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Published reports of delayed hemolytic anemia after treatment with artesunate for severe malaria--worldwide, 2010-2012.

Artesunate has been recommended by the World Health Organization (WHO) as the first-line treatment for severe malaria since 2010. It is not licensed in the United States but is available from CDC under an investigational new drug (IND) protocol. During 2010-2012, a total of 19 cases of delayed hemolytic anemia after treatment of severe malaria with artesunate were published in the peer-reviewed medical literature, but no such cases have been reported in the United States. CDC Malaria Branch staff reviewed each published report of delayed hemolysis after artesunate use. Based on the pathogenesis of malaria, the hemolysis likely is a result of severe malaria and not the treatment itself. However, artesunate used in the United States is produced by the U.S. Army Medical Materiel Development Activity, and artesunate used outside of the United States is not. An unrecognized difference might exist between the U.S. artesunate and the artesunate used elsewhere. Alternatively, cases of artesunate-associated hemolysis might have occurred in the United States but were not reported. To better assess these possibilities, CDC has amended the artesunate IND protocol and now recommends that persons treated for severe malaria with artesunate be followed for 4 weeks after treatment and evaluated for hemolytic anemia.

A literature search was performed using the terms "artesunate" and either "hemolytic anemia" or "delayed anemia." All reports were reviewed, and additional case reports referenced in these reports also were obtained and reviewed. Case reports were considered relevant if the patient had received artesunate therapy for the treatment of severe malaria and then experienced worsening hemolytic anemia after initial clinical improvement and resolution of parasitemia. In total, six articles (describing 19 cases) fit these requirements. One incident of hemolytic anemia was reported in two different articles, one published in 2002 and the other in 2010. Only the 2010 report is included in this summary.

All cases except one were in adults (median age: 50 years; age range: 5-71 years) (Table). Eighteen patients had traveled to sub-Saharan Africa, and one to India. All 12 patients with documentation of parasitemia were hyperparasitemic (>5% of red blood cells [RBCs] infected), with a mean highest parasitemia reported of 22% (range: 7%-45%). Seven of the patients also received artemether-lumefantrine, an oral drug similar to artesunate, for either initial treatment or to complete the treatment regimen. Ten patients received nonartemisinin antimalarials before or after artesunate therapy. All 14 patients for whom multiple hemoglobin measurements were available had a reduction in hemoglobin within the first week of treatment, from a mean of 12.3 g/dL on admission to 8.8 g/dL on follow-up. Seven patients received transfusions with either packed RBCs or platelets during their initial presentation, including three who received exchange transfusions. All patients responded well to artesunate therapy, and complete parasite clearance was documented on average by day 5.

For all patients, hemolysis and worsening anemia were described after parasite clearance, 8-32 days after completion of artesunate therapy. The mean hemoglobin nadir was 6.2 g/dL (range: 4.4-8.6 g/dL) (n = 18). Other reported laboratory measurements supported the diagnosis of hemolysis including elevated lactate dehydrogenase, low or absent haptoglobin, elevated bilirubin, and/or elevated reticulocyte count (n = 12). Twelve patients required transfusions, ranging from 2-24 units, after artesunate treatment. The hemolysis resolved, and hemoglobin improved in all patients within 4-8 weeks after artesunate therapy. Two patients had documented moderate anemia more than 30 days after treatment.

Two studies included information on patients with severe malaria both with and without delayed hemolysis. One reported that the six patients with hemolysis had received a higher mean cumulative dose of artesunate than the 19 patients without hemolysis (12.8 mg/kg versus 7.6 mg/kg) (1). However, the mean cumulative dose in patients with hemolysis in the other article was 7.2 mg/kg, and no correlation between dose and hemolysis was observed (2). Although not specifically discussed, the reported parasitemia in the patients with delayed hemolysis was higher in both studies (mean parasitemia of 16% versus 11%, and median parasitemia of 27% versus 5%, respectively).

Editorial Note

This review of published cases found reports of 19 cases of delayed hemolysis after artesunate therapy for severe malaria in nonendemic countries outside of the United States. Thus far, no published studies have assessed whether artesunate actually causes or increases the risk for delayed hemolysis; therefore, it remains unknown whether the hemolysis described is a direct effect of the treatment or simply a consequence of severe malaria itself.

