Case 32-2006 — A 3-Year-Old Girl with Fever after a Visit to Africa
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《新英格兰医药杂志》
Presentation of Case
Dr. Christine M. Cserti: A 3-year-old girl was admitted to this hospital because of fever and parasites in the peripheral blood.
Three weeks earlier, the patient and her 5-year-old brother and mother had traveled to Nigeria to visit relatives. Antimalarial chemoprophylaxis had been prescribed for the patient's mother but not for the children. They stayed in an urban hotel, were not near standing water, did not travel in the countryside, and did not recall any mosquito bites. When they returned to the United States, 5 days before admission, fever, rigors, lethargy, nausea, and vomiting developed in both children. The patient had a temperature ranging from 38.9° to 40°C, despite the administration of antipyretic agents.
Two days before admission, laboratory tests were obtained by the patient's primary care physician (Table 1). Analysis of the peripheral-blood smear, reported the next day, showed parasites that were consistent with the presence of malaria. The parents were told to take the patient to the emergency department of this hospital.
Table 1. Results of Laboratory Tests.
The child had been born after a full-term, uncomplicated pregnancy in the United States; her parents were Nigerian. She had had no serious previous illnesses, and her immunizations were up to date. There was no family history of hemoglobinopathy. Her mother had had malaria during her childhood in Nigeria.
On physical examination, the patient was initially alert, interactive, and in no distress. She then became sleepy with a cranky but consolable demeanor. Her blood pressure was 110/45 mm Hg, with a pulse of 124 beats per minute; the respirations were 36 per minute, and the oxygen saturation was 100% while she was breathing ambient air. Her temperature was 38.8°C, height 102 cm, and weight 15 kg. The skin was warm to the touch, with brisk capillary refill; there were no cutaneous eruptions, petechiae, or visible insect bites. The sclerae were nonicteric. Cardiac examination revealed a hyperdynamic precordium, a regular rate and rhythm, and no murmurs. There was no lymphadenopathy or hepatosplenomegaly. The remainder of the physical examination, including a detailed neurologic examination, revealed no abnormalities.
Urinalysis showed trace ketones and protein. Examination of a thin smear of the peripheral blood revealed that 4 to 5% of the patient's erythrocytes were infected with parasites, the appearance of which was consistent with Plasmodium falciparum. Specimens of blood were sent for bacterial culture. Laboratory-test results are shown in Table 1. A chest radiograph showed mild pulmonary vascular engorgement.
Oral quinine sulfate, doxycycline, and acetaminophen were administered, and the patient was admitted to the pediatric intensive care unit. Twelve hours after presentation, her temperature was 40.3°C and she had a generalized tonic–clonic seizure, which lasted approximately 4 minutes and ended during the intravenous administration of a bolus of lorazepam. Treatment with fosphenytoin was initiated, and ceftriaxone was added. An electroencephalogram revealed no ongoing seizure activity. Examination of another blood smear showed increased parasitemia, with an estimated 21% of erythrocytes infected. Treatment with oral quinine sulfate was discontinued, and doxycycline and quinidine gluconate were administered intravenously. Continuous electrocardiographic monitoring was initiated.
Conscious sedation was induced with small doses of midazolam, ketamine, and fentanyl for the placement of a central venous catheter. After insertion of the catheter, the mean arterial blood pressure fell to 40 to 50 mm Hg and did not respond to intravenous fluids. A dopamine infusion was administered at a rate of 5 to 12 μg per kilogram of body weight per minute to maintain the systolic blood pressure at 80 to 100 mm Hg and the diastolic blood pressure at 30 to 58 mm Hg. Twenty-one hours after presentation, a specimen of arterial blood, drawn while the patient was breathing ambient air, had a pH of 7.31, a partial pressure of carbon dioxide of 38 mm Hg, a partial pressure of oxygen of 89 mm Hg, and a bicarbonate level of 19 mmol per liter.
An additional therapeutic intervention was recommended by a consultant in infectious diseases.
Differential Diagnosis
Dr. Cserti: When the patient arrived in the emergency department of this hospital, a preliminary diagnosis of malaria had already been made in another laboratory. Accurate speciation of plasmodium is essential for predicting the clinical course and selecting the most appropriate therapy. The species causing disease in humans (P. vivax, P. falciparum, P. malariae, and P. ovale) differ in their geographic distribution and pathogenicity, with P. falciparum being the deadliest.1 Differences in the morphologic features of the parasite at various stages of development, the presence or absence of some stages in the peripheral blood, and the morphologic characteristics of the infected red cells permit accurate speciation in most cases (Table 2).
Table 2. Differential Diagnosis of Plasmodium Infection on Peripheral-Blood Smears.
Microscopical examination remains the gold standard for the diagnosis of malaria, permitting simultaneous speciation and quantitation, although newer techniques may be available in the future.3 In this hospital, the quickest way to make the diagnosis of malaria is to perform a qualitative buffy-coat test. This method takes about 15 minutes and allows one to see parasites. However, this test is not quantitative, does not yield a species diagnosis, and does not distinguish between malaria and babesia. In this case, the test was inconclusive because of technical problems.
