
sterilizing (i.e., the parasites are not completely cleared unless
antimalarial treatment is received), and the parasites often re-
mains in the blood at low levels. It is, however, not clear how
long P. falciparum infection can persist without reexposure. At
the time when malaria was induced to treat neurosyphilis, P.
falciparum infection was generally prepatent for up to 4 weeks
in patients with primary infection and persisted as asymptom-
atic parasitemia for a maximum duration of 618 months [2].
The incubation time and duration of infection may be extended
because of partial immunity. Studies of infection persistence in
areas of endemicity are, however, restricted by the risk of new
infections. In countries where malaria is not endemic, second-
ary P. falciparum infections have occurred through blood trans-
fusion from asymptomatic semi-immune donors a few years
after exposure [4]. Individuals with prior residence in countries
of endemicity are, therefore, deferred from blood donation for
3 years in the United States [5]. In semi-immune individuals,
infection can persist as low-level parasitemia without symp-
toms. Here, a P. falciparum infection developed into acute ma-
laria after 4 years. Unfortunately, there was no blood sample
available to establish how long the parasites were present in
the peripheral blood before causing disease.
During his rst years of life, our patient was likely to have
acquired some immunity against malaria. He had, however,
made only occasional visits to Togo after emigrating to Sweden
and, thus, had limited exposure and opportunities to stimulate
the maintenance of such immunity. At the suspected time of
infection, the patient was taking meoquine prophylaxis and
probably received some kind of antimalarial treatment for an
undiagnosed febrile episode. These antimalarial drugs were ob-
viously not optimal to prevent or clear the infection, either
because of poor efciency or because of insufcient intake;
however, they may have reduced the parasitemia to a level where
a partial immunity was able to control the infection.
Moreover, the patient had sickle cell disease. Hemoglobi-
nopathies are well recognized as protective against malaria and
are most prevalent in parts of the world where malaria is or
has been highly endemic [6]. The sickle cell disease trait, which

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BRIEF REPORT CID 2008:47 (15 August) e41
is most common in West Africa, results in an equal concen-
tration of hemoglobin S and hemoglobin C, which separately
have no signicant pathology; however, these forms together
cause a clinical syndrome similar to sickle cell anemia. Sepa-
rately, hemoglobin S and hemoglobin C protect against malaria
through the inhibition of parasite growth; however, the effect
when combined as sickle cell disease is not as well established
[6]. The RBC polymorphism may indeed have contributed to
the suppression of parasitemia to a subclinical level. It is unclear
whether P. falciparum infection triggered a suspected sickle cri-
sis or whether the crisismaybe triggered by another infec-
tionpropagated a chronic subpatent parasitemia to develop
into clinical malaria. Sickle cell disease often leads to impaired
spleen function, and P. falciparum infection has been found to
emerge in individuals who have undergone splenectomy [7].
The function of the spleen in our patient may have been of
key importance for the control and chronicity of infection.
In partially immune individuals with persistent low-level par-
asitemia, symptomatic malaria is believed to result from new
infections due to antigenically different parasites to which the
host is not immune [8]. Here, the absence of reexposure dem-
onstrates that clinical symptoms can develop from a chronic
infection. The parasites may have undergone antigenic variation
of the polymorphic P. falciparum erythrocyte membrane pro-
tein 1 and, thus, presented as new to the immune system.
Such antigenic variation, a mechanism by which the parasite
switches the expression of surface antigens and thereby evades
clearance in the spleen, may also be triggered by the spleen
itself [9]. The nding of trophozoites and schizonts, which are
not normally detected in the peripheral blood of patients with
P. falciparum infection, suggests altered sequestration and re-
duced clearance of late-stage parasites (gure 1). This supports
impaired spleen function as contributing to activationof disease
and may contradict the absolute need of an antigenically dif-
ferent parasite for the development of clinical malaria.
Our case leads to an intriguing question: where had the
parasites resided for so long? Had they been multiplying in the
blood and remained at subpatent levels through continuous
immune clearance? Or, as has recently been suggested, does P.
falciparum infection also have dormant stages [10], perhaps in
lymphoid tissue [11], that are perhaps induced by antimalarial
drugs [12]? In addition to demonstrating an interesting clinical
situation and the need to consider P. falciparum malaria a long
time after exposure, our case raises several questions regarding
the understanding of the biologic characteristics and the host-
parasite interactions of P. falciparum infection.
Acknowledgments
We thank Rita Lind, for providing photographs, and Lillemor Karlsson
and Berit Schmidt, for parasitological expertise.
Potential conicts of interest. All authors: no conicts.
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