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BRIEF REPORT
Overwhelming Parasitemia with
Plasmodium falciparum Infection in a
Patient Receiving Infliximab Therapy
for Rheumatoid Arthritis
Estella M. Geraghty,1 Bryan Ristow,3 Shelley M. Gordon,2,3
and Paul Aronowitz3
1
Department of Internal Medicine, University of California Davis, Sacramento;
and Departments of 2Infectious Diseases and 3Internal Medicine, California
Pacific Medical Center, San Francisco, California
We describe a 45-year-old woman receiving infliximab therapy for rheumatoid arthritis who developed an overwhelming Plasmodium falciparum infection with cerebral malaria.
Physicians should be aware that patients receiving tumor
necrosis factor inhibitors, such as infliximab, may be at increased risk of life-threatening malarial infections.
Despite recent enthusiasm for TNF inhibitors as disease-modifying agents for treatment of rheumatoid arthritis, concern
remains about their potential to suppress important aspects of
the immune system. The TNF inhibitors (i.e., etanercept, infliximab, and adalimumab) have been lauded for their efficacy
in reducing the signs and symptoms of disease and increasing
functional status. Although initial studies indicating the safety
of these agents were reassuring, the studies included !1000
participants [1]; therefore, the risk of infrequent adverse reactions may have been underrepresented [2]. Of particular concern is the increased rate of intracellular infections associated
with these drugs; tuberculosis risk has been most well publicized, but risk exists for other granulomatous diseases, as well
as for infections with Salmonella, Listeria, and Legionella species
[3]. The incidence of pyogenic skin and soft-tissue infections
has also increased. Little is known, however, about the role of
TNF inhibitors for treatment of malaria.
Case report. A 45-year-old intensive care unit (ICU) nurse
presented to the emergency department 4 days after returning
Received 20 October 2006; accepted 30 January 2007; electronically published 2 April
2007.
Reprints or correspondence: Dr. Estella M. Geraghty, Dept. of Internal Medicine, University
of California Davis, 4150 V St., PSSB 2400, Sacramento, CA 95817 (Estella
[email protected]).
Clinical Infectious Diseases 2007; 44:e82–e84
2007 by the Infectious Diseases Society of America. All rights reserved.
1058-4838/2007/4410-00E2$15.00
DOI: 10.1086/515402
e82 • CID 2007:44 (15 May) • BRIEF REPORT
from a vacation in Mali, Africa. Her past medical history was
notable only for rheumatoid arthritis. She had received 1 dose
of methotrexate 1 month prior to her vacation, and she was
receiving weekly injections of infliximab. While in Mali, the
patient used mosquito netting and mosquito repellent, but she
chose not to take malaria chemoprophylaxis, although it had
been recommended by her physician. The day after her return
to the United States, the patient developed a fever (temperature,
40.3C), which was initially treated at home with acetaminophen. In the emergency department, the patient complained
of headache, dizziness, anorexia, myalgias, and fever with
drenching sweats.
Physical examination revealed an ill-appearing woman with
a temperature of 39.0C and an oxygen saturation by pulse
oximeter of 97%. She was awake and alert and had no evidence
of neurologic abnormalities. There were no rashes or petechiae.
Laboratory data revealed a WBC count of 4700 cells/mL, with
55% neutrophils and 32% band forms. The platelet count was
21,000 platelets/mL, hematocrit was 38%, and a blood smear
(figure 1) revealed Plasmodium falciparum malaria parasitemia.
On the night of hospital admission, the degree of parasitemia
was not quantitated; upon later review of blood smears, it was
estimated to be 150%. The blood urea nitrogen level was 15
mg/dL, the creatinine level was 0.7 mg/dL, the total bilirubin
level was 1.9 mg/dL, the aspartate aminotransferase level was
Figure 1. The patient’s thin blood smear revealing the characteristic
intraerythrocytic ring forms (trophozoites) associated with Plasmodium
falciparum infection. Note both the overwhelming degree of parasitemia
and the paucity of platelets. Wright Giemsa stain with oil immersion
original magnification, ⫻100.
71 U/L, the alanine aminotransferase level was 50 U/L, the
ionized calcium level was 4.0 mg/dL, the d-dimer level was 401
ng/mL, the fibrinogen level was 259 ng/mL, and the international normalized ratio was 1.1.
The patient was admitted to the hospital for treatment of P.
falciparum infection with quinine sulfate and doxycycline,
which she was able to take orally. Twelve h after admission,
the patient developed slurred speech and had difficulty constructing sentences. Examination revealed weakness of the left
upper extremity and left ptosis. CT of the brain exhibited no
acute pathology; a diagnosis of cerebral malaria was made. The
patient was transferred to the ICU for closer monitoring.
Within 2 h of transfer to the ICU, the patient’s mental status
declined further, and she had a generalized tonic-clonic seizure.
