Plasmodium Falciparum Malaria Occurring 8 Years After Leaving an Endemic Area ⁎ Paul E

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Diagnostic Microbiology and Infectious Disease 63 (2009) 105–107 www.elsevier.com/locate/diagmicrobio

Plasmodium falciparum malaria occurring 8 years after leaving an endemic area ⁎ Paul E. Szmitkoa, Magdie L. Kohna, Andrew E. Simora,b, aDepartment of Medicine, Sunnybrook Health Sciences Centre, University of Toronto, Toronto, Ontario, Canada M4N 3M5 bDepartment of Microbiology, Sunnybrook Health Sciences Centre, University of Toronto, Toronto, Ontario, Canada M4N 3M5 Received 3 June 2008; accepted 19 August 2008

Abstract

A 29-year-old patient who was born in Angola developed Plasmodium falciparum malaria 8 years after leaving Africa. She had not returned to a malaria-endemic area, and there were no apparent risks of local or nosocomial acquisition of malaria in Canada. She recovered after treatment with oral quinine sulfate and doxycycline. © 2008 Elsevier Inc. All rights reserved.

Keywords: Malaria; Plasmodium falciparum

1. Introduction P. falciparum, which is the predominant cause of malaria in Africa, accounts for most cases of severe disease and almost Malaria remains a leading cause of global morbidity and all malaria-related deaths. The incubation period for malaria mortality. More than 1 million deaths may be attributed to due to P. falciparum is typically less than 1 month, and most malaria each year, and more than 3 billion people live in patients present with onset of symptoms within 1 or 2 months malarial endemic regions (Newman et al., 2004; Snow et al., of exposure (Jelinek et al., 1994; Svenson et al., 1995). In the 2005). Although it is not endemic to the United States, United States, 98% of patients with P. falciparum malaria Canada, or Europe, malaria still represents a significant but presented within 3 months of departure from a malaria- preventable imported disease. In the United States, 1528 endemicarea(Schwartz et al., 2003). Therefore, the cases of malaria were reported in 2005, resulting in 7 deaths diagnosis may be missed or delayed in patients who present (Thwing et al., 2007). In Canada, about 400 cases are with malaria more than 1 year after leaving an endemic area. reported annually, associated with 1 or 2 deaths each year In this article, we describe a patient who developed P. (Kain et al., 2001; Suh et al., 2004). Disease in North falciparum malaria 8 years after leaving Angola, her country America and Europe generally occurs in travelers to endemic of birth. No other source of her infection was identified. areas, including those returning to their home countries A previously healthy 29-year-old woman was admitted to believing themselves to be immune (Kain et al., 2001; hospital in Toronto, Ontario, in May 2007 with a 3-day Newman et al., 2004). Thus, the timely diagnosis and history of general malaise, fever, chills, anorexia, nausea, treatment of malaria remains relevant in developed nations, vomiting, and watery stools. She did not have melena, rectal especially as international travel continues to grow. bleeding, or hematemesis, and there were no respiratory or In humans, 4 species of plasmodia are associated with urinary symptoms. She was not taking any medications. malaria: Plasmodium falciparum, Plasmodium vivax, Plas- There had not been any recent travel, and she was unaware of modium ovale, and Plasmodium malariae. Infection by any sick contacts. There was no history of intravenous drug use, and she lived in an urban area of Toronto, not near the airport. The patient had immigrated to Canada from Angola ⁎ Corresponding author. Department of Microbiology, Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada M4N 3M5. Tel.: +1 416 in 1999 and had not traveled outside Canada since 2002, 480 4549; fax: +1 416 480 6990. when she had visited family in Portugal. While still living in E-mail address: [email protected] (A.E. Simor). Angola, she had been treated for malaria and had made a