The most sensitive test for the presence of parasites is a stained thick blood film because of the relatively high volume of blood that can be examined.4 In this case, thin blood smears were examined because they are better for species identification. In New England, it is particularly important to distinguish malarial parasites from babesia, another parasite of erythrocytes that is common in this region. The diagnosis was confirmed in this patient with the use of conventional light-microscopical examination of Giemsa-stained blood smears. Features consistent with P. falciparum malaria included a high percentage of parasitized cells, the presence of multiple ring forms per erythrocyte, ring forms with double chromatin dots ("headphone" configuration), appliqué forms, the complete absence of schizonts, the absence of eosinophilic stippling (Schüffner's dots), and the preservation of red-cell size and color (Figure 1). The absence of mature thicker trophozoites and of schizonts on the peripheral-blood smear is central to the pathogenicity of P. falciparum, since these forms adhere to the endothelium of blood vessels and are thus sequestered in the microvasculature.5 The presence of hemozoin, a brown birefringent crystal formed from the breakdown of hemoglobin in the digestive organelle of the parasite,6 distinguishes malaria from babesiosis and suggests a poor prognosis if present in a high proportion of cells,7 but hemozoin was not seen in this case.
Figure 1. Peripheral-Blood Smear Obtained 12 Hours after the Patient's Arrival in the Emergency Department.
A Giemsa-stained peripheral-blood smear shows approximately a 20% level of parasitemia, with both fine (early) ring-form trophozoites (long black arrow) and thicker (maturing) ring-form trophozoites (short black arrow). Some erythrocytes contain two ring forms, and certain ring forms occur in the double-chromatin–dotted (headphone) configuration (curved arrow). An appliqué form is also present (white arrow). Schizonts, eosinophilic stippling (Schüffner's dots), and hemozoin are absent.
The quantitation of parasitemia has traditionally been used as an indicator of the severity of disease, with predictive value not only at presentation but also throughout a course of treatment.8 However, quantitation may underestimate the burden of disease if parasitized erythrocytes are sequestered in the vasculature,9 and it may overestimate the disease burden if there is an increase in the number of early ring forms after the disruption of schizonts by therapy.10 Nevertheless, parasite levels should be measured within the first 24 hours after the initiation of therapy to detect early therapeutic failure due to drug-resistant P. falciparum. In general, effective therapy should cause a marked reduction in the level of parasitemia within the first 24 hours. Current diagnostic guidelines recommend monitoring levels of parasitemia in hospitalized patients 24, 48, and 72 hours after the initiation of therapy.11 In this patient, the level of parasitemia rose from 5% to 21% after the initiation of therapy.
Although the presence of banana-shaped gametocytes is pathognomonic of P. falciparum malaria, they are not seen on the peripheral-blood smear until 7 to 10 days after infection. The first gametocyte was not seen in this patient's blood until 1 week after admission. Given the incubation period of 8 to 11 days that is characteristic of P. falciparum, the patient probably contracted the parasite within 5 to 8 days after her arrival in Nigeria.
Discussion of Management
Dr. Iain P. Fraser: This case illustrates the importance of effective prophylaxis, accurate diagnostic testing, and rapid administration of appropriate therapy for malaria. Although it is both preventable and curable, malaria still accounts for more than 1 million deaths per year, the majority of which are in children under 5 years of age.12 Increasing rates of international travel (with more than 20 million U.S. residents traveling each year to malarious regions of the world) suggest that primary care providers will be caring increasingly for patients at risk for this infection. Malaria is the most frequent cause of systemic febrile illness without localizing symptoms in travelers returning from the developing world,13 so vigilance is needed on the part of providers practicing in areas where malaria is not endemic.
Antimalarial Prophylaxis
This patient was born in the United States to parents who had been born in Africa but had lived in the United States for several years. Travelers, especially children, who are visiting friends and relatives in Africa are at particular risk for malaria, because they may not receive appropriate antimalarial prophylaxis for many reasons. Travelers who have lived previously in regions where malaria is endemic may mistakenly believe that both they and their children are immunologically protected from infection, not recognizing that immunity that develops in such regions wanes rapidly in the absence of repeated exposure. Patients sometimes report that they never received prophylaxis as children or that their relatives in the region are well despite not having received prophylaxis. Health care providers may erroneously suggest that antimalarial prophylaxis is appropriate only for older patients or that the adverse effects of such prophylaxis outweigh its benefits, as was apparently the case with this family. However, infection by P. falciparum is an important risk among travelers to sub-Saharan Africa and other areas where the disease is endemic, and the risk of severe illness or death is increased among nonimmune travelers, even if they have previously lived in such an area.
Antimalarial prophylaxis should include measures to limit exposure to insects,14 including sleeping in screened or air-conditioned rooms, using protective clothing and bed nets (insecticides such as permethrin can be applied to both to increase their efficacy), using insect repellents such as N,N-diethyl-3-methylbenzamide (DEET), using insect sprays or coils to clear rooms on arrival, and understanding that plasmodium-carrying mosquitoes feed at night. This family stayed in an urban hotel, which was probably air-conditioned, but since the family believed the risk of exposure was low, it is unlikely that they used insect repellents while outdoors.
The selection of effective antimalarial chemoprophylaxis requires knowledge of the patient's travel plans combined with up-to-date information regarding resistance to antimalarial drugs.15 This information is readily available from a variety of sources on the Internet (e.g., www.cdc.gov/travel/regionalmalaria/index.htm). In addition, the patient's age, clinical factors such as preexisting diseases (especially cardiac-conduction abnormalities and neuropsychiatric disorders) and concomitant medications, and personal preferences (e.g., daily vs. weekly dosing) need to be considered. For this patient's travel to Nigeria, chemoprophylaxis would have had to be active against chloroquine-resistant P. falciparum. Options for her would have been either weekly doses of mefloquine starting 1 week before travel and continuing for 4 weeks after her return or daily doses of combination therapy with atovaquone and proguanil starting 1 to 2 days before travel and continuing for 1 week after her return.