In 2010, a total of 176 cases of severe malaria in the United States were reported to CDC, 39 (22%) of which were in patients who received artesunate through the CDC IND protocol (3). Thus far, delayed hemolytic anemia has not been reported in patients treated with artesunate in the United States. Artesunate has been recommended by WHO as first-line treatment for severe malaria since 2010. It has been shown to be superior to quinine, with increased survival and decreased adverse events (4). Recently, many nonendemic countries have begun to use artesunate in patients with travel-associated severe malaria. The United States is the only country where the artesunate used has been certified as meeting good manufacturing practice (GMP) standards. In all other countries, the only form of artesunate available has not been certified as having been produced according to GMP standards, but has been prequalified by WHO as an essential drug (1,5). WHO prequalification involves a review of safety data and a manufacturing site assessment but is not thought to be as stringent as GMP certification. Various authors have expressed concern that these delayed hemolytic events might be a direct toxicity of the non-GMP artesunate that is currently used outside of the United States (1,2). However, based on this review on malaria and hemolysis, there appear to be more compelling mechanisms that might explain these delayed hemolytic events related to the pathogenesis of severe malaria itself.

There have been multiple published reports of hemolytic anemia in malaria not associated with artesunate. These include reports of "blackwater fever" (dark red or black urine associated with acute malaria) and prolonged hemolytic anemia in severe malaria patients treated with older antimalarial medications. In 1979, one study showed that circulating RBCs in patients with acute malaria continued to have a decreased life-span for up to 4-5 weeks after parasite clearance. Patients in this study treated with chloroquine experienced a mean 9% decline in their hemoglobin, occurring 3-22 days after completion of their treatment. Researchers also detected mild suppression of RBC production and complement-containing immune complexes on RBC surfaces after infection, likely promoting increased splenic removal of RBCs (6). A study conducted in The Gambia showed that patients with severe malaria, but without severe anemia, experienced an initial drop in hemoglobin when started on treatment. In addition, in a subset of children without hemoglobinopathies or glucose-6-phosphate dehydrogenase deficiency (n = 17), 16 were direct antiglobulin test (DAT)-positive, and nine were positive for immunoglobulin G autoantibodies, with higher parasitemia being associated with increased DAT positivity (7). In 1993, researchers in Germany detected immunoglobulin M antiglycolytic antibodies in patients with severe malaria and prolonged hemolysis after parasite clearance. These antibodies were only present in patients with severe malaria from Plasmodium falciparum, persisted up to >40 days after treatment, and resolved as hemolysis resolved. The typical hemoglobin nadir in this study occurred 6-12 days postdiagnosis (8).

In 1997, a study using antibodies against ring-infected erythrocyte surface antigens (RESA) to label P. falciparum-infected cells found that RBCs with the RESA antigen, but without parasites, could be detected if labeled in vivo. This led to the hypothesis that the spleen or another organ removed or killed the parasites without destroying the RBCs (9). A follow-up study found that, in patients with severe malaria, artesunate treatment generated a much higher number of unparasitized RESA-positive RBCs than quinine. It also noted that artesunate-treated RBCs were more deformable then quinine-treated or parasitized RBCs, likely further extending their lifespan (10). This increase in RBCs surviving after parasitemia, albeit with a shorter lifespan than healthy RBCs, might explain the delayed postartesunate treatment decrease in hemoglobin observed in the cases reported.

Further comparative data would be required to determine how artesunate influences the risks for this complication, both in travelers and in the increasing proportion of patients receiving artesunate for severe malaria in highly endemic countries. There is insufficient evidence at present to attribute these few reported hemolytic events directly to artesunate treatment itself, and these events should not reduce confidence in artesunate, which has many other benefits for patients with severe malaria. In addition, all patients with reported delayed hemolysis have recovered without long-term complications. However, to further understand the relationship between delayed hemolysis and artesunate use, CDC is requesting that patients treated with artesunate in the United States be evaluated and have their hemoglobin assessed 4 weeks after treatment. Significant declines in hemoglobin should be reported to CDC's Malaria Branch and should prompt an evaluation for hemolysis and closer monitoring.