She underwent intubation for airway protection, and phenytoin
therapy was initiated. Quinine and doxycycline therapies were
continued via nasogastric tube. Thirty-six h after admission,
the patient’s hematocrit decreased to 26%, and the overall degree of parasitemia on her blood smear decreased to 4.6%. She
received an RBC exchange transfusion with 8 U of packed
RBCs. A blood smear performed a few hours after the procedure revealed a further reduction of her parasitemia to !1%.
The patient’s mental status improved over the next 3 days, and
she underwent extubation.
After 9 days of hospitalization, the patient was discharged.
At that time, she was afebrile and had mild gait instability and
residual left-side ptosis. Phenytoin therapy was discontinued.
Over the next month, with ongoing physical, occupational, and
speech therapy, the patient achieved complete neurologic recovery, with resumption of her normal activities. She subsequently returned to her job as an ICU nurse.
Discussion. Malaria parasites live and divide inside erythrocytes. In the process, they alter the RBC membrane, making
it subject to splenic clearance and hemolysis. The rupture of
RBCs leads to a release of proinflammatory cytokines, including
TNF-a. TNF-a appears to have many roles in the pathophysiology of malarial infections, but precise mechanisms are not
well understood. At lower levels, TNF-a has a pleiotropic antimalarial effect and, thus, is beneficial for fighting infection.
However, at higher levels, its effect may be detrimental [4, 5].
Higher levels of TNF-a may cause increased vascular release
of nitric oxide, causing interference with neurotransmission
and vasodilation, a process thought to increase the risk of cerebral edema [4]. In cerebral malaria, sequestration of parasites
in the microvasculature is believed to lead to local production
of inflammatory mediators, including TNF-a, leading to upregulation of glycoproteins, such as intercellular adhesion molecule-1. This, in turn, leads to further sequestration [6].
Administration of antibodies against TNF-a for treatment
of cerebral malaria has not been found to affect mortality [7].
Recently, an in vitro model suggested that LMP-420, an inhib-
itor of TNF mRNA, strongly inhibits endothelial adhesiveness
for P. falciparum–infected RBCs and inhibits the release of endothelial microparticles [8]. This approach has yet to be shown
effective in clinical trial.
The addition of TNF inhibitors to the armamentarium of
medications used to treat rheumatoid arthritis has revolutionized the treatment of the disease. Because these agents successfully inhibit the progression of structural damage, a more
aggressive early approach has become routine [9]. However,
these agents also affect host immunity, disrupting the cell-mediated immune response to intracellular pathogens [10]. There
is a clear association between the TNF inhibitors (especially
infliximab) and increased risk of opportunistic infections, such
as tuberculosis, histoplasmosis, listeriosis, and Pneumocystis
[11]. To our knowledge, increased risk of severe P. falciparum
infection, including cerebral malaria, has not previously been
reported.
We believe that the overwhelming P. falciparum parasitemia
and cerebral malaria seen in this patient may have been associated with her use of infliximab for management of rheumatoid arthritis. Although it may be argued that her use of
methotrexate 1 month prior to her infection confounds this
association, we make the following 3 points: (1) the pharmacokinetics of methotrexate in rheumatoid arthritis reveal a terminal half-life of 6 h [12], indicating that drug effects are
minimal after 30 days; (2) the risk of infection is higher for
patients with rheumatoid arthritis treated with infliximab plus
methotrexate, compared with methotrexate alone, suggesting
that the higher incidence of serious infection is attributable to
infliximab [13, 14]; and (3) the role of TNF-a for treatment
of malaria provides a plausible biologic explanation for the
severe level of parasitemia experienced by this patient. Although
we attribute this patient’s high degree of parasitemia and cerebra malaria to her recent use of a TNF-a inhibitor, one might
speculate that our patient’s lack of manifestations of severe
malaria, such as acute respiratory distress syndrome, and even
her salutary recovery might have been a result of a protective
effect of TNF inhibition.
TNF inhibitors provide proven efficacy for the management
of an often refractory rheumatologic disease, and patients will
likely benefit from increasing use of TNF inhibitors in the future
[10]. Unfortunately, these disease-modifying agents also appear
to increase the frequency and severity of certain infections [11].
We report a case of overwhelming P. falciparum parasitemia
with cerebral malaria in a 45-year-old woman undergoing treatment with infliximab for rheumatoid arthritis. It is imperative
that clinicians are aware of the possibility of life-threatening
malaria infections associated with infliximab. The importance
of appropriate recommendations for malaria chemoprophylaxis
for patients traveling to regions where malaria is endemic cannot be overemphasized.
BRIEF REPORT • CID 2007:44 (15 May) • e83
Acknowledgments
Potential conflicts of interest. All authors: no conflicts.
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