Treatment of P. falciparum Malaria
Infection with P. falciparum in a nonimmune host carries marked risks of illness and death and should be considered a medical emergency, as it was in this case. Partial immunity may be present in children who are older than 6 years of age, have a history of malaria, and have recently resided in a region where malaria is endemic, none of which apply to this child.16 Once malarial parasites are identified on a blood smear, further evaluation and therapy should be initiated without delay, since the risk of death from malaria is greatest early in the course of the disease. If accurate identification of the plasmodium species is not possible, the patient should be treated presumptively for P. falciparum until speciation has been performed. In general, all nonimmune patients with P. falciparum malaria should be treated in a hospital until a clear response to therapy has been documented, oral therapy is being tolerated, and appropriate follow-up can be ensured.
The initial evaluation should focus on differentiating an uncomplicated infection from severe infection (Table 3). Hypoglycemia is an important complication of childhood malaria, and close monitoring of blood glucose levels and prevention of hypoglycemia by means of therapy with intravenous fluids are key components of care. Patients with uncomplicated P. falciparum malaria can be treated with oral antimalarial drugs. Options available for the treatment of chloroquine-resistant P. falciparum in the United States include quinine in combination with doxycycline, clindamycin, or atovaquone plus proguanil. In this case, apart from an initial level of parasitemia in the range of 5%, there were no features of severe malaria when the patient was first seen. Oral antimalarial therapy was initiated in the pediatric intensive care unit.
Table 3. Clinical and Laboratory Features of Severe Plasmodium falciparum Malaria.
During the first 12 hours of therapy, the hematocrit decreased and the patient had a brief generalized tonic–clonic seizure along with a documented increase in the level of parasitemia to 21%, indicating severe malaria. Severe malaria requires parenteral therapy, and intravenous quinidine is the mainstay of therapy. The use of this drug requires close cardiac monitoring, with dose reduction if cardiotoxic effects develop. Intravenous therapy should be continued until the level of parasitemia is less than 1% and the patient is able to tolerate oral medications. This patient's antimalarial drugs were immediately switched to the intravenous route, broad-spectrum antibiotics were added to include treatment of possible bacterial coinfection, and the intensive-care therapy was optimized. We then consulted the Blood Transfusion Service regarding a possible exchange transfusion.
Dr. Walter H. Dzik: P. falciparum infection can cause profound anemia, thrombocytopenia, and disseminated intravascular coagulation, all of which developed in this patient. The pathophysiology leading to these hematologic effects is summarized in Figure 2. P. falciparum gains access to the erythrocyte through a highly complex interaction between the parasite and red-cell surface molecules.16 Infected red cells express cell-surface proteins encoded by the parasite genome. In particular, P. falciparum erythrocyte membrane protein 1 mediates adhesion of infected cells to platelets and to vascular endothelial cells, occluding vessels and causing critical organ ischemia.17,18 Whereas any endothelial bed appears to be at risk, adhesion of infected cells in the cerebral circulation and in the placental circulation of pregnant patients can result in devastating clinical outcomes. This patient had a seizure, raising concern about cerebral malaria.
Figure 2. Presumed Pathophysiology of the Hematologic Effects of Plasmodium falciparum Infection.
P. falciparum gains entry to the red cell through complex interactions involving sialic acid residues and red-cell membrane protein band 3. Once the cell is infected, P. falciparum erythrocyte membrane protein 1 (PfEMP-1) is expressed on the cell surface. Infected cells can form rosette aggregates with platelets by binding to CD36 on platelets, thereby contributing to thrombocytopenia and vascular occlusion. Infected red cells expressing PfEMP-1 become sequestered in the microcirculation by binding to vascular endothelial adhesion molecules including CD36, chondroitin sulfate A, intercellular adhesion molecule (ICAM-1), and heparan sulfate. The resulting endothelial damage and organ ischemia, combined with hemolysis and exposure to phosphatidylserine as well as macrophage activation and expression of tissue factor, promote disseminated intravascular coagulation.
Thrombocytopenia is common in P. falciparum infection and occurred in this patient. The exact pathophysiology is not known, but both the adherence of infected red cells to platelets and disseminated intravascular coagulation are likely to be contributing factors. Thus, one would expect thrombocytopenia to correlate with red-cell sequestration and serve as a useful clinical marker for cerebral malaria or other end-organ damage during infection. Disseminated intravascular coagulation develops in some patients with severe P. falciparum (Figure 2). The elevation of circulating d-dimers is common in P. falciparum infection,19 and prolongation of the international normalized ratio often occurs, although severe fibrinogen consumption and diffuse bleeding are very unusual. Severe malaria results in several signals for thrombin activation, including tissue ischemia, membrane lysis, exposure of phosphatidylserine, and tissue factor release, and it is important to avoid administration of procoagulant medications in response to abnormal coagulation test results. In this case, there was laboratory evidence of disseminated intravascular coagulation without clinical signs.