What is already known on this topic?

Recent reports of delayed hemolytic anemia after artesunate treatment for severe malaria in nonendemic countries other than the United States have generated concern that this phenomenon might be related to the treatment.

What is added by this report?

Published reports describing prolonged hemolytic anemia in severe malaria not associated with artesunate treatment suggest multiple possible causes related to the pathogenesis of severe malaria infection itself.

What are the implications for public health practice?

Additional data are needed. Clinicians treating patients for severe malaria with artesunate should monitor the patient for 4 weeks after treatment, assess for hemolysis if anemia is present, and report any episodes of delayed hemolysis to CDC.

References

(1.) Zoller T, Junghanss T, Kapaun A, et al. Intravenous artesunate for severe malaria in travelers, Europe. Emerg Infect Dis 2011;17:771-7.

(2.) Kreeftmeijer-Vegter AR, van Genderen PJ, Visser LG, et al. Treatment outcome of intravenous artesunate in patients with severe malaria in the Netherlands and Belgium. Malar J 2012;11:102.

(3.) CDC. Malaria surveillance-United States, 2010. MMWR 2012;61 (No. SS-2).

(4.) Dondorp AM, Fanello CI, Hendriksen IC, et al. Artesunate versus quinine in the treatment of severe falciparum malaria in African children (AQUAMAT): an open-label, randomised trial. Lancet 2010;376: 1647-57.

(5.) World Health Organization. Prequalification programme: a United Nations programme managed by WHO. Geneva, Switzerland: World Health Organization; 2010. Available at http://apps.who.int/prequal.

(6.) Woodruff AW, Ansdell VE, Pettitt LE. Cause of anaemia in malaria. Lancet 1979;1:1055-7.

(7.) Abdalla S, Weatherall DJ, Wickramasinghe SN, Hughes M. The anaemia of P. falciparum malaria. Br J Haematol 1980;46:171-83.

(8.) Ritter K, Kuhlencord A, Thomssen R, Bommer W. Prolonged haemolytic anaemia in malaria and autoantibodies against triosephosphate isomerase. Lancet 1993;342:1333-4.

(9.) Angus BJ, Chotivanich K, Udomsangpetch R, White NJ. In vivo removal of malaria parasites from red blood cells without their destruction in acute falciparum malaria. Blood 1997;90:2037-40.

(10.) Chotivanich K, Udomsangpetch R, Dondorp A, et al. The mechanisms of parasite clearance after antimalarial treatment of Plasmodium falciparum malaria. J Infect Dis 2000;182:629-33.

Reported by

Melissa Briggs, MD, Paul M. Arguin, MD, Div of Parasitic Diseases and Malaria, Center for Global Health, CDC. Corresponding contributor: Melissa Briggs, vka5@cdc.gov, 404-718-4805.
TABLE. Articles and cases reported in the literature involving delayed
hemolytic anemia after treatment with artesunate, by selected
characteristics--worldwide, 2010-2012

Case       Location               Case description

Rolling T, Schmiedel S, Wichmann D, et al. Post-treatment haemolysis
in severe imported malaria after intravenous artesunate: case report
of three patients with hyperparasitaemia. Malar J 2012;11:169.

Case 1     Germany                German female aged 19 yrs with
                                  hypotension and hyperparasitemia

Case 2     Germany                German male aged 54 yrs with
                                  somnolence, hypotension,
                                  hyperbilirubinemia,
                                  hyperparasitemia, and acute renal
                                  failure

Case 3     Germany                German male aged 55 yrs with fever,
                                  acute renal failure,
                                  hyperbilirubinemia, and
                                  hyperparasitemia

Kreeftmeijer-Vegter AR, van Genderen PJ, Visser LG. Treatment outcome
of intravenous artesunate in patients with severe malaria in the
Netherlands and Belgium. Malar J 2012;11:102. ([dagger])

Case 4     Netherlands/Belgium    Male aged 53 yrs with jaundice,
                                  impaired consciousness, and
                                  hyperparasitemia

Case 5     Netherlands/Belgium    Female aged 50 yrs with impaired
                                  consciousness, jaundice, acidosis,
                                  renal impairment, and
                                  hyperparasitemia

