| Abstract|| |
A 26-year-old male got admitted with fever of 103°F with chills and rigor for 6 days. He was diagnosed with Plasmodium falciparum infection by peripheral blood smear examination, later confirmed by polymerase chain reaction analysis. Blood smear showed 2% parasitemia. As the patient was hypotensive, intravenous artesunate was started. Two days later, he reported passing "Coca-Cola"-colored urine. Examination revealed tachycardia, anemia, and mild icterus. Serum free hemoglobin and lactate dehydrogenase was elevated whereas haptoglobin was very low. Urine showed the presence of hemoglobin without red blood cells. Glucose-6-phosphate dehydrogenase assay was normal. Chloroquine, primaquine, and quinine levels in blood were undetectable. There was no evidence of any coinfection. Artesunate was stopped suspecting a causal relationship. Intravenous quinine was started. The urine showed progressive clearance over 3 days, and the patient recovered. The strong temporal association of initiating artesunate and occurrence of hemoglobinuria suggested the possible etiological implication which is not documented before.
Keywords: Artesunate, hemolysis, malaria
|How to cite this article:|
Karak A, Samanta B, Maheshwari R, Talukdar A. Artesunate-induced hemoglobinuria in falciparum malaria. Ann Trop Med Public Health 2016;9:340-3
|How to cite this URL:|
Karak A, Samanta B, Maheshwari R, Talukdar A. Artesunate-induced hemoglobinuria in falciparum malaria. Ann Trop Med Public Health [serial online] 2016 [cited 2021 Mar 9];9:340-3. Available from: https://www.atmph.org/text.asp?2016/9/5/340/190189
| Introduction|| |
Hemoglobinuria is a well-known complication seen in malaria, primarily in falciparum infection. Blackwater fever occurs due to massive intravascular hemolysis. Free hemoglobin gets filtered by the kidney which imparts the dark "Coca-Cola" color of the urine. Etiology of hemolysis is not completely understood. Relationship with parasitemia is not established with hemoglobinuria. Common causes of intravascular hemolysis in malaria are oxidant drugs and glucose-6-phosphate dehydrogenase (G6PD) deficiency. Quinine has long been associated with intravascular hemolysis and hemoglobinuria especially in patients receiving intermittent inadequate doses. Coinfections and other mechanisms of hemolysis like immune hemolysis need to be kept in mind. The incidence of hemoglobinuria in falciparum malaria has reduced mainly due to the use of artemisinin-based combination therapy, with artesunate being one of the members. Although cases of hemolysis have been documented before with artesunate without direct correlation, this case shows a strong etiological association between artesunate and hemoglobinuria and represents an unique situation wherein artesunate caused hemoglobinuria in a patient without any risk factor for hemoglobinuria like G6PD deficiency or history of malaria infection and exposure to antimalarials or exposure to oxidant drugs.
| Case Report|| |
A 26-year-old male patient presented with a 6-day history of high-grade fever with chills and rigors. Physical examination revealed hypotension and hepatosplenomegaly. There was no anemia and the urine color was normal. The patient was diagnosed with Plasmodium falciparum malaria based on the presence of trophozoites in the peripheral blood. Polymerase chain reaction analysis confirmed the falciparum monoinfection [Figure 1]. The patient did not give history of any medication intake from outside. The presence of hypotension prompted us to initiate treatment with intravenous artesunate at the WHO-recommended dose. Two days after initiation of artesunate, the patient reported passage of "Coca-Cola"- colored urine [Figure 2]. Subsequent examination revealed newly developing anemia, mild icterus, and persistent hepatosplenomegaly.
|Figure 1: Polymerase chain reaction analysis showing Plasmodium falciparum monoinfection|
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Initial investigations on admission including complete blood count, liver function tests, and renal function tests did not reveal any abnormality. Hemoglobin was 12.6 g/dl with a normal reticulocyte count. Peripheral blood smear showed trophozoites of P. falciparum with 2% parasitemia. After 2 days of initiation of artesunate when the patient started noticing dark "Coca-Cola" colored urine, hemoglobin came down to 6.8 g/dl. Corrected reticulocyte count was 3.8%, bilirubin of 4.3 mg/dl with unconjugated bilirubin of 3.4 mg/dl, urea was 92 mg/dl, and creatinine 1.9 mg/dl. On centrifugation of the blood, the serum was dark colored favoring intravascular hemolysis [Figure 3]. Serum free hemoglobin and lactate dehydrogenase (LDH) was elevated, and haptoglobin was very low. Urine dipstick was positive for blood but microscopic examination failed to demonstrate any red blood cells (RBCs). Urine showed the presence of hemoglobin by spectrophotometric method. G6PD level was normal. Blood levels of chloroquine, primaquine and quinine were ordered to rule out previous exposure to these antimalarials. The levels were undetectable. Serologies for coinfection such as leptospira, dengue, and HIV were negative. Immune hemolysis was excluded by performing direct antiglobulin test.
In the differential diagnosis, we kept those etiologies which can potentially cause intravascular hemolysis and subsequent dark "Coca-Cola"- colored urine in a patient of falciparum malaria, such as G6PD deficiency, oxidant drug use, coinfections, and immune hemolysis. A possibility of artesunate as the cause of hemolysis was also kept due to the strong temporal association. Subsequent investigations ruled out the initial differential diagnoses.