Severe Malaria and Exchange Transfusion
The Blood Transfusion Service was asked to consider an exchange transfusion for this patient. Either a whole-blood exchange transfusion or a specific red-cell exchange transfusion has been used in the treatment of severe malaria. The rationale for an exchange transfusion includes reductions in the parasite burden and in the signals for disseminated intravascular coagulation and the removal of infected red cells. In this case, we thought that more infected red cells could be removed by a specific red-cell exchange with the use of apheresis equipment than could be safely removed by means of whole-blood exchange. Exchange transfusions carry greater risks for children with a small blood volume, and this case was complicated by pressor-dependent hypotension, seizure, acidosis, and disseminated intravascular coagulation. Red-cell exchange by means of apheresis is not without risk; complications include hypovolemia, circulatory overload, cardiac arrhythmia (due to citrate-induced toxicity in patients receiving quinidine), transfusion reactions, and the need for venous access with a large-bore catheter.
After consideration of the risks and benefits, we performed a two-blood-volume red-cell exchange which was completed in 2.5 hours. The patient had no adverse effects and was noticeably more alert and responsive at the conclusion of the procedure. Table 1 shows the patient's laboratory values before the red-cell exchange (12 hours after her arrival in the emergency department) and after the exchange (31 hours after her arrival).
Although the rationale for red-cell exchange in severe malaria is compelling, there are no prospective clinical trials comparing this therapy with others.20 Although some retrospective case series and numerous case reports have suggested a benefit, these reports are subject to substantial reporting bias and lack controls.21,22 Although definitive recommendations cannot be made, it would seem that red-cell exchange (or whole-blood exchange), if available, should be considered in cases of severe malaria complicated by clinical signs of cerebral malaria, acute lung injury, severe hemolysis with acidemia, shock, or a high (or rising) level of parasitemia despite adequate intravenous antimalarial medication.
Dr. Eric F. Grabowski (Hematology–Oncology): Does an exchange transfusion remove the red cells that are "stuck" in the vascular endothelial beds? If so, would a longer, more aggressive exchange help in removing these cells?
Dr. Dzik: I think it is unlikely that an exchange transfusion will remove the cells already sequestered in the microvasculature. However, we can remove circulating infected cells and presumably prevent further sequestration.
Dr. Mark S. Pasternack (Pediatrics): Can you tell us about the patient's brother?
Dr. Fraser: Although the patient's 5-year-old brother was not referred for treatment, he accompanied the family to the emergency department, where the staff recommended that he be evaluated as well. If one child has malaria, all children who are traveling need to be evaluated. His level of parasitemia was initially just under 1%. He was treated at first with quinine and doxycycline, but later that day his parasitemia level increased to 7%. He was then treated with intravenous quinidine and doxycycline and did well.
Dr. Nancy Lee Harris (Pathology): His sister had a fever and a generalized tonic–clonic seizure. Do you think the seizure was due to the fever or to cerebral malaria?
Dr. Fraser: The fact that this was a single seizure without subsequent loss of consciousness suggests that it was more likely to have been a simple febrile seizure. However, at the time, we were concerned about evolving cerebral malaria or concomitant bacterial meningitis.
Dr. Harris: What is the role of immunity in mitigating the seriousness of malarial infection?
Dr. Fraser: In areas where malaria is endemic, repeated exposure to infected mosquitoes reduces not only the risk of infection but also the severity of illness. The beneficial effects of the immune response provide a biologic basis for ongoing research for a malaria vaccine.
Anatomical Diagnosis
Severe Plasmodium falciparum malaria.
No potential conflict of interest relevant to this article was reported.
Source Information
From the Department of Pediatrics (I.P.F.) and the Blood Transfusion Service (C.M.C., W.H.D.), Massachusetts General Hospital; and the Departments of Pediatrics (I.P.F.) and Pathology (C.M.C., W.H.D.), Harvard Medical School.
References
World malaria report 2005. Geneva: World Health Organization, 2005. (Accessed September 25, 2006, at http://www.rbm.who.int/wmr2005/html/1-2.htm.)
Garcia LS. Diagnostic medical parasitology. 4th ed. Washington, DC: ASM Press, 2001:159-92.
H?nscheid T. Diagnosis of malaria: a review of alternatives to conventional microscopy. Clin Lab Haematol 1999;21:235-245.
Moody A. Rapid diagnostic tests for malaria parasites. Clin Microbiol Rev 2002;15:66-78.
Yipp BG, Anand S, Schollaardt T, Patel KD, Looareesuwan S, Ho M. Synergism of multiple adhesion molecules in mediating cytoadherence of Plasmodium falciparum-infected erythrocytes to microvascular endothelial cells under flow. Blood 2000;96:2292-2298.
Noland GS, Briones N, Sullivan DJ Jr. The shape and size of hemozoin crystals distinguishes diverse Plasmodium species. Mol Biochem Parasitol 2003;130:91-99.
Lyke KE, Diallo DA, Dicko A, et al. Association of intraleukocytic Plasmodium falciparum malaria pigment with disease severity, clinical manifestations, and prognosis in severe malaria. Am J Trop Med Hyg 2003;69:253-259.
Watt G, Shanks GD, Phintuyothin P. Prognostic significance of rises in parasitaemia during treatment of falciparum malaria. Trans R Soc Trop Med Hyg 1992;86:359-360.
Sowunmi A, Walker O, Salako LA. Hyperparasitaemia: not a reliable indicator of severity or poor prognosis in falciparum malaria in children in endemic African countries. Ann Trop Pediatr 1992;12:155-8.
White NJ. Assessment of the pharmacodynamic properties of antimalarial drugs in vivo. Antimicrob Agents Chemother 1997;41:1413-1422.
Snow RW, Guerra CA, Noor AM, Myint HY, Hay SI. The global distribution of clinical episodes of Plasmodium falciparum malaria. Nature 2005;434:214-217.