Case 6     Netherlands/Belgium    Female aged 50 yrs with jaundice and
                                  hyperparasitemia

Case 7     Netherlands/Belgium    Female aged 44 yrs with
                                  hyperparasitemia

Case 8     Netherlands/Belgium    Male aged 5 yrs with shock, impaired
                                  consciousness, and hyperparasitemia

Case 9     Netherlands/Belgium    Female aged 50 yrs with jaundice,
                                  hemoglobinuria, and hyperparasitemia

Case 10    Netherlands/Belgium    Female aged 71 yrs with impaired
                                  consciousness, acidosis,
                                  hypoglycemia, respiratory distress,
                                  renal impairment, and
                                  hyperparasitemia

Zoller T, Junghanss T, Kapaun A, et al. Intravenous artesunate for
severe malaria in travelers, Europe. Emerg Infect Dis 2011;17:771-7.

Case 11    Europe                 Female aged 30 yrs with
                                  hyperparasitemia

Case 12    Europe                 Female aged 54 yrs with HIV,
                                  admitted with hyperparasitemia and
                                  cerebral malaria

Case 13    Heidelberg, Germany    Male aged 32 yrs with
                                  hyperparasitemia

Case 14    Helsingborg, Sweden    Male aged 46 yrs with diabetes
                                  mellitus admitted with malaria,
                                  renal failure, and jaundice

Case 15    Bergen, Norway         Male aged 49 yrs with renal failure,
                                  jaundice, disseminated intravascular
                                  coagulation, and hyperparasitemia

Case 16    Europe                 Female aged 34 yrs with renal
                                  failure, shock, and hyperparasitemia

Caramello P, Balbiano R, De Blasi T, et al. Severe malaria, artesunate
and haemolysis. J Antimicrob Chemother 2012;67:2053-4.

Case 17    Italy                  Italian woman aged 22 yrs with
                                  fever, splenomegaly, jaundice, and
                                  hyperparasitemia

Kano S. Artemisinin-based combination therapies and their introduction
in Japan. J Infect Chemother 2010;16:375-82.

Case 18    Japan                  Japanese woman aged 68 yrs

Case 19    Japan                  Japanese man aged 54 yrs

               Peak
           parasitemia       Initial      Artesunate      Follow-up
Case         reported       treatment     total dose      treatment

Rolling T, Schmiedel S, Wichmann D, et al. Post-treatment haemolysis
in severe imported malaria after intravenous artesunate: case report
of three patients with hyperparasitaemia. Malar J 2012;11:169.

Case 1         14%         Mefloquine       8 mg/kg       Mefloquine

Case 2         21%         Artesunate       9 mg/kg      Atovaquone/
                                                          proguanil

Case 3         20%         Artesunate       9 mg/kg      Atovaquone/
                                                          proguanil

Kreeftmeijer-Vegter AR, van Genderen PJ, Visser LG. Treatment outcome
of intravenous artesunate in patients with severe malaria in the
Netherlands and Belgium. Malar J 2012;11:102. ([dagger])

Case 4         34%           Quinine          NA         Atovaquone/
                                                          proguanil

Case 5         19%         Artesunate         NA         Atovaquone/
                                                          proguanil

Case 6         11%         Artesunate         NA         Atovaquone/
                                                          proguanil

Case 7         37%           Quinine          NA

Case 8         12%           Quinine          NA         Artemether-
                                                         lumefantrine

Case 9         30%         Artesunate         NA         Artemether-
                                                         lumefantrine

Case 10        20%           Quinine          NA         Artemether-
                                                         lumefantrine

Zoller T, Junghanss T, Kapaun A, et al. Intravenous artesunate for
severe malaria in travelers, Europe. Emerg Infect Dis 2011;17:771-7.

Case 11        20%        Artesunate + dox 12 mg/kg          None

Case 12        20%        Artesunate + dox 12 mg/kg          None

Case 13        30%         Artesunate      12 mg/kg      Atovaquone-
                                                          proguanil

Case 14         4%         Artesunate      20 mg/kg          None

Case 15         9%        Artesunate + dox 12 mg/kg      Artemether-
                                                         lumefantrine

Case 16        10%        Artesunate + dox 10 mg/kg      Artemether-
                                                         lumefantrine

Caramello P, Balbiano R, De Blasi T, et al. Severe malaria, artesunate
and haemolysis. J Antimicrob Chemother 2012;67:2053-4.