Artesunate was stopped suspecting it to be the etiological agent of hemolysis and hemoglobinuria. As the patient was not previously exposed to quinine as evidenced by the undetectable levels in blood, the patient was started on intravenous quinine at recommended doses. To tide over the hemolytic crisis and symptomatic anemia, the patient was given packed RBC transfusions. Gradually he started to recover, and he was shifted on oral quinine along with doxycycline to complete 7 days of treatment.
Peripheral smear at the end of the treatment showed clearance of parasites from blood. Hemoglobin increased to 9.8 g/dl; reticulocyte count normalized, LDH was normal, centrifuged sample of serum returned to normal color [Figure 4]. Jaundice subsided, and renal parameters also improved. Urine color returned to normal [Figure 5]. He was discharged on day 9. On follow-up, all the blood parameters were normal. He is presently doing well.
|Figure 4: Normal-colored blood serum on centrifugation after stopping artesunate therapy|
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|Figure 5: Normal-colored urine after withholding artesunate therapy (day 7)|
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| Discussion|| |
Malaria is a highly endemic infectious disease in the Indian subcontinent. ,, Clinical malaria is caused by four types of plasmodia. P. falciparum has long been associated with severe malaria. Severe malaria has been defined by the WHO, with hemoglobinuria being one of its defining features.  Blackwater fever occurs due to massive intravascular hemolysis, leading to liberation of free hemoglobin in the serum which exceeds the binding capacity of haptoglobin. Free hemoglobin gets filtered by the kidney which imparts the dark color of the urine. Most commonly implicated malaria parasite for hemoglobinuria is P. falciparum. , Exact etiology is not known but several factors have been historically associated with hemoglobinuria such as G6PD deficiency, oxidant drug use, coinfections, and associated immune hemolysis. Quinine has been implicated as one of the most common antimalarials as the cause of hemolysis especially in patients previously exposed to quinine in inadequate doses intermittently. An immune interaction between quinine sensitized infected RBCs and quinine leading to the destruction of the RBCs has been implicated.  Artemisinin-based combination therapy has become the mainstay of anti-malarial therapy in the recent years due to the highly prevalent chloroquine resistance.  Dihydroartemisinin-piperaquine has a highly active peroxide bridge which has been implicated as a cause of blackwater fever in a patient with multiple past episodes of malaria infection. The patient had exposure to multiple antimalarials including artesunate for the treatment of the past episodes of malaria.  Artesunate has been implicated as a cause of hemolysis in previous studies.  However, such a strong temporal association of artesunate with hemoglobinuria in a patient without any risk factor for hemolysis such as G6PD deficiency, oxidant drug use, previous exposure to different antimalarials, and co-infections has not been documented before. The strong temporal association of artesunate with hemoglobinuria suggests that physicians and internists prescribing artesunate for complicated malaria should be aware of this remote possibility.
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| References|| |
Singh G, Urhekar AD, Maheshwari U, Sharma S, Raksha. Prevalence of malaria in a tertiary care hospital in Navi Mumbai, India. J Bacteriol Parasitol 2015;6:221.
Patil V. Complicated falciparum malaria in western Maharashtra. Trop Parasitol 2012;2:49-54.
Kochar DK, Kochar SK, Agrawal RP, Sabir M, Nayak KC, Agrawal TD, et al.
The changing spectrum of severe falciparum malaria: A clinical study from Bikaner (northwest India). J Vector Borne Dis 2006;43:104-8.
Severe and complicated malaria. World Health Organization, Division of Control of Tropical Diseases. Trans R Soc Trop Med Hyg 1990;84 Suppl 2:1-65.
Van den Ende J, Coppens G, Verstraeten T, Van Haegenborgh T, Depraetere K, Van Gompel A, et al.
Recurrence of blackwater fever: Triggering of relapses by different antimalarials. Trop Med Int Health 1998;3:632-9.
Rogier C, Imbert P, Tall A, Sokhna C, Spiegel A, Trape JF. Epidemiological and clinical aspects of blackwater fever among African children suffering frequent malaria attacks. Trans R Soc Trop Med Hyg 2003;97:193-7.
Tran TH, Day NP, Ly VC, Nguyen TH, Pham PL, Nguyen HP, et al.
Blackwater fever in southern Vietnam: A prospective descriptive study of 50 cases. Clin Infect Dis 1996;23:1274-81.
WHO. Guidelines for the Treatment of Malaria. 2 nd
ed. Geneva: WHO; 2010.
Lon C, Spring M, Sok S, Chann S, Bun R, Ittiverakul M, et al.
Blackwater fever in an uncomplicated Plasmodium falciparum
patient treated with dihydroartemisinin-piperaquine. Malar J 2014;13:96.
Caramello P, Balbiano R, De Blasi T, Chiriotto M, Deagostini M, Calleri G. Severe malaria, artesunate and haemolysis. J Antimicrob Chemother 2012;67:2053-4.
Department of General Medicine, Medical College, 88, College Street, Kolkata - 700 073, West Bengal
Source of Support: None, Conflict of Interest: None
[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5]