Freedman DO, Weld LH, Kozarsky PE, et al. Spectrum of disease and relation to place of exposure among ill returned travelers. N Engl J Med 2006;354:119-130.
Hill DR. The burden of illness in international travelers. N Engl J Med 2006;354:115-117.
Franco-Paredes C, Santos-Preciado JI. Problem pathogens: prevention of malaria in travellers. Lancet Infect Dis 2006;6:139-149.
Stauffer WM, Fischer PR. Diagnosis and treatment of malaria in children. Clin Infect Dis 2003;37:1340-1348.
Miller LH, Baruch DI, Marsh K, Doumbo OK. The pathogenic basis of malaria. Nature 2002;415:673-679.
Fairhurst RM, Baruch DI, Brittain NJ, et al. Abnormal display of PfEMP-1 on erythrocytes carrying haemoglobin C may protect against malaria. Nature 2005;435:1117-1121.
Sherman IW, Eda S, Winograd E. Cytoadherence and sequestration in Plasmodium falciparum: defining the ties that bind. Microbes Infect 2003;5:897-909.
Bruneel F, Hocqueloux I, Alberti C, et al. The clinical spectrum of severe imported falciparum malaria in the intensive care unit: report of 188 cases in adults. Am J Respir Crit Care Med 2003;167:684-689.
Riddle MS, Jackson JL, Sanders JW, Blazes DL. Exchange transfusion as an adjunct therapy in severe Plasmodium falciparum malaria: a meta-analysis. Clin Infect Dis 2002;34:1192-1198.
Hoontrakoon S, Suputtamongkol Y. Exchange transfusion as an adjunct to the treatment of severe falciparum malaria. Trop Med Int Health 1998;3:156-161.
Burchard GD, Kroger J, Knobloch J, et al. Exchange blood transfusion in severe falciparum malaria: retrospective evaluation of 61 patients treated with, compared to 63 patients treated without, exchange transfusion. Trop Med Int Health 1997;2:733-740.(Iain P. Fraser, M.B., Ch.)
Dr. Christine M. Cserti: A 3-year-old girl was admitted to this hospital because of fever and parasites in the peripheral blood.
Three weeks earlier, the patient and her 5-year-old brother and mother had traveled to Nigeria to visit relatives. Antimalarial chemoprophylaxis had been prescribed for the patient's mother but not for the children. They stayed in an urban hotel, were not near standing water, did not travel in the countryside, and did not recall any mosquito bites. When they returned to the United States, 5 days before admission, fever, rigors, lethargy, nausea, and vomiting developed in both children. The patient had a temperature ranging from 38.9° to 40°C, despite the administration of antipyretic agents.
Two days before admission, laboratory tests were obtained by the patient's primary care physician (Table 1). Analysis of the peripheral-blood smear, reported the next day, showed parasites that were consistent with the presence of malaria. The parents were told to take the patient to the emergency department of this hospital.
Table 1. Results of Laboratory Tests.
The child had been born after a full-term, uncomplicated pregnancy in the United States; her parents were Nigerian. She had had no serious previous illnesses, and her immunizations were up to date. There was no family history of hemoglobinopathy. Her mother had had malaria during her childhood in Nigeria.
On physical examination, the patient was initially alert, interactive, and in no distress. She then became sleepy with a cranky but consolable demeanor. Her blood pressure was 110/45 mm Hg, with a pulse of 124 beats per minute; the respirations were 36 per minute, and the oxygen saturation was 100% while she was breathing ambient air. Her temperature was 38.8°C, height 102 cm, and weight 15 kg. The skin was warm to the touch, with brisk capillary refill; there were no cutaneous eruptions, petechiae, or visible insect bites. The sclerae were nonicteric. Cardiac examination revealed a hyperdynamic precordium, a regular rate and rhythm, and no murmurs. There was no lymphadenopathy or hepatosplenomegaly. The remainder of the physical examination, including a detailed neurologic examination, revealed no abnormalities.
Urinalysis showed trace ketones and protein. Examination of a thin smear of the peripheral blood revealed that 4 to 5% of the patient's erythrocytes were infected with parasites, the appearance of which was consistent with Plasmodium falciparum. Specimens of blood were sent for bacterial culture. Laboratory-test results are shown in Table 1. A chest radiograph showed mild pulmonary vascular engorgement.
Oral quinine sulfate, doxycycline, and acetaminophen were administered, and the patient was admitted to the pediatric intensive care unit. Twelve hours after presentation, her temperature was 40.3°C and she had a generalized tonic–clonic seizure, which lasted approximately 4 minutes and ended during the intravenous administration of a bolus of lorazepam. Treatment with fosphenytoin was initiated, and ceftriaxone was added. An electroencephalogram revealed no ongoing seizure activity. Examination of another blood smear showed increased parasitemia, with an estimated 21% of erythrocytes infected. Treatment with oral quinine sulfate was discontinued, and doxycycline and quinidine gluconate were administered intravenously. Continuous electrocardiographic monitoring was initiated.
Conscious sedation was induced with small doses of midazolam, ketamine, and fentanyl for the placement of a central venous catheter. After insertion of the catheter, the mean arterial blood pressure fell to 40 to 50 mm Hg and did not respond to intravenous fluids. A dopamine infusion was administered at a rate of 5 to 12 μg per kilogram of body weight per minute to maintain the systolic blood pressure at 80 to 100 mm Hg and the diastolic blood pressure at 30 to 58 mm Hg. Twenty-one hours after presentation, a specimen of arterial blood, drawn while the patient was breathing ambient air, had a pH of 7.31, a partial pressure of carbon dioxide of 38 mm Hg, a partial pressure of oxygen of 89 mm Hg, and a bicarbonate level of 19 mmol per liter.
