• View in gallery

    Hemoglobin and lactate dehydrogenase (LDH) trends for patients 1 and 2. Arrows indicate transfusions and number of packed cells.

  • 1.

    Dondorp A, Nosten F, Stepniewska K, Day N, White N, South East Asian Quinine Artesunate Malaria Trial (SEAQUAMAT) Group, 2005. Artesunate versus quinine for treatment of severe falciparum malaria: a randomised trial. Lancet 366: 717725.

    • Search Google Scholar
    • Export Citation
  • 2.

    Dondorp AM, Fanello CI, Hendriksen IC, Gomes E, Seni A, Chhaganlal KD, Bojang K, Olaosebikan R, Anunobi N, Maitland K, Kivaya E, Agbenyega T, Nguah SB, Evans J, Gesase S, Kahabuka C, Mtove G, Nadjm B, Deen J, Mwanga-Amumpaire J, Nansumba M, Karema C, Umulisa N, Uwimana A, Mokuolu OA, Adedoyin OT, Johnson WB, Tshefu AK, Onyamboko MA, Sakulthaew T, Ngum WP, Silamut K, Stepniewska K, Woodrow CJ, Bethell D, Wills B, Oneko M, Peto TE, von Seidlein L, Day NP, White NJ; AQUAMAT Group, 2010. Artesunate versus quinine in the treatment of severe falciparum malaria in African children (AQUAMAT): an open-label, randomised trial. Lancet 376: 16471657.

    • Search Google Scholar
    • Export Citation
  • 3.

    World Health Organization, 2015. Guidelines for the Treatment of Malaria. Geneva, Switzerland: World Health Organization, 318.Available at: http://www.who.int/malaria/publications/atoz/9789241549127/en/.

    • Search Google Scholar
    • Export Citation
  • 4.

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

    • Search Google Scholar
    • Export Citation
  • 5.

    Caramello P, Balbiano R, De Blasi T, Chiriotto M, Deagostini M, Calleri G, 2012. Severe malaria, artesunate and haemolysis. J Antimicrob Chemother 67: 20532054.

    • Search Google Scholar
    • Export Citation
  • 6.

    Kreeftmeijer-Vegter AR, van Genderen PJ, Visser LG, Bierman WF, Clerinx J, van Veldhuizen CK, de Vries PJ, 2012. Treatment outcome of intravenous artesunate in patients with severe malaria in The Netherlands and Belgium. Malar J 11: 102.

    • Search Google Scholar
    • Export Citation
  • 7.

    Kano S, 2010. Artemisinin-based combination therapies and their introduction in Japan. J Infect Chemother 16: 375382.

  • 8.

    Zoller T, Junghanss T, Kapaun A, Gjorup I, Richter J, Hugo-Persson M, Morch K, Foroutan B, Suttorp N, Yurek S, Flick H, 2011. Intravenous artesunate for severe malaria in travelers, Europe. Emerg Infect Dis 17: 771777.

    • Search Google Scholar
    • Export Citation
  • 9.

    Rehman K, Lotsch F, Kremsner PG, Ramharter M, 2014. Haemolysis associated with the treatment of malaria with artemisinin derivatives: a systematic review of current evidence. Int J Infect Dis 29: 268273.

    • Search Google Scholar
    • Export Citation
  • 10.

    Raffray L, Receveur MC, Beguet M, Lauroua P, Pistone T, Malvy D, 2014. Severe delayed autoimmune haemolytic anaemia following artesunate administration in severe malaria: a case report. Malar J 13: 398.

    • Search Google Scholar
    • Export Citation
  • 11.

    Rolling T, Agbenyega T, Issifou S, Adegnika AA, Sylverken J, Spahlinger D, Ansong D, Lohr SJ, Burchard GD, May J, Mordmuller B, Krishna S, Kremsner PG, Cramer JP, 2014. Delayed hemolysis after treatment with parenteral artesunate in African children with severe malaria—a double-center prospective study. J Infect Dis 209: 19211928.

    • Search Google Scholar
    • Export Citation
  • 12.

    Rolling T, Wichmann D, Schmiedel S, Burchard GD, Kluge S, Cramer JP, 2013. Artesunate versus quinine in the treatment of severe imported malaria: comparative analysis of adverse events focussing on delayed haemolysis. Malar J 12: 241.

    • Search Google Scholar
    • Export Citation
  • 13.

    Centers for Disease Control and Prevention (CDC), 2013. Published reports of delayed hemolytic anemia after treatment with artesunate for severe malaria—worldwide, 2010–2012. MMWR 62: 58.

    • Search Google Scholar
    • Export Citation
  • 14.

