The Journal of Emergency Medicine, Vol. 44, No. 2, pp. e211–e215, 2013Copyright � 2013 Elsevier Inc.

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doi:10.1016/j.jemermed.2012.02.051

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ClinicalCommunications: Adults

A CASE OF IMPORTED SEVERE PLASMODIUM FALCIPARUM MALARIAIN THE EMERGENCY DEPARTMENT AND THE CURRENT ROLE

OF EXCHANGE TRANSFUSION TREATMENT

Hania Habeeb, MD,* Jill R. Ripper, MD,* Alice Cohen, MD,† and Patrick B. Hinfey, MD*

*Department of Emergency Medicine and †Frederick B. Cohen Comprehensive Cancer and Blood Disorders Center,Newark Beth Israel Medical Center, Newark, New Jersey

Reprint Address: Patrick B. Hinfey, MD, Department of Emergency Medicine, Newark Beth Israel Medical Center,201 Lyons Avenue at Osborne Terrace, Newark, NJ 07112

, Abstract—Background: The role of exchange transfu-sion in the management of severe malaria is not well docu-mented in Emergency Medicine literature. Objectives: Thegoal of this article is to review the importance of consideringmalaria in the differential diagnosis of the febrile returnedtraveler and to discuss the role of exchange transfusion inthe management of severe Plasmodium falciparum malaria.Case Report: A 59-year-old woman presented to the Emer-gency Department (ED) with severe P. falciparum malaria.Her physical examination was remarkable for scleral icterus,dry mucous membranes, and tachycardia. Her completeblood count revealed a white blood cell count of 6.9 k/uL,with 71% segmented neutrophils, 19% bands, a hemoglobinlevel of 11.9 g/dL, hematocrit of 37.2%, and a platelet countof 9 k/uL. Hepatorenal impairment was present and malariaparasites with ring formwere seen onmalaria prep in 18% ofred blood cells. The patient was treated with fluids, platelets,quinidine gluconate, doxycycline, and exchange transfusionwith significant improvement in the patient’s clinical condi-tion. Conclusions: The high level of parasitemia presentingwith acute kidney injury, hyperbilirubinemia, and thrombo-cytopenia supported the use of exchange transfusion asadjunct therapy. Exchange transfusion was a reasonable con-sideration in this case and was well tolerated by our patient.Institutions that are equipped with apheresis units shouldevaluate each case individually in concert with Centers forDisease Control experts and local consultants and weigh therisks and benefits of the use of exchange transfusion as anadjunct in the treatment of severe P. falciparummalaria. � 2013 Elsevier Inc.

ptember 2011; FINAL SUBMISSION RECEIVED: 28ebruary 2012

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, Keywords—severe malaria; exchange transfusion;P. falciparum

INTRODUCTION

Many cases of imported malaria initially present to theEmergency Department (ED) in the United States andother non-endemic areas (1,2). The treatment ofuncomplicated Plasmodium falciparum (P. falciparum)malaria in areas without chloroquine-resistant strains,including Central America west of the Panama Canal,Haiti, the Dominican Republic, and most of the MiddleEast, is oral chloroquine (3). The treatment for casesof severe malaria, as defined by theWorld Health Organi-zation (WHO), is not straightforward (Table 1) (4,5).The goal of this article is to review the importance ofconsidering malaria in the differential diagnosis ofthe febrile returned traveler and to discuss the role ofexchange transfusion in the management of severeP. falciparum malaria. We report the case of a patientwith severe P. falciparum malaria whose conditionimproved after exchange transfusion.

CASE REPORT

A previously healthy 59-year-old woman presented to theED complaining of subjective fevers, abdominal pain,nausea, vomiting, and diarrhea after returning from Haiti

November 2011;

Table 1. World Health Organization Criteria (1990) and Added Criteria (2000) of Severe Plasmodium falciparum Malaria

Clinical Manifestation Features and Laboratory Values

Cerebral malaria Unarousable coma not attributable to any other cause, with a Glasgow Coma Scalescore# 9. Coma should persist for at least 30 min after a generalized convulsion