An additional therapeutic intervention was recommended by a consultant in infectious diseases.
Differential Diagnosis
Dr. Cserti: When the patient arrived in the emergency department of this hospital, a preliminary diagnosis of malaria had already been made in another laboratory. Accurate speciation of plasmodium is essential for predicting the clinical course and selecting the most appropriate therapy. The species causing disease in humans (P. vivax, P. falciparum, P. malariae, and P. ovale) differ in their geographic distribution and pathogenicity, with P. falciparum being the deadliest.1 Differences in the morphologic features of the parasite at various stages of development, the presence or absence of some stages in the peripheral blood, and the morphologic characteristics of the infected red cells permit accurate speciation in most cases (Table 2).
Table 2. Differential Diagnosis of Plasmodium Infection on Peripheral-Blood Smears.
Microscopical examination remains the gold standard for the diagnosis of malaria, permitting simultaneous speciation and quantitation, although newer techniques may be available in the future.3 In this hospital, the quickest way to make the diagnosis of malaria is to perform a qualitative buffy-coat test. This method takes about 15 minutes and allows one to see parasites. However, this test is not quantitative, does not yield a species diagnosis, and does not distinguish between malaria and babesia. In this case, the test was inconclusive because of technical problems.
The most sensitive test for the presence of parasites is a stained thick blood film because of the relatively high volume of blood that can be examined.4 In this case, thin blood smears were examined because they are better for species identification. In New England, it is particularly important to distinguish malarial parasites from babesia, another parasite of erythrocytes that is common in this region. The diagnosis was confirmed in this patient with the use of conventional light-microscopical examination of Giemsa-stained blood smears. Features consistent with P. falciparum malaria included a high percentage of parasitized cells, the presence of multiple ring forms per erythrocyte, ring forms with double chromatin dots ("headphone" configuration), appliqué forms, the complete absence of schizonts, the absence of eosinophilic stippling (Schüffner's dots), and the preservation of red-cell size and color (Figure 1). The absence of mature thicker trophozoites and of schizonts on the peripheral-blood smear is central to the pathogenicity of P. falciparum, since these forms adhere to the endothelium of blood vessels and are thus sequestered in the microvasculature.5 The presence of hemozoin, a brown birefringent crystal formed from the breakdown of hemoglobin in the digestive organelle of the parasite,6 distinguishes malaria from babesiosis and suggests a poor prognosis if present in a high proportion of cells,7 but hemozoin was not seen in this case.
Figure 1. Peripheral-Blood Smear Obtained 12 Hours after the Patient's Arrival in the Emergency Department.
A Giemsa-stained peripheral-blood smear shows approximately a 20% level of parasitemia, with both fine (early) ring-form trophozoites (long black arrow) and thicker (maturing) ring-form trophozoites (short black arrow). Some erythrocytes contain two ring forms, and certain ring forms occur in the double-chromatin–dotted (headphone) configuration (curved arrow). An appliqué form is also present (white arrow). Schizonts, eosinophilic stippling (Schüffner's dots), and hemozoin are absent.
The quantitation of parasitemia has traditionally been used as an indicator of the severity of disease, with predictive value not only at presentation but also throughout a course of treatment.8 However, quantitation may underestimate the burden of disease if parasitized erythrocytes are sequestered in the vasculature,9 and it may overestimate the disease burden if there is an increase in the number of early ring forms after the disruption of schizonts by therapy.10 Nevertheless, parasite levels should be measured within the first 24 hours after the initiation of therapy to detect early therapeutic failure due to drug-resistant P. falciparum. In general, effective therapy should cause a marked reduction in the level of parasitemia within the first 24 hours. Current diagnostic guidelines recommend monitoring levels of parasitemia in hospitalized patients 24, 48, and 72 hours after the initiation of therapy.11 In this patient, the level of parasitemia rose from 5% to 21% after the initiation of therapy.
Although the presence of banana-shaped gametocytes is pathognomonic of P. falciparum malaria, they are not seen on the peripheral-blood smear until 7 to 10 days after infection. The first gametocyte was not seen in this patient's blood until 1 week after admission. Given the incubation period of 8 to 11 days that is characteristic of P. falciparum, the patient probably contracted the parasite within 5 to 8 days after her arrival in Nigeria.
Discussion of Management
Dr. Iain P. Fraser: This case illustrates the importance of effective prophylaxis, accurate diagnostic testing, and rapid administration of appropriate therapy for malaria. Although it is both preventable and curable, malaria still accounts for more than 1 million deaths per year, the majority of which are in children under 5 years of age.12 Increasing rates of international travel (with more than 20 million U.S. residents traveling each year to malarious regions of the world) suggest that primary care providers will be caring increasingly for patients at risk for this infection. Malaria is the most frequent cause of systemic febrile illness without localizing symptoms in travelers returning from the developing world,13 so vigilance is needed on the part of providers practicing in areas where malaria is not endemic.