    Paczkowski MM, Landman KL, Arguin PM; Centers for Disease Control and Prevention (CDC), 2014. Update on cases of delayed hemolysis after parenteral artesunate therapy for malaria—United States, 2008 and 2013. MMWR 63: 753755.

    • Search Google Scholar
    • Export Citation
  • 15.

    Lee J, Krajden S, Graham C, Boggild AK, Pavenski K, Keystone JS, Kain KC, 2015. Severe delayed hemolysis associated with regulated parenteral antimalarial drug. Emerg Infect Dis 21: 164166.

    • Search Google Scholar
    • Export Citation
  • 16.

    Shokoples SE, Ndao M, Kowalewska-Grochowska K, Yanow SK, 2009. Multiplexed real-time PCR assay for discrimination of Plasmodium species with improved sensitivity for mixed infections. J Clin Microbiol 47: 975980.

    • Search Google Scholar
    • Export Citation
  • 17.

    Committee to Advise on Tropical Medicine and Travel (CATMAT), 2014. Canadian Recommendations for the Prevention and Treatment of Malaria. Ottawa, Canada: Public Health Agency of Canada, 135. Available at: http://publications.gc.ca/collections/collection_2014/aspc-phac/HP40-102-2014-eng.pdf.

    • Search Google Scholar
    • Export Citation
  • 18.

    Haldar K, Mohandas N, 2009. Malaria, erythrocytic infection, and anemia. Hematology Am Soc Hematol Educ Program 2009: 8793.

  • 19.

    Price RN, Simpson JA, Nosten F, Luxemburger C, Hkirjaroen L, ter Kuile F, Chongsuphajaisiddhi T, White NJ, 2001. Factors contributing to anemia after uncomplicated falciparum malaria. Am J Trop Med Hyg 65: 614622.

    • Search Google Scholar
    • Export Citation
  • 20.

    Jaureguiberry S, Ndour PA, Roussel C, Ader F, Safeukui I, Nguyen M, Biligui S, Ciceron L, Mouri O, Kendjo E, Bricaire F, Vray M, Angoulvant A, Mayaux J, Haldar K, Mazier D, Danis M, Caumes E, Thellier M, Buffet P; French Artesunate Working Group, 2014. Postartesunate delayed hemolysis is a predictable event related to the lifesaving effect of artemisinins. Blood 124: 167175.

    • Search Google Scholar
    • Export Citation
  • 21.

    Gu HM, Warhurst DC, Peters W, 1986. Hemolysis induced by artemisinin and its derivatives in vitro. Zhongguo Yao Li Xue Bao 7: 269272.

  • 22.

    De Nardo P, Oliva A, Giancola ML, Ghirga P, Mencarini P, Bibas M, Nicastri E, Antinori A, Corpolongo A, 2013. Haemolytic anaemia after oral artemether-lumefantrine treatment in a patient affected by severe imported falciparum malaria. Infection 41: 863865.

    • Search Google Scholar
    • Export Citation

 

 

 

 

Delayed Hemolysis After Parenteral Artesunate Therapy for Severe Malaria in Two Returning Canadian Travelers

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  • Department of Medical Microbiology, University of Alberta, Alberta, Canada; Department of Medicine, Division of Hematology, University of Alberta, Alberta, Canada; Department of Medicine, Division of Infectious Diseases, University of Alberta, Alberta, Canada

Delayed hemolysis after parenteral artesunate has been described in Europe and Asia, but until recently had not been reported in patients receiving the artesunate product used in the United States and Canada. We report two cases of severe delayed hemolysis after the treatment with intravenous artesunate in Canada.

Background

Artesunate reduces mortality from severe malaria in adults and children with fewer adverse effects compared with the previous standard of intravenous quinine.1,2 Since 2010, the World Health Organization has recommended artemisinins as first-line therapy for severe malaria.3 Parenteral artesunate is available through the Canadian Malaria Network (CMN) with supplies positioned in multiple centers across the country. The artesunate supplied to CMN and the Centers for Disease Control and Prevention (CDC) is produced under good manufacturing practice, and obtained from the Walter Reed Army Institute of Research, Silver Spring, MD. Until recently, this drug class had appeared remarkably free of serious adverse effects. Recent case series from Europe, Asia, and subsequently Africa describe patients treated with intravenous artesunate products who experienced post-artemisinin delayed hemolysis (PADH).412 Until recently, there had been no reports of this complication among patients treated with parenteral artesunate in North America.1315

According to a recently proposed definition, PADH is characterized by a decrease of ≥ 10% hemoglobin level in the setting of a haptoglobin level < 0.1 g/L and an increase of lactate dehydrogenase (LDH) > 390 U/L at least 7 days after initiation of parenteral artesunate.14