Case 17         7%         Artemether-        NA              NA
                          lumefantrine

Kano S. Artemisinin-based combination therapies and their introduction
in Japan. J Infect Chemother 2010;16:375-82.

Case 18        45%         Artesunate         NA              NA

Case 19         NA         Artesunate         NA              NA

           Parasite    Initial     Hgb
           clearance     Hgb      nadir    Day of    Other laboratory
Case         time      (g/dL)    (g/dL)    nadir *       findings

Rolling T, Schmiedel S, Wichmann D, et al. Post-treatment haemolysis
in severe imported malaria after intravenous artesunate: case report
of three patients with hyperparasitaemia. Malar J 2012;11:169.

Case 1      5 days      12.0       8.6       14      LDH 1,010

Case 2      7 days       NA        5.7       14      LDH increased
                                                     Haptoglobin
                                                     absent DAT IgG+

Case 3     NA (<1%      14.7       6.6       15      LDH increased
           on day 3)                                 Haptoglobin
                                                     absent DAT
                                                     negative

Kreeftmeijer-Vegter AR, van Genderen PJ, Visser LG. Treatment outcome
of intravenous artesunate in patients with severe malaria in the
Netherlands and Belgium. Malar J 2012;11:102. ([dagger])

Case 4      4 days      12.9       6.9       20      DAT C3d+

Case 5      3 days      14.0       7.0       30      NA

Case 6      3 days      11.4       4.5       13      DAT negative

Case 7      4 days       9.7       6.1       15      DAT C3d+ IgG+

Case 8      4 days       9.8       6.1        8      DAT negative
                                                     Hemacult negative

Case 9      10 days     11.6       6.9       13      DAT IgG+ IgM+
                                                     Hemacult negative
                                                     G6PD normal

Case 10     7 days       8.1       6.0       13      DAT negative

Zoller T, Junghanss T, Kapaun A, et al. Intravenous artesunate for
severe malaria in travelers, Europe. Emerg Infect Dis 2011;17:771-7.

Case 11     79 hrs      11.3       5.7       15      LDH 1,437
                                                     Reticulocytes
                                                     10.2% DAT
                                                     negative G6PD
                                                     normal

Case 12     158 hrs     13.2       6.1       32      LDH 805

Case 13     104 hrs     13.4       5.3       19      LDH 672

Case 14     48 hrs      13.4       7.8       15      LDH 660
                                                     Reticulocytes
                                                     increased

Case 15     35 hrs      15.5       5.7       15      LDH 1,489
                                                     Reticulocytes
                                                     increased
                                                     Haptglobin <0.1

Case 16       NA        14.2       5.8       16      LDH 444
                                                     Reticulocytes
                                                     increased
                                                     Haptoglobin <0.8
                                                     G6PD normal

Caramello P, Balbiano R, De Blasi T, et al. Severe malaria, artesunate
and haemolysis. J Antimicrob Chemother 2012;67:2053-4.

Case 17     4 days       NA        5.6       13      LDH 2,406
                                                     DAT negative
                                                     G6PD normal

Kano S. Artemisinin-based combination therapies and their introduction
in Japan. J Infect Chemother 2010;16:375-82.

Case 18      1 day       NA        NA        11      NA

Case 19      1 day       NA        4.4       15      LDH 1,483

Abbreviations: Hgb = hemoglobin; LDH = lactate dehydrogenase (in U-
L); DAT=direct antiglobulin test; G6PD=glucose-6-phosphate
dehydrogenase; NA = not available; IgG = immunoglobulin G; IgM =
immunoglobulin M.

* Day of nadir = days after first dose of artesunate.

([dagger]) Initial Hgb, for this article only, interpreted from
published graphs of hemoglobin over time.
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Author:Briggs, Melissa; Arguin, Paul M.
Publication:Morbidity and Mortality Weekly Report
Article Type:Report
Geographic Code:9JAPA
Date:Jan 11, 2013
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