Antimalarial Prophylaxis
This patient was born in the United States to parents who had been born in Africa but had lived in the United States for several years. Travelers, especially children, who are visiting friends and relatives in Africa are at particular risk for malaria, because they may not receive appropriate antimalarial prophylaxis for many reasons. Travelers who have lived previously in regions where malaria is endemic may mistakenly believe that both they and their children are immunologically protected from infection, not recognizing that immunity that develops in such regions wanes rapidly in the absence of repeated exposure. Patients sometimes report that they never received prophylaxis as children or that their relatives in the region are well despite not having received prophylaxis. Health care providers may erroneously suggest that antimalarial prophylaxis is appropriate only for older patients or that the adverse effects of such prophylaxis outweigh its benefits, as was apparently the case with this family. However, infection by P. falciparum is an important risk among travelers to sub-Saharan Africa and other areas where the disease is endemic, and the risk of severe illness or death is increased among nonimmune travelers, even if they have previously lived in such an area.
Antimalarial prophylaxis should include measures to limit exposure to insects,14 including sleeping in screened or air-conditioned rooms, using protective clothing and bed nets (insecticides such as permethrin can be applied to both to increase their efficacy), using insect repellents such as N,N-diethyl-3-methylbenzamide (DEET), using insect sprays or coils to clear rooms on arrival, and understanding that plasmodium-carrying mosquitoes feed at night. This family stayed in an urban hotel, which was probably air-conditioned, but since the family believed the risk of exposure was low, it is unlikely that they used insect repellents while outdoors.
The selection of effective antimalarial chemoprophylaxis requires knowledge of the patient's travel plans combined with up-to-date information regarding resistance to antimalarial drugs.15 This information is readily available from a variety of sources on the Internet (e.g., www.cdc.gov/travel/regionalmalaria/index.htm). In addition, the patient's age, clinical factors such as preexisting diseases (especially cardiac-conduction abnormalities and neuropsychiatric disorders) and concomitant medications, and personal preferences (e.g., daily vs. weekly dosing) need to be considered. For this patient's travel to Nigeria, chemoprophylaxis would have had to be active against chloroquine-resistant P. falciparum. Options for her would have been either weekly doses of mefloquine starting 1 week before travel and continuing for 4 weeks after her return or daily doses of combination therapy with atovaquone and proguanil starting 1 to 2 days before travel and continuing for 1 week after her return.
Treatment of P. falciparum Malaria
Infection with P. falciparum in a nonimmune host carries marked risks of illness and death and should be considered a medical emergency, as it was in this case. Partial immunity may be present in children who are older than 6 years of age, have a history of malaria, and have recently resided in a region where malaria is endemic, none of which apply to this child.16 Once malarial parasites are identified on a blood smear, further evaluation and therapy should be initiated without delay, since the risk of death from malaria is greatest early in the course of the disease. If accurate identification of the plasmodium species is not possible, the patient should be treated presumptively for P. falciparum until speciation has been performed. In general, all nonimmune patients with P. falciparum malaria should be treated in a hospital until a clear response to therapy has been documented, oral therapy is being tolerated, and appropriate follow-up can be ensured.
The initial evaluation should focus on differentiating an uncomplicated infection from severe infection (Table 3). Hypoglycemia is an important complication of childhood malaria, and close monitoring of blood glucose levels and prevention of hypoglycemia by means of therapy with intravenous fluids are key components of care. Patients with uncomplicated P. falciparum malaria can be treated with oral antimalarial drugs. Options available for the treatment of chloroquine-resistant P. falciparum in the United States include quinine in combination with doxycycline, clindamycin, or atovaquone plus proguanil. In this case, apart from an initial level of parasitemia in the range of 5%, there were no features of severe malaria when the patient was first seen. Oral antimalarial therapy was initiated in the pediatric intensive care unit.
Table 3. Clinical and Laboratory Features of Severe Plasmodium falciparum Malaria.
During the first 12 hours of therapy, the hematocrit decreased and the patient had a brief generalized tonic–clonic seizure along with a documented increase in the level of parasitemia to 21%, indicating severe malaria. Severe malaria requires parenteral therapy, and intravenous quinidine is the mainstay of therapy. The use of this drug requires close cardiac monitoring, with dose reduction if cardiotoxic effects develop. Intravenous therapy should be continued until the level of parasitemia is less than 1% and the patient is able to tolerate oral medications. This patient's antimalarial drugs were immediately switched to the intravenous route, broad-spectrum antibiotics were added to include treatment of possible bacterial coinfection, and the intensive-care therapy was optimized. We then consulted the Blood Transfusion Service regarding a possible exchange transfusion.
Dr. Walter H. Dzik: P. falciparum infection can cause profound anemia, thrombocytopenia, and disseminated intravascular coagulation, all of which developed in this patient. The pathophysiology leading to these hematologic effects is summarized in Figure 2. P. falciparum gains access to the erythrocyte through a highly complex interaction between the parasite and red-cell surface molecules.16 Infected red cells express cell-surface proteins encoded by the parasite genome. In particular, P. falciparum erythrocyte membrane protein 1 mediates adhesion of infected cells to platelets and to vascular endothelial cells, occluding vessels and causing critical organ ischemia.17,18 Whereas any endothelial bed appears to be at risk, adhesion of infected cells in the cerebral circulation and in the placental circulation of pregnant patients can result in devastating clinical outcomes. This patient had a seizure, raising concern about cerebral malaria.
Figure 2. Presumed Pathophysiology of the Hematologic Effects of Plasmodium falciparum Infection.