0732-8893/$ – see front matter © 2008 Elsevier Inc. All rights reserved. doi:10.1016/j.diagmicrobio.2008.08.017 106 P.E. Szmitko et al. / Diagnostic Microbiology and Infectious Disease 63 (2009) 105–107 Table 1 no bacteria, crystals, or casts. The chest x-ray was normal, Results of the initial laboratory investigations and the electrocardiogram showed sinus tachycardia. Laboratory test (normal values) Patient's results Examination of the peripheral blood film showed spher- Hemoglobin (115–165 g/L) 101 g/L ocytes, but no schistocytes. There were numerous red blood Leukocyte count (4.0–11.0 × 109/L) 8.4 × 109/L cells with malarial infestation, including multiple ring forms Platelet count (150–400 × 109/L) 68 × 109/L (Fig. 1). The level of parasitemia was 5.4%. Malaria due to – Serum glucose, random (4.0 8.0 mmol/L) 7.9 mmol/L P. falciparum was diagnosed, and this was later confirmed by Serum creatinine (44–106 μmol/L) 355 μmol/L Serum bilirubin (b20.0 μmol/L) 30 μmol/L a polymerase chain reaction assay (Farcas et al., 2006). Serum aspartate aminotransferase (b31 IU/L) 29 IU/L As soon as the blood film results became available, Serum alanine aminotransferase (b31 IU/L) 29 IU/L treatment was started with oral quinine sulfate (600 mg 3 Serum alkaline phosphatase (40–120 IU/L) 73 IU/L times per day) and doxycycline (100 mg twice a day) for a – Serum lactate dehydrogenase (100 250 IU/L) 363 IU/L total of 7 days. Within 48 h of starting treatment, she became Serum haptoglobin (0.3–2.0 g/L) b0.2 g/L HCG screen Negative afebrile, and her gastrointestinal symptoms resolved. Para- sitemia peaked at 6% 24 h after presentation, and by day 4 of HCG = human chorionic gonadotrophin. treatment, no malarial parasites were seen. However, her hemoglobin dropped to a low of 68 g/L on the day after admission. She was transfused with 2 U of packed red blood good recovery. She had received a blood transfusion in cells, and on discharge from hospital, her hemoglobin was Angola in 1997 while she was giving birth to her 1st child; 89 g/L. Her platelets recovered to 370 × 109/L, and her renal this had been her only transfusion of blood products. function normalized with rehydration. Blood and urine On admission to hospital, she was alert and oriented with cultures yielded no growth. Stool samples were negative fever (38.5 °C), blood pressure of 115/75 mm Hg without a for bacterial and viral enteric pathogens, and for ova and postural change, and tachycardia (114 beats/min). Her parasites. At a follow-up visit 3 weeks after discharge from respiratory rate was 26/min, and she had an oxygen hospital, she appeared to be clinically well and reported no saturation of 97% while breathing room air. There was no further episodes of fever, chills, or gastrointestinal symptoms. rash, scleral icterus, or lymphadenopathy. The lungs were Although the patient's clinical presentation and labora- clear, and cardiac examination revealed normal heart sounds tory findings were consistent with malaria, this diagnosis without murmurs. There was mild discomfort on deep was not initially considered because there had been no travel palpation of the epigastrium, but there were no abdominal to a malaria-endemic area for at least 8 years, and there was masses or organomegaly. Neurologic and musculoskeletal no reason to consider local or nosocomial acquisition of examinations were normal. malaria (Brook et al., 1994; Mungai et al., 2001). A The initial laboratory investigations are summarized in diagnosis of thrombotic thrombocytopenic purpura was Table 1. Urinalysis revealed 1+ hemoglobinuria and initially considered because of the presence of fever, renal proteinuria. Microscopic urine examination revealed 2 to 5 impairment, thrombocytopenia, and hemolytic anemia. It erythrocytes and 0 to 1 leukocytes per high-power field, with was for this reason that an urgent examination of the

