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Post-treatment haemolysis in severe imported malaria after intravenous artesunate: case report of three patients with hyperparasitaemia.

Rolling T, Schmiedel S, Wichmann D, Wittkopf D, Burchard GD, Cramer JP - Malar. J. (2012)

Bottom Line: Little evidence, however, is available on long-term safety.Reticulocyte production index remained inadequately low in the 7 - 14 days following the first dose of artesunate despite rapid parasite clearance.Further investigations are needed to assess frequency and pathophysiological background of this complication.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Internal Medicine I, Section for Tropical Medicine and Infectious Diseases, University Medical Centre Hamburg-Eppendorf (UKE), Martinistrasse 52, 20246 Hamburg, Germany. t.rolling@uke.de

ABSTRACT
Parenteral artesunate has been shown to be a superior treatment option compared to parenteral quinine in adults and children with severe malaria. Little evidence, however, is available on long-term safety. Recently, cases of late-onset haemolysis after parenteral treatment with artesunate have been reported in European travellers with imported Plasmodium falciparum malaria. Therefore, an extended follow-up of adult patients treated for severe imported malaria was started in August 2011 at the University Medical Center Hamburg-Eppendorf. Until January 2012, three patients with hyperparasitaemia (range: 14-21%) were included for analysis. In all three patients, delayed haemolysis was detected in the second week after the first dose of intravenous artesunate. Reticulocyte production index remained inadequately low in the 7 - 14 days following the first dose of artesunate despite rapid parasite clearance. Post-treatment haemolysis after parenteral artesunate may be of clinical relevance in particular in imported severe malaria characterized by high parasite levels. Extended follow-up of at least 30 days including controls of haematological parameters after artesunate treatment seems to be indicated. Further investigations are needed to assess frequency and pathophysiological background of this complication.

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Related in: MedlinePlus

Time course of haemoglobin (Hb) levels / reticulocyte production index (RPI) as well as lactate dehydrogenase (LDH) levels in patient 1 (A and B), patient 2 (C and D, arrows indicating time points of transfusions) and patient 3 (E and F).
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Figure 1: Time course of haemoglobin (Hb) levels / reticulocyte production index (RPI) as well as lactate dehydrogenase (LDH) levels in patient 1 (A and B), patient 2 (C and D, arrows indicating time points of transfusions) and patient 3 (E and F).

Mentions: The first patient was a 19-year old German female without migrational background presenting without any co-morbidities or prior medication who stayed in Uganda for three weeks. She did not take any malaria prophylaxis. Four days after returning to Germany she developed fever and headaches. At the emergency department of a community hospital, she was diagnosed with uncomplicated malaria and showed 2% parasitaemia. She was transferred to a tertiary care centre specializing in tropical medicine for treatment of uncomplicated malaria. At the first evaluation in the emergency department (day 0), she did not fulfill any of the WHO criteria for severe malaria [7], and in line with the guidelines by the German Society of Tropical Medicine and International Health (DTG) treatment with mefloquine was initiated (starting with 750 mg) [10]. Over the next three to four hours, the patient’s clinical condition deteriorated. She became somnolent and her blood pressure dropped to 80/50 mmHg with a pulse rate of 108 bpm. At this time point, Giemsa-stained blood microscopy revealed a parasitaemia of 14%. The patient was now classified as complicated life-threatening malaria and was transferred to the intensive care unit. Intravenous artesunate (Guilin pharmaceutical factory, China) was given in four doses of 120 mg on day 0 and after 12, 24 and 48 hours equivalent to a total dose of 8mg/kg body weight. Because of thrombocytopenia of 15,000/μl (normal range: 150,000-400,000), she received one unit of packed thrombocytes. Indirect Coombs’ test was negative at this time. On day 1, her clinical condition improved strikingly and she was transferred to a regular ward on day 2. Anti-malarial treatment was continued orally with mefloquine (500 mg on day 2 followed by 250 mg eight hours later, equivalent to a total dose of 1500 mg including the initial dose of 750 mg on day 0). Parasitaemia declined rapidly from initially 14% to 10% after 12h and finally to less than 1% on day 3. On day 5, parasites were cleared. Two days later, the patient developed fever again and showed radiological signs of lung infiltration. Piperacillin-Sulbactam was started for hospital acquired pneumonia for 7 days. Hb dropped from 12 mg/dl (normal range: 12.3 - 15.3) at presentation to 10.2 mg/dl on day 2, stabilized between days 2 and 4 and decreased again in the following days to 8.6 g/dl on day 14. The decrease in Hb was accompanied by a second rise in lactate dehydrogenase (LDH) to 1010 U/l indicative of haemolytic anaemia (Figure 1A and 1B). Blood microscopy remained negative at this time point. Because of a slow but continuous clinical improvement she was discharged from hospital but follow-up was continued at the tropical medicine outpatient clinic. On day 16, the lowest Hb was measured but was accompanied with a significant rise in reticulocytes. Hb increased further during the following two weeks up to 11.2 g/dl (normal range: 12.3 - 15.3) on day 30 when the patient was without further clinical complaints.