P. falciparum gains entry to the red cell through complex interactions involving sialic acid residues and red-cell membrane protein band 3. Once the cell is infected, P. falciparum erythrocyte membrane protein 1 (PfEMP-1) is expressed on the cell surface. Infected cells can form rosette aggregates with platelets by binding to CD36 on platelets, thereby contributing to thrombocytopenia and vascular occlusion. Infected red cells expressing PfEMP-1 become sequestered in the microcirculation by binding to vascular endothelial adhesion molecules including CD36, chondroitin sulfate A, intercellular adhesion molecule (ICAM-1), and heparan sulfate. The resulting endothelial damage and organ ischemia, combined with hemolysis and exposure to phosphatidylserine as well as macrophage activation and expression of tissue factor, promote disseminated intravascular coagulation.
Thrombocytopenia is common in P. falciparum infection and occurred in this patient. The exact pathophysiology is not known, but both the adherence of infected red cells to platelets and disseminated intravascular coagulation are likely to be contributing factors. Thus, one would expect thrombocytopenia to correlate with red-cell sequestration and serve as a useful clinical marker for cerebral malaria or other end-organ damage during infection. Disseminated intravascular coagulation develops in some patients with severe P. falciparum (Figure 2). The elevation of circulating d-dimers is common in P. falciparum infection,19 and prolongation of the international normalized ratio often occurs, although severe fibrinogen consumption and diffuse bleeding are very unusual. Severe malaria results in several signals for thrombin activation, including tissue ischemia, membrane lysis, exposure of phosphatidylserine, and tissue factor release, and it is important to avoid administration of procoagulant medications in response to abnormal coagulation test results. In this case, there was laboratory evidence of disseminated intravascular coagulation without clinical signs.
Severe Malaria and Exchange Transfusion
The Blood Transfusion Service was asked to consider an exchange transfusion for this patient. Either a whole-blood exchange transfusion or a specific red-cell exchange transfusion has been used in the treatment of severe malaria. The rationale for an exchange transfusion includes reductions in the parasite burden and in the signals for disseminated intravascular coagulation and the removal of infected red cells. In this case, we thought that more infected red cells could be removed by a specific red-cell exchange with the use of apheresis equipment than could be safely removed by means of whole-blood exchange. Exchange transfusions carry greater risks for children with a small blood volume, and this case was complicated by pressor-dependent hypotension, seizure, acidosis, and disseminated intravascular coagulation. Red-cell exchange by means of apheresis is not without risk; complications include hypovolemia, circulatory overload, cardiac arrhythmia (due to citrate-induced toxicity in patients receiving quinidine), transfusion reactions, and the need for venous access with a large-bore catheter.
After consideration of the risks and benefits, we performed a two-blood-volume red-cell exchange which was completed in 2.5 hours. The patient had no adverse effects and was noticeably more alert and responsive at the conclusion of the procedure. Table 1 shows the patient's laboratory values before the red-cell exchange (12 hours after her arrival in the emergency department) and after the exchange (31 hours after her arrival).
Although the rationale for red-cell exchange in severe malaria is compelling, there are no prospective clinical trials comparing this therapy with others.20 Although some retrospective case series and numerous case reports have suggested a benefit, these reports are subject to substantial reporting bias and lack controls.21,22 Although definitive recommendations cannot be made, it would seem that red-cell exchange (or whole-blood exchange), if available, should be considered in cases of severe malaria complicated by clinical signs of cerebral malaria, acute lung injury, severe hemolysis with acidemia, shock, or a high (or rising) level of parasitemia despite adequate intravenous antimalarial medication.
Dr. Eric F. Grabowski (Hematology–Oncology): Does an exchange transfusion remove the red cells that are "stuck" in the vascular endothelial beds? If so, would a longer, more aggressive exchange help in removing these cells?
Dr. Dzik: I think it is unlikely that an exchange transfusion will remove the cells already sequestered in the microvasculature. However, we can remove circulating infected cells and presumably prevent further sequestration.
Dr. Mark S. Pasternack (Pediatrics): Can you tell us about the patient's brother?
Dr. Fraser: Although the patient's 5-year-old brother was not referred for treatment, he accompanied the family to the emergency department, where the staff recommended that he be evaluated as well. If one child has malaria, all children who are traveling need to be evaluated. His level of parasitemia was initially just under 1%. He was treated at first with quinine and doxycycline, but later that day his parasitemia level increased to 7%. He was then treated with intravenous quinidine and doxycycline and did well.
Dr. Nancy Lee Harris (Pathology): His sister had a fever and a generalized tonic–clonic seizure. Do you think the seizure was due to the fever or to cerebral malaria?
Dr. Fraser: The fact that this was a single seizure without subsequent loss of consciousness suggests that it was more likely to have been a simple febrile seizure. However, at the time, we were concerned about evolving cerebral malaria or concomitant bacterial meningitis.
Dr. Harris: What is the role of immunity in mitigating the seriousness of malarial infection?
Dr. Fraser: In areas where malaria is endemic, repeated exposure to infected mosquitoes reduces not only the risk of infection but also the severity of illness. The beneficial effects of the immune response provide a biologic basis for ongoing research for a malaria vaccine.
Anatomical Diagnosis
Severe Plasmodium falciparum malaria.
No potential conflict of interest relevant to this article was reported.
Source Information
From the Department of Pediatrics (I.P.F.) and the Blood Transfusion Service (C.M.C., W.H.D.), Massachusetts General Hospital; and the Departments of Pediatrics (I.P.F.) and Pathology (C.M.C., W.H.D.), Harvard Medical School.
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