Fig. 1. The diagnosis of P. falciparum malaria was made by the examination of a thin peripheral blood film initially ordered to rule out the presence of schistocytes in possible thrombotic thrombocytopenic purpura (panel A—Wright's stain). Thick and thin peripheral blood smears, stained with Giemsa stain (panel B—thin smear, higher magnification), remain the standard for routine clinical diagnosis. They allow for both species identification and quantification by assessing the percentage of erythrocytes infected on the film. The blood film derived from our patient contained morphologic features that were diagnostic of P. falciparum, namely, the presence of multiple ring forms per erythrocyte (black arrows), thin ring forms with double chromatin dots (arrow heads), and rings that were found in the periphery of the red cells (appliqué) (blue arrows) and the preservation of red-cell size and color. P.E. Szmitko et al. / Diagnostic Microbiology and Infectious Disease 63 (2009) 105–107 107 peripheral blood film was requested, and this subsequently Kevin Kain for performing the malaria polymerase chain established the correct diagnosis. reaction assay. Late recrudescence of P. falciparum malaria, though extremely uncommon, has been reported previously. References P. falciparum malaria was diagnosed in a pregnant woman 4 years after her last stay in an endemic area (Giobbia et al., Besson P, Robert JF, Reviron J, Richard-Lenoble D, Gentilini M (1976) A 2005). The delayed presentation was attributed to the propos de deux observations du paludisme transfusionnel: essai de pregnancy, impairing her preexisting immune equilibrium prevention associant un test d'immunofluorescence indirecte aux and acting as a trigger. However, there are also a few reports critères de selection clinique. Rev Fr Transfus Immunohematol 19: 369–373. of nonpregnant adults developing malaria due to Bouchaud O, Cot M, Kong S, Durand R, Schiemann R, Ralaimazava P, P. falciparum 4 or more years after leaving an endemic Couland JP, Le Bras J, Deloron P (2005) Do African immigrants living region (Eloy et al., 1998; Kyrönseppä et al., 1989). It is in France have long-term malarial immunity? Am J Trop Med Hyg 72: thought that preexisting partial immunity from repeated prior 21–25. exposures may account for prolonged asymptomatic infec- Brook JH, Genese CA, Bloland PB, Zucker JR, Spitalny KC (1994) Brief reports: malaria probably locally acquired in New Jersey. N Engl J Med tion of malaria due to P. falciparum. This has been described 331:22–23. after transfusion-associated malaria; the longest documented Eloy O, Zuily E, Greder-Belan A, Bouchot C, Ghnassia JC, Legros F (1998) interval between prior exposure to malaria and the donation Paludisme a Plasmodium falciparum quatre ans apres le retour de zone of blood products that transmitted P. falciparum infection is d'endemie. Presse Med 27:1898. 13 years (Besson et al., 1976). We believe that our patient was Farcas GA, Soeller R, Zhong K, Zahirieh A, Kain KC (2006) Real-time polymerase chain reaction assay for the rapid detection and character- likely infected while still in Angola, and that the infection ization of chloroquine-resistant Plasmodium falciparum malaria in remained latent for at least 8 years, possibly because of partial returned travelers. Clin Infect Dis 42:622–627. immunity (Bouchaud et al., 2005). Giobbia M, Tonon E, Zanatta A, Cesaris L, Vaglia A, Bisoffi Z (2005) Late As the patient exhibited features of severe malaria with a recrudescence of Plasmodium falciparum malaria in a pregnant woman: – parasitemia of greater than 5% and the presence of acute a case report. Int J Infect Dis 9:234 235. Griffith KS, Lewis LS, Mali S, Parise ME (2007) Treatment of malaria in the renal failure, treatment needed to be initiated immediately. United States. A systematic review. JAMA 297:2264–2277. Delays in starting effective therapy for P. falciparum malaria Jelinek T, Nothdurft HD, Loscher T (1994) Malaria in nonimmune travelers: have been associated with mortality rates exceeding 20% a synopsis of history, symptoms and treatment in 160 patients. J Travel (Murphy and Oldfield, 1996). The treatment of malaria Med 1:199–202. depends on the infecting plasmodia species and the Kain KC, MacPherson DW, Kelton T, Keystone JS, Mendelson J, MacLean JD (2001) Malaria deaths in visitors to Canada and in Canadian geographic area of acquisition, which affects the likelihood travelers: a case series. Can Med Assoc J 164:654–659. of drug resistance and the severity of disease. Because we Kyrönseppä H, Tiula E, Repo H, Lähdevirta J (1989) Diagnosis of believed this patient's infection had been acquired in Angola, falciparum malaria delayed by long incubation period and misleading therapy for presumed chloroquine-resistant malaria was presenting symptoms: life-saving role of manual leucocyte differential – started in accordance with treatment guidelines (Griffith count. Scand J Infect Dis 21:117 118. Mungai M, Tegtmeier G, Chamberland M, Parise M (2001) Transfusion- et al., 2007). transmitted malaria in the United States from 1963 through 1999. N Engl In summary, the diagnosis of malaria was not initially J Med 344:1973–1978. suspected in this patient because of the long interval (more Murphy GS, Oldfield III EC (1996) Falciparum malaria. Infect Dis Clin than 8 years) between exposure in a malaria-endemic area North Am 10:747–775. and her clinical presentation with a febrile illness. We Newman RD, Parise ME, Barber AM, Steketee RW (2004) Malaria-related deaths among U.S. travelers, 1963–2001. Ann Intern Med 141: speculate that this prolonged time span may have been 547–555. related to partial immunity in someone who would have been Schwartz E, Parise M, Kozarsky P, Cetron M (2003) Delayed onset of repeatedly reinfected while growing up in Angola. Although malaria—implications for chemoprophylaxis in travelers. N Engl J Med such a prolonged interval between exposure and the onset of 349:1510–1516. clinical disease is atypical, this case serves as a reminder that Snow RW, Guerra CA, Noor AM, Myint HY, Hay SI (2005) The global distribution of clinical episodes of Plasmodium falciparum malaria. the possibility of malaria should be considered in patients Nature 434:214–217. from endemic malarial regions, no matter how long they Suh KN, Kain KC, Keystone JS (2004) Malaria. Can Med Assoc J 170: have been away. 1693–1702. Svenson JE, MacLean JD, Gyorkos TW, Keystone J (1995) Imported Acknowledgments malaria. Clinical presentation and examination of symptomatic travelers. Arch Intern Med 155:861–868. Thwing J, Skarbinski J, Newman RD, Barber AM, Mali S, Roberts JM, The authors thank Drs Alden Chesney and Marciano Slutsker L, Arguin PM (2007) Malaria surveillance—United States, Reis for providing the images of the blood film and Dr 2005. MMWR Surveill Summ 56:23–40.