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Abstract

  1. Top of page
  2. Abstract
  3. Clinical Case Report
  4. Molecular Characterization
  5. Discussion
  6. Acknowledgments
  7. Declaration of Interests
  8. References

A previously healthy febrile patient with travel history to Nicaragua showed rapid clinical deterioration with hemodynamic shock and anuria. Diagnosis of severe malaria was established based on intra-erythrocytic parasites and antimalarial treatment was initiated. However, upon reevaluation Babesia microti infection was suspected and molecular characterization by polymerase chain reaction and sequence analysis was performed.


Clinical Case Report

  1. Top of page
  2. Abstract
  3. Clinical Case Report
  4. Molecular Characterization
  5. Discussion
  6. Acknowledgments
  7. Declaration of Interests
  8. References

A 63-year-old previously healthy male Austrian resident of US-American origin presented with ongoing fever for 2 weeks at the emergency department of the Vienna General Hospital in August 2009. The patient reported frequent short course overseas working assignments due to his employment by an international organization. Eight weeks prior to presentation he had been on a 7-day mission to the capital of Nicaragua. Following current travel recommendations, he had not taken malaria chemoprophylaxis and did not recall mosquito bites, freshwater exposure, or clinical symptoms during his travel. Six weeks after the journey to Nicaragua, pandemic H1N1 influenza infection was ruled out by polymerase chain reaction (PCR) analysis and an unspecific viral infection was assumed as the most likely cause of the febrile disease. As a result of further worsening of symptoms the patient decided to attend the emergency department at the Vienna General Hospital.

Mild tachypnoea and pallor were observed at clinical examination and pronounced thrombocytopenia and normocytic, normochrome anemia were found in the blood count (platelet count: 28 g/L, Hb 8.4 g/dL). Lactate dehydrogenase was highly elevated (1,392 U/L, normal range: <248) indicating active hemolysis and liver enzymes and C-reactive protein (CRP) was moderately increased [aspartate aminotransferase (AST) 152 U/L, normal range: <35 U/L, alenine aminotransferase (ALT) 48 U/L, normal range <45 U/L, CRP 14 mg/dL, normal range: <0.5 mg/dL].

On the basis of the patient's history of travel and clinical and laboratory signs of hemolysis, blood smears were examined and a rapid test for malaria was performed (BinaxNOW, Binax, Inc., Scarborough, ME, USA). Despite a repeatedly negative test result a high percentage of parasitized red blood cells was observed in microscopic examination of blood smears. The diagnosis of Plasmodium falciparum malaria was established based on the microscopic findings of abundant double chromatin and multiply infected red blood cells. Following World Health Organization definitions the disease course was defined as severe malaria due to the presence of renal insufficiency and anemia. Antiparasitic treatment with intravenous quinine in combination with clindamycin was initiated.

Within the first hours of treatment the clinical condition of the patient deteriorated rapidly and transferral to the intensive care unit became necessary due to hemodynamic shock and anuria. Catecholamine support was initiated under continuous intra-arterial blood pressure monitoring and blood transfusions, thrombocyte substitution, and fresh frozen plasma were administered. Over the following 4 days the condition of the patient stabilized despite radiologic evidence for incipient pulmonary edema; blood smears showed a complete clearance of intra-erythrocytic parasites, and the patient was finally discharged with complete clinical recovery.

Upon reevaluation of the patient's case several peculiarities conflicting with the diagnosis of falciparum malaria became obvious: an extremely low risk of malarial transmission in Managua, an incubation period of more than 6 weeks in the absence of chemoprophylaxis, the known reliability of rapid tests for malaria in the presence of high parasitemia, and most importantly, an atypical morphology of parasitized red blood cells with a high percentage of multiply infected erythrocytes with up to six intracellular ring forms (Figure 1).1,2 On the basis of findings of the intracellular parasites, which were smaller than usual for Plasmodia spp. and the absence of schizonts, gametocytes, and malaria pigment in microscopic reexamination, the diagnosis of Babesia microti infection was established and blood specimens were further investigated for serologic and molecular biological markers.

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Figure 1. Blood smear of patient at initial presentation (1,000× magnification).

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Molecular Characterization

  1. Top of page
  2. Abstract
  3. Clinical Case Report
  4. Molecular Characterization
  5. Discussion
  6. Acknowledgments
  7. Declaration of Interests
  8. References

Antibody-specific serology was negative for Plasmodium spp. and for whole cell antigen of Babesia divergens in specimens collected at initial presentation and at follow-up visits. DNA amplification (MutaGel® Babesia-PCR; ImmunDiagnostik, Bensheim, Germany) showed a Babesia-specific band at ∼210 bp. Positive samples were retested employing a second PCR protocol amplifying the highly variable ribosomal internal transcribed spacer region 1 of all known Babesia species. Amplicons with 535 bp were detected and showed a 100% sequence identity in the amplified region to the B. microti strains ATCC30222 (AB190459; initially isolated in the Congo from a forest mouse and designated Babesia rodhaini) and GI (AB112337).3,4 Sequence data were deposited at GenBank (accession number: GU230755)

Upon information of the change in the definitive diagnosis from falciparum malaria to babesiosis and re-exploration of the travel history, the patient recalled having spent 4 weeks with outdoor recreational activities in Massachusetts, USA, after his travel to Nicaragua. This region is known as the epicenter of B. microti transmission in the United States and infection of the patient most probably occurred at this occasion. A standard course of oral azithromycin-atovaquone treatment was prescribed for 7 days in order to prevent recrudescence of babesiosis as the initial treatment with quinine-clindamycin which was shorter than recommended for this indication.