Post-treatment haemolysis in severe imported malaria after intravenous artesunate: case report of three patients with hyperparasitaemia.

Rolling T, Schmiedel S, Wichmann D, Wittkopf D, Burchard GD, Cramer JP - Malar. J. (2012)

Time course of haemoglobin (Hb) levels / reticulocyte production index (RPI) as well as lactate dehydrogenase (LDH) levels in patient 1 (A and B), patient 2 (C and D, arrows indicating time points of transfusions) and patient 3 (E and F).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3472247&req=5

Figure 1: Time course of haemoglobin (Hb) levels / reticulocyte production index (RPI) as well as lactate dehydrogenase (LDH) levels in patient 1 (A and B), patient 2 (C and D, arrows indicating time points of transfusions) and patient 3 (E and F).
Mentions: The first patient was a 19-year old German female without migrational background presenting without any co-morbidities or prior medication who stayed in Uganda for three weeks. She did not take any malaria prophylaxis. Four days after returning to Germany she developed fever and headaches. At the emergency department of a community hospital, she was diagnosed with uncomplicated malaria and showed 2% parasitaemia. She was transferred to a tertiary care centre specializing in tropical medicine for treatment of uncomplicated malaria. At the first evaluation in the emergency department (day 0), she did not fulfill any of the WHO criteria for severe malaria [7], and in line with the guidelines by the German Society of Tropical Medicine and International Health (DTG) treatment with mefloquine was initiated (starting with 750 mg) [10]. Over the next three to four hours, the patient’s clinical condition deteriorated. She became somnolent and her blood pressure dropped to 80/50 mmHg with a pulse rate of 108 bpm. At this time point, Giemsa-stained blood microscopy revealed a parasitaemia of 14%. The patient was now classified as complicated life-threatening malaria and was transferred to the intensive care unit. Intravenous artesunate (Guilin pharmaceutical factory, China) was given in four doses of 120 mg on day 0 and after 12, 24 and 48 hours equivalent to a total dose of 8mg/kg body weight. Because of thrombocytopenia of 15,000/μl (normal range: 150,000-400,000), she received one unit of packed thrombocytes. Indirect Coombs’ test was negative at this time. On day 1, her clinical condition improved strikingly and she was transferred to a regular ward on day 2. Anti-malarial treatment was continued orally with mefloquine (500 mg on day 2 followed by 250 mg eight hours later, equivalent to a total dose of 1500 mg including the initial dose of 750 mg on day 0). Parasitaemia declined rapidly from initially 14% to 10% after 12h and finally to less than 1% on day 3. On day 5, parasites were cleared. Two days later, the patient developed fever again and showed radiological signs of lung infiltration. Piperacillin-Sulbactam was started for hospital acquired pneumonia for 7 days. Hb dropped from 12 mg/dl (normal range: 12.3 - 15.3) at presentation to 10.2 mg/dl on day 2, stabilized between days 2 and 4 and decreased again in the following days to 8.6 g/dl on day 14. The decrease in Hb was accompanied by a second rise in lactate dehydrogenase (LDH) to 1010 U/l indicative of haemolytic anaemia (Figure 1A and 1B). Blood microscopy remained negative at this time point. Because of a slow but continuous clinical improvement she was discharged from hospital but follow-up was continued at the tropical medicine outpatient clinic. On day 16, the lowest Hb was measured but was accompanied with a significant rise in reticulocytes. Hb increased further during the following two weeks up to 11.2 g/dl (normal range: 12.3 - 15.3) on day 30 when the patient was without further clinical complaints.

Bottom Line: Little evidence, however, is available on long-term safety.Reticulocyte production index remained inadequately low in the 7 - 14 days following the first dose of artesunate despite rapid parasite clearance.Further investigations are needed to assess frequency and pathophysiological background of this complication.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Internal Medicine I, Section for Tropical Medicine and Infectious Diseases, University Medical Centre Hamburg-Eppendorf (UKE), Martinistrasse 52, 20246 Hamburg, Germany. t.rolling@uke.de

ABSTRACT
Parenteral artesunate has been shown to be a superior treatment option compared to parenteral quinine in adults and children with severe malaria. Little evidence, however, is available on long-term safety. Recently, cases of late-onset haemolysis after parenteral treatment with artesunate have been reported in European travellers with imported Plasmodium falciparum malaria. Therefore, an extended follow-up of adult patients treated for severe imported malaria was started in August 2011 at the University Medical Center Hamburg-Eppendorf. Until January 2012, three patients with hyperparasitaemia (range: 14-21%) were included for analysis. In all three patients, delayed haemolysis was detected in the second week after the first dose of intravenous artesunate. Reticulocyte production index remained inadequately low in the 7 - 14 days following the first dose of artesunate despite rapid parasite clearance. Post-treatment haemolysis after parenteral artesunate may be of clinical relevance in particular in imported severe malaria characterized by high parasite levels. Extended follow-up of at least 30 days including controls of haematological parameters after artesunate treatment seems to be indicated. Further investigations are needed to assess frequency and pathophysiological background of this complication.

Show MeSH
Related in: MedlinePlus