Severe anemia Hematocrit < 15% or hemoglobin < 50 g/L in the presence of parasite count > 10,000/mLRenal failure Urine output < 400 mL/24 h in adults (<12 mL/kg/24 h in children) and a serum

creatinine > 265 mmol/L (>3.0 mg/dL) despite adequate volume repletionPulmonary edema or acute respiratory

distress syndrome (ARDS)Breathlessness, bilateral crackles, and other features of pulmonary edema. The acute

lung injury score is calculated on the basis of radiographic densities, severity ofhypoxemia, and positive end-expiratory pressure

Hypoglycemia Whole blood glucose concentration < 2.2 mmol/L (<40 mg/dL)Hypotension and shock (algid malaria) Systolic blood pressure < 50 mm Hg in children aged 1–5 years or < 70 mm Hg in

patients > 5 years, cold and clammy skin or a core-skin temperature difference > 10�CAbnormal bleeding or disseminated

intravascular coagulationSpontaneous bleeding from gums, nose, gastrointestinal tract, or laboratory evidence of

disseminated intravascular coagulationRepeated generalized convulsions $ 3 convulsions observed within 24 hAcidemia/acidosis Arterial pH < 7.25 or acidosis (plasma bicarbonate < 15 mmol/L)Hemoglobinuria Macroscopic black, brown, or red urine; not associated with effects of oxidant drugs

or enzyme defects like G6PD deficiencyImpaired consciousness Generally arousable mental conditionProstration or weakness Extreme weakness, needs supportHyperparasitemia > 5% parasitized erythrocytes or > 250,000 parasites/mL (in non-immune individuals)Hyperpyrexia Core body temperature > 40�CHyperbilirubinemia (jaundice) Total bilirubin > 43 mmol/L (> 2.5 mg/dL)

G6PD = glucose-6-phosphate dehydrogenase.

e212 H. Habeeb et al.

4 days prior after a 5-month stay in that country. The pa-tient noted that the fevers had begun 6 days prior and re-ported a 1-day history of nausea and vomiting and a 2-dayhistory of diarrhea. While in Haiti, she did not receive an-timalarial prophylaxis and had no sick contacts, but shereported being bitten by mosquitoes. Medicationsincluded clonidine for hypertension, and there were noknown drug allergies. She was unemployed, lived alone,and denied smoking, alcohol, or drug consumption.

On her initial presentation, her vital signs were as fol-lows: temperature of 37.3�C (99.2�F), heart rate of 118beats/min, blood pressure of 103/68 mmHg, and respira-tory rate of 20 breaths/min, with an oxygen saturation of96% on room air. She appeared in moderate discomfort.Her physical examination was remarkable for scleralicterus, dry mucous membranes, and tachycardia. Ab-dominal examination revealed right upper quadrant ten-derness, positive Murphy’s sign, and no reboundtenderness or guarding. Her complete blood count re-vealed a white blood cell count of 6.9 k/uL, with 71%segmented neutrophils, 19% bands, a hemoglobin levelof 11.9 g/dL, hematocrit of 37.2%, and a platelet countof 9 k/uL. Hepatorenal impairment was present, witha blood urea nitrogen of 54 mg/dL, a creatinine of3.11 mg/dL, alkaline phosphatase of 173 units/L, totalbilirubin of 10.9 mg/dL, direct bilirubin of 7.70 mg/dL,aspartate aminotransferase of 193 units/L, and alanineaminotransferase of 141 units/L. Additional laboratorydata are as follows: lactate dehydrogenase 868 units/L,D-dimer > 10.5 ug/mL, and malaria parasites with ringformwere seen onmalaria prep in 18%of red blood cells.Her chest X-ray study was negative, and abdominal

ultrasound demonstrated a mildly ectatic common bileduct and no evidence of cholelithiasis.

A diagnosis of severe P. falciparummalaria was made.The patient received fluid boluses of normal saline, oneunit of single donor platelets, and had placement of a he-modialysis catheter. Following Centers for Disease Con-trol (CDC) Malaria Treatment Guidelines, a loading doseof 10 mg/kg of quinidine gluconate was infused intrave-nously over 1 h, followed by a continuous infusion of0.02 mg/kg/min over 4 h every 8 h, then 24 mg/kg over4 h in addition to doxycycline 100 mg by mouth (per os[p.o.]) twice a day (b.i.d.) (3). CDC guidelines recom-mend exchange transfusion for a parasite density ofmore than 10%. The patient was admitted to the IntensiveCare Unit where exchange transfusion with 10 units ofpacked red blood cells was performed without complica-tions, with a post-transfusion hematocrit of 36.1%. Thepatient reported improvement in symptoms after receiv-ing fluids. Vital signs stabilized after administration ofantibiotics, platelets, and exchange transfusion.