Discussion

  1. Top of page
  2. Abstract
  3. Clinical Case Report
  4. Molecular Characterization
  5. Discussion
  6. Acknowledgments
  7. Declaration of Interests
  8. References

This case report—the first human case of B. microti infection reported from Austria—strikingly illustrates the difficulties of correctly diagnosing Babesia infection.5 Misdiagnosis was due to an at the first sight compelling travel history to a tropical region in combination with clinical and laboratory signs of hemolytic anemia and intra-erythrocytic ring-shaped parasites suggestive for malaria. Given the dramatic clinical disease course, necessitating—despite the absence of any underlying disease or immunosuppression—admission to the intensive care unit for treatment of hemodynamic shock, it is understandable that the initial diagnosis of severe P. falciparum malaria was established. Fortunately enough—and in contrast to recently updated recommendations for the treatment of severe malaria at our institution favoring the use of intravenous artesunate—quinine-clindamycin combination therapy was initiated in this case.6 The decision for this regimen—a standard treatment for severe falciparum malaria and at the same time the treatment of choice for Babesia infection—may well have saved the life of our patient, as available evidence indicates that artemisinins are not as active against Babesia infection as quinine-clindamycin therapy.7,8

Correct microscopic recognition of babesiosis is a challenge in non-endemic regions foremost due to the rarity of the disease. Interestingly, serology is also an imperfect diagnostic tool. Delayed antibody response and a low cross reactivity between different Babesia spp. may lead to negative serologic results despite active Babesia spp. infection as observed in our case. PCR detection of Babesia-specific DNA in patients' blood may therefore serve as diagnostic gold standard providing at the same time the direct proof of infection and enabling species determination by further sequence analysis.

B. divergens is the most widely distributed species in Europe and leads to clinical disease almost exclusively in splenectomized patients. Consistently, to date only one clinical case of Babesia spp. infection has been reported from Austria.5 However, New World babesiosis—most commonly caused by B. microti—often occurs in otherwise healthy individuals and may lead to potentially life-threatening complications.

One of the underlying reasons for the incorrect diagnosis of falciparum malaria was the selective reporting of potentially hazardous geographic exposure by the patient by exclusively reporting the travel to Latin America and not mentioning the subsequent and four times longer residence in Massachusetts, USA.9 This fact may remind physicians once again of actively pursuing the patient's history with utmost diligence—even if a diagnosis may seem likely at first sight.

Acknowledgments

  1. Top of page
  2. Abstract
  3. Clinical Case Report
  4. Molecular Characterization
  5. Discussion
  6. Acknowledgments
  7. Declaration of Interests
  8. References

The authors wish to thank Iveta Häfeli, Medical Parasitology, Institute of Specific Prophylaxis and Tropical Medicine, Medical University of Vienna, for excellent technical assistance. The authors acknowledge Prof. Schwarzinger's help in photographic documentation of blood smears.

References

  1. Top of page
  2. Abstract
  3. Clinical Case Report
  4. Molecular Characterization
  5. Discussion
  6. Acknowledgments
  7. Declaration of Interests
  8. References
  • 1
    Health information for travelers to Nicaragua. Atlanta, Centers for Disease Control and Prevention. Available at: http://wwwnc.cdc.gov/travel/destinations/nicaragua.aspx. (Accessed 2010 Jan 14).
  • 2
    Wongsrichanalai C, Barcus MJ, Muth S, et al. A review of malaria diagnostic tools: microscopy and rapid diagnostic test (RDT). Am J Trop Med Hyg 2007; 77(Suppl 6): 119127.
  • 3
    Blaschitz M, Nardoslaysky-Gföller M, Kanzler M, et al. Babesia species occurring in Austrian Ixodes ricinus ticks. Appl Environ Microbiol 2008; 74:48414846.
  • 4
    Nicholas KB, Nicholas HB., Jr, Deerfield II DW. GeneDoc: analysis and visualization of genetic variation. Embnet News 1997; 4:14.
  • 5
    Herwaldt BL, Caccio S, Gherlinzoni F, et al. Molecular characterization of a non-Babesia divergens organism causing zoonotic babesiosis in Europe. Emerg Infect Dis 2003; 9:942948.
  • 6
    World Health Organization. Malaria Treatment Guidelines. 2nd Ed. Geneva: World Health Organization, 2010.
  • 7
    Krause PJ, Lepore T, Sikand VK, et al. Atovaquone and azithromycin for the treatment of babesiosis. N Engl J Med 2000; 16343(20):14541458.
  • 8
    Marley SE, Eberhard ML, Steurer FJ, et al. Evaluation of selected antiprotozoal drugs in the Babesia microti-hamster model. Antimicrob Agents Chemother 1997; 41:9194.
  • 9
    Ruebush TK II, Juranek DD, Spielman A, et al. Epidemiology of human babesiosis on Nantucket Island. Am J Trop Med Hyg 1981; 30:937941.