Case 1

In December 2013, a 44-year-old male presented to the emergency department, University of Alberta Hospital in Edmonton, Alberta, Canada, with fever and confusion, 4 days after returning from 1 month working in Cameroon. He had taken no malaria chemoprophylaxis or treatment, and specifically, had not received any artemisinin derivative. His only medical history was of treated hypertension; chronic hepatitis C infection was diagnosed during this hospitalization. On examination, he was hypotensive, febrile to 40°C, and markedly jaundiced. At presentation, his hemoglobin level was 164 g/L (6% nucleated red blood cells [RBCs]), white blood cell count 17.3 × 109/L, and platelets 4 × 109/L. Plasmodium falciparum trophozoites with schizonts were observed in the peripheral blood smear with a parasitemia of 12.3%. Speciation was confirmed by real-time polymerase chain reaction.16 He required immediate intubation and ventilation for a depressed level of consciousness. Intravenous artesunate at 2.4 mg/kg/dose was administered at 0, 12, 24, and 48 hours post admission (total: 9.6 mg/kg). On day 3, thin and thick smears were negative. Oral atovaquone 1 g/proguanil 400 mg was given daily for 3 days. Acute kidney injury required continuous renal replacement therapy for 4 days, followed by a single dialysis 3 days later.

His hemoglobin level began to drop immediately after admission (Figure 1); increasing red cell transfusions were required after a nadir of 68 g/L was reached on day 15. Hemolysis markers—a presenting total bilirubin of 634 μmol/L and LDH peaking at 1,369 U/L—were present immediately, consistent with acute malaria. On day 2, the haptoglobin was undetectable. The haptoglobin became detectable on day 8 of admission, but again dropped below the level of detection (< 0.10 g/L, normal 0.30–2.00 g/L). On day 25, the patient met all criteria for PADH with a hemoglobin level of 78 g/L, undetectable haptoglobin, a reticulocyte percentage of 15.7%, and LDH level 426 U/L. Between days 15 and 28, the patient received 11 units of packed RBCs before hematological recovery; by day 47 his hemoglobin level was up to 98 g/L, and had finally normalized at 141 g/L at 3.5 months post presentation.

Figure 1.
Figure 1.

Hemoglobin and lactate dehydrogenase (LDH) trends for patients 1 and 2. Arrows indicate transfusions and number of packed cells.

Citation: The American Society of Tropical Medicine and Hygiene 93, 4; 10.4269/ajtmh.15-0268

No other explanation was found for his anemia. At no time were the blood film findings consistent with a microangiopathic or autoimmune hemolytic process. Coagulation parameters were not suggestive of disseminated intravascular coagulation. Blood loss studies, including colonoscopy and abdominal computed tomography, were negative. Vitamin B12, folate, and iron levels were normal. The direct antiglobulin test became weakly positive on January 13 (immunoglobulin G positive, complement negative), but the eluate was nonspecific. All clinically relevant antibodies (anti-D, C, c, E, e, Cw, K, k, Fya, Fyb, Jka, Jkb, M, N, S, and s) were excluded from both plasma and eluate by the reference transfusion laboratory of northern Alberta, and all antibody screens remained negative.

Case 2

In September 2014, a previously healthy 55-year-old man presented to the emergency department at the University of Alberta Hospital with fever, nausea, and vomiting 5 days after returning from the Democratic Republic of Congo, where he had been working for the previous 5 weeks. He had not been taking malaria prophylaxis. On assessment, he was confused, febrile at 38.8°C, and tachycardic with a blood pressure of 85/46 mmHg, and had tender hepatomegaly. His malaria diagnosis was delayed for several hours by the laboratory protocols in place for possible Ebola. Laboratory investigation revealed an anemia of 105 g/L, thrombocytopenia at 19 × 109/L, leucopenia of 3.7 × 109/L, and a lactate of 7.9 mmol/L. His bilirubin peaked at 58 μmol/L with an LDH of 878 U/L and a P. falciparum parasitemia of 35%. Intravenous artesunate therapy, 2.4 mg/kg/dose, was given at 0, 12, 24, and 48 hours post admission. His intensive care unit stay was uncomplicated and the parasitemia had cleared 72 hours post artesunate initiation. Treatment was completed with 3 days of oral atovaquone 1 g/proguanil 400 mg and the patient was discharged home on day 6. His last hemoglobin measurement taken in hospital was 77 g/L (Figure 1), with his bilirubin improved to 11 μmol/L and LDH to 390 U/L. No RBC transfusions were administered during his hospital stay.