By the evening on the day of admission, the patientwas transferred to the medical floor and the malarialparasite density load was reduced to 3.2%. On day 2,the patient was reportedly weak with bony pain and hadno appetite. Serial electrocardiograms demonstrated pro-longed QTc intervals that improved with magnesium sul-fate administration. The malarial load was < 1%, anddoxycycline and quinidine gluconate were discontinued.Based on consultation with an infectious diseases special-ist, the patient was started on the following chloroquineregimen: day 1 600 mg p.o. b.i.d. and 500 mg p.o. dailyfor 2 subsequent days. Platelet count increased from

Plasmodium falciparum Malaria in the ED e213

9 k/uL to 15 k/uL, and clinical and laboratory indicatorsof liver and renal function were markedly improved. Onday 3, the renal function improved and the platelet countrose to 32 k/uL, with nomalarial parasites seen on periph-eral smear. On day 4, the patient was discharged homewith over-the-counter ferrous sulfate, folic acid, vitaminB12, and a follow-up visit.

DISCUSSION

With increased ease of international travel to and fromareas with endemic malaria, Emergency Physicians areoften the first-line medical providers for patients present-ing to health care personnel with malaria. Malaria shouldbe considered in the differential diagnosis of patients whohave been in endemic areas in the recent year or two, pre-senting with fever. Most severe cases of malaria anddeaths related to malaria are caused by P. falciparum.In 1990, the WHO established criteria for severe malariaand in 2000, revised these criteria to include other clinicalmanifestations and laboratory values (3,4). Table 1 isa summary of these criteria.

Mortality rates of severe imported P. falciparum ma-laria vary from 5% to 30%, making early diagnosis andinitiation of parenteral therapy important (6–8). Thecase described in this article is a case of severe malariapresenting with acute kidney injury, hyperparasitemia,hyperbilirubinemia, and thrombocytopenia. Accordingto CDC guidelines, patients with severe malaria shouldbe treated aggressively with parenteral antimalarialtherapy (3). Therapy includes quinidine gluconate asthe agent of choice, combined with intravenous doxycy-cline, tetracycline, or clindamycin until the patient canbe switched to oral therapy. Parenteral quinidine gluco-nate should be administered in an intensive care settingdue to its association with ventricular dysrhythmias,hypotension, hypoglycemia, and prolongation of theQTc interval. Our patient did experience prolongationof the QTc interval, which was successfully treatedwith magnesium sulfate.

A review of the literature demonstrated a generalawareness of the role of exchange transfusion in the treat-ment of severe malaria among Internal Medicine, Hema-tology, and Infectious Disease journals, but currentliterature regarding exchange transfusion as a treatmentoption was not as prevalent among Emergency Medicineliterature. We were impressed by the unawareness of therole of exchange transfusion treatment among the Emer-gency Medicine community, and therefore decided topresent one of the first case reports in Emergency Medi-cine literature. Journal of American Medical Associationpublished a systematic review of the treatment of malariain the United States in 2007 to familiarize U.S. cliniciansand laboratory personnel with the diagnosis and treat-

ment of malaria (9). Among Emergency Medicine publi-cations, in 2005, Badiaga et al. reported on the clinicalpresentation of severe imported malaria cases diagnosedfrom 1996 to 2002, with no mention of the role of ex-change transfusion for treatment (10). In a 1993 reviewof features pertinent to the Emergency Physician, Jotteand Scott described the potential utilization of exchangetransfusion as a means of rapidly reducing parasitemiaand mortality (2).

Exchange transfusion has been an option in the treat-ment of severe malaria since 1974, with apparent benefit.Miller et al. studied 17 patients who were treated forsevere or complicated P. falciparummalaria in the UnitedStates between 1985 and 1987 (11). Miller et al. con-cluded that the continuous infusion of quinidine gluco-nate is well tolerated alone, and in combination withexchange transfusion is effective in the treatment ofsevere or complicated malaria (11). Several case reportshave been published citing the successful use of exchangetransfusion therapy in severe cases of malaria with hyper-parasitemia or when conventional measures have failed.It is thought to have beneficial effects by the rapid reduc-tion of parasitemia, improvement in the rheologic proper-ties of blood, and reduction of toxic factors such ascytokines (12).

However, the benefit of exchange transfusion in thetreatment of severe malaria remains unclear in theabsence of a randomized controlled trial. Powell andGrima concluded that a large, multicenter trial ofexchange transfusion in severe malaria was very unlikelygiven the fulminant nature of the disease with significantmortality in the first few days of presentation (12). Addi-tionally, conducting a prospective trialmay be difficult be-cause high-prevalence areas may have limited access toexchange transfusion. However, retrospective studiescomparing adjunct exchange transfusion to anti-malarials alone have been conducted, and concluding rec-ommendations are summarized byShelat et al. (13). Theserecommendations included performing exchange transfu-sion for the following:P. falciparum parasitemia of > 10%with other evidence of severe infection, or with parasite-mia of > 30% with systemic complications such as acuterenal failure or acute respiratory distress syndrome, andaworsening clinical condition despite appropriate antima-larial medications and supportive therapy (14–17).

The CDC recommends that exchange transfusion bestrongly considered for the following: persons with a par-asite density of more than 10% or if complications such ascerebral malaria, acute respiratory distress syndrome, orrenal complications exist (3). The guidelines also recom-mend that the parasite density should be monitored every12 h until it is < 1%.

Before consideration of exchange transfusion, confir-mation of Plasmodium species is necessary. At our

e214 H. Habeeb et al.

institution, the malaria peripheral smear slide is preparedand read by hematology laboratory technicians andreviewed by clinical pathologists. If a Hematologist isinvolved, as in this case, the slide is also reviewed bya Hematologist. The mechanics of exchange transfusionis performed under the supervision of an apheresis spe-cialist or a Hematologist. Our institution subcontractswith the New York Blood Center, which sends an apher-esis nurse to perform the exchange. Equipment and bloodis onsite. The case patient was type- and cross-matchedfor packed red blood cells. A full exchange was calcu-lated at approximately 70 cc/kg, and each unit at approx-imately 200 cc. For example, a 60-kg person would needa 4.2-L exchange. A Shiley catheter was inserted for theexchange. Once started, the exchange takes 2–3 h.

Risks associated with exchange transfusion includefluid overload, febrile and allergic reactions, metabolicdisturbances, red blood cell alloantibody sensitization,transmissible infection, and line sepsis (3). Given thepotential risks associated with exchange transfusion, itwould be more reasonable to evaluate each caseindividually and to compare the risks and benefits ona case-by-case basis. In this case, it was reasonable toconsider exchange transfusion according to CDC recom-mendations. The high level of parasitemia presentingwith acute kidney injury, hyperbilirubinemia, and throm-bocytopenia supported the use of exchange transfusion asadjunct therapy. Additionally, exchange transfusion wasa reasonable consideration in this case because the bene-fits of such adjunct therapy outweighed the risks of theprocedure, similar to the case report published by Shelatet al. (13). The availability of pathogen-free blood prod-ucts, intensive care facilities, and technical expertisedecreased the potential risks associated with exchangetransfusion. Taking this into consideration, along withthe fact that severe P. falciparum is still associated withsignificant case fatality despite optimal antimalarial andsupportive treatment, adjunct exchange transfusion ther-apy was implemented.

Lastly, a meta-analysis by Riddle et al. demonstratedthat exchange transfusion was not associated witha more favorable survival rate, even when corrected forhigh level of parasitemia or the number of WHO criteriademonstrated (18). In considering use of adjunct ex-change transfusion therapy, it is equally important to rec-ognize that studies have evaluated the efficacy and safetyof adjunct therapy in comparison to conventional paren-teral antimalarial treatment. Van Genderen et al. conduct-ed a retrospective cohort study and reported no casefatalities observed in the adjunct therapy group comparedto the conventional parenteral antimalarial treatmentgroup (19). The authors conclude that exchange trans-fusion may be safely implemented in the presence of

intensive care facilities and availability of safe bloodproducts (19).

CONCLUSIONS

Though the prevalence of malaria in North America islow, we present this case to raise awareness among Emer-gency Physicians, particularly those practicing in ethni-cally diverse areas, of the clinical presentation andcomplications associated with malaria. Treatment mustbe initiated as soon as diagnostic laboratory confirmationis received. In severe malaria cases, CDC guidelinesshould be followed with strict attention to the recommen-dations for exchange transfusion. CDC provides a 24-hMalaria Hotline that provides consultations for cliniciansneeding guidance on diagnosis or management of malariacases. Institutions that are equipped with apheresis unitsshould evaluate each case individually in concert withCDC experts and local consultants, and weigh the risksand benefits of the use of exchange transfusion as an ad-junct in the treatment of severe P. falciparum malaria.

REFERENCES

1. Kockaerts Y, Vanhees S, Knockaert DC, Verhaegen J, Lontie M,Peetermans WE. Imported malaria in 1990s: a review of 101patients. Eur J Emerg Med 2001;8:287–90.

2. Jotte RS, Scott J. Malaria: review of features pertinent to the emer-gency physician. J Emerg Med 1993;11:729–36.

3. Centers for Disease Control and Prevention (CDC). Treatmentguidelines. Treatment of malaria (guidelines for clinicians).Atlanta, GA: CDC; June 2009.

4. Severe and complicated malaria. World Health Organization, Divi-sion of Control of Tropical Diseases. Trans R Soc Trop Med Hyg1990;84(Suppl 2):S1–65.

5. Severe falciparum malaria. World Health Organization, Communi-cable Diseases Cluster. Trans R Soc Trop Med Hyg 2000;94(Suppl 1):S1–90.

6. Matteelli A, Colombini P, Gulletta F, Castelli F, Carosi G. Epidemi-ological features and case management practices of importedmalaria in northern Italy 1991–1995. Trop Med Int Health 1999;4:653–7.

7. Jelinek T, Schulte C, Behrens R, et al. Imported Falciparummalariain Europe: sentinel surveillance data from the European network onsurveillance of imported infectious diseases. Clin Infect Dis 2002;34:572–6.

8. Bruneel F, Hocqueloux L, Alberti C, et al. The clinical spectrum ofsevere imported malaria in the intensive care unit: report of 188cases in adults. Am J Respir Crit Care Med 2003;167:684–9.

9. Griffith KS, Lewis LS, Mali S, Parise ME. Treatment of malaria inthe United States: a systematic review. JAMA 2007;297:2264–77.

10. Badiaga S, Brouqui P, Carpentier JP, et al. Severe imported malaria:clinical presentation at the time of hospital admission and outcomein 42 cases diagnosed from 1996 to 2002. J Emerg Med 2005;29:375–82.

11. Miller KD, Greenberg AE, Campbell CC. Treatment of severemalaria in the United States with a continuous infusion of quini-dine gluconate and exchange transfusion. N Engl J Med 1989;321:65–70.

12. Powell VI, Grima K. Exchange transfusion for malaria and Babesiainfection. Transfus Med Rev 2002;16:239–50.

Plasmodium falciparum Malaria in the ED e215

13. Shelat SG, Lott JP, Braga MS. Considerations on the use of adjunctred blood cell exchange transfusion in the treatment of severe Plas-modium falciparum malaria. Transfusion 2010;50:875–80.

14. McCaslin RI, Pikis A, Rodriguez WJ. Pediatric Plasmodium falci-parummalaria: a ten-year experience fromWashington, DC. PediatrInfect Dis J 1994;13:709–15.

15. Pinanong M. Exchange transfusion therapy in severe complicatedmalaria. J Med Assoc Thai 1997;80:332–7.

16. Srichaikul T, Leelasiri A, Polvicha P, et al. Exchange transfusiontherapy in severe complicated malaria. Southeast Asian J TropMed Public Health 1993;24(Suppl 1):100–5.

17. Alfandari S, Dixmier G, Guery B, Leroy O, Georges H,Beaucairel G. Exchange transfusion for severe malaria. Infection2001;29:96–7.

18. Riddle MS, Jackson JL, Sanders JW, Blazes DL. Exchange transfu-sion as an adjunct therapy in severe Plasmodium falciparum ma-laria. Clin Infect Dis 2002;34:1192–8.

19. Van Genderen PJ, Hesselink DA, Bezemer JM, Wismans PJ,Overbosch D. Efficacy and safety of exchange transfusion as anadjunct therapy for severe Plasmodium falciparum malaria in non-immune travelers: a 10-year single-center experience with a stan-dardized treatment protocol. Transfusion 2010;50:787–94.