Fifteen days post artesunate initiation, he presented to the emergency department with increasing weakness and was found to have a hemoglobin level of 59 g/L with normal platelets of 161 × 109/L and total white blood cell count of 6.2 × 109/L. His haptoglobin was < 0.1 g/L, LDH increased to 1,015 U/L, and bilirubin to 40 μmol/L with a reticulocyte percentage up to 12.9% (Figure 1). As in the first case, no other explanation was found for his acute anemia with any history of bleeding, negative direct antiglobulin test, normal vitamin B12 level, and normal thyroid, liver, and kidney function. There were no peripheral blood smear findings suggestive of a microangiopathic or autoimmune hemolytic process, nor any further malarial parasites. He required 2 units of packed RBCs. His bilirubin and haptoglobin normalized 20 days post artesunate treatment.

Both of these presumed serious drug adverse effects were reported to the Canadian Malaria Network.

Discussion

Severe malaria is uncommon in Canada, with an average of 14 imported cases per year17; artesunate is the drug of choice in these patients. Anemia is one of the most important complications of malaria, primarily among children in endemic areas. Multiple mechanisms contribute to malarial anemia including direct and indirect effects on both parasitized and noninfected erythrocytes, mediated in part by malarial proteins and host immune response as well as enhanced splenic activity and decreased or ineffective erythropoeisis.18 Cases of artemisinin-related hemolysis may not have been recognized in the past because they were attributed to these relatively common, established mechanisms of anemia. The degree and timing of hemolytic anemia described in the case series from Europe and in our patients lie outside the range of previous experience with malaria treatment. In uncomplicated malaria, the hemoglobin nadir is usually around 1 week after treatment initiation with a rapid recovery to normal over the subsequent 3–4 weeks.19

In our first patient, hospital discharge was delayed since the concept PADH was not recognized and the patient underwent invasive procedures in an attempt to explain his anemia. Previously, it was suggested that the absence of cases of PADH reported from North America might be explained by the differences between the artesunate products used in North America and Europe.13 Aside from the two cases reported here, one retrospective and one prospectively identified case that meet the case definition for PADH, were recently identified by the CDC14 and one further case was reported from Canada.15 These cases would appear to refute the hypothesis that PADH is attributable to a specific drug formulation. With the introduction of more active surveillance on the part of CDC, the lower number of reports of PADH in North America relative to Europe remains incompletely explained. In the previously reported non-North American cases of PADH, most patients had high parasitemias and had been treated with higher doses of intravenous artesunate (8–20 mg/kg).

Recent work has provided a likely mechanism contributing to PADH. In contrast with other antimalarials, artemisinins kill and expel the parasites without destroying the erythrocyte. These altered, “pitted,” erythrocytes remain in circulation. The delayed, synchronous destruction of this population of pitted erythrocytes accounts for the delayed hemolysis.20 Hemolysis with exposure of RBCs to high doses of several artemisinin derivatives has also been described in vitro.21

Conclusion

Accumulating evidence supports an association between intravenous artesunate (and possibly other artemisinin derivatives)22 and delayed hemolysis. All patients receiving intravenous artesunate should have systematic follow-up of hemoglobin levels up to 4 weeks post treatment. This will enable recognition of patients with delayed onset anemia and better define the frequency and characteristics of this phenomenon, particularly in North America.

ACKNOWLEDGMENTS

We would like to thank Suresh Reddy for his contribution to the patient's care and Susan Nahirniak for her expert advice in ruling out delayed transfusion reaction as a likely explanation for patient 1's hemolysis.

  • 1.

    Dondorp A, Nosten F, Stepniewska K, Day N, White N, South East Asian Quinine Artesunate Malaria Trial (SEAQUAMAT) Group, 2005. Artesunate versus quinine for treatment of severe falciparum malaria: a randomised trial. Lancet 366: 717725.

    • Search Google Scholar
    • Export Citation
  • 2.

    Dondorp AM, Fanello CI, Hendriksen IC, Gomes E, Seni A, Chhaganlal KD, Bojang K, Olaosebikan R, Anunobi N, Maitland K, Kivaya E, Agbenyega T, Nguah SB, Evans J, Gesase S, Kahabuka C, Mtove G, Nadjm B, Deen J, Mwanga-Amumpaire J, Nansumba M, Karema C, Umulisa N, Uwimana A, Mokuolu OA, Adedoyin OT, Johnson WB, Tshefu AK, Onyamboko MA, Sakulthaew T, Ngum WP, Silamut K, Stepniewska K, Woodrow CJ, Bethell D, Wills B, Oneko M, Peto TE, von Seidlein L, Day NP, White NJ; AQUAMAT Group, 2010. Artesunate versus quinine in the treatment of severe falciparum malaria in African children (AQUAMAT): an open-label, randomised trial. Lancet 376: 16471657.

    • Search Google Scholar
    • Export Citation
  • 3.

    World Health Organization, 2015. Guidelines for the Treatment of Malaria. Geneva, Switzerland: World Health Organization, 318.Available at: http://www.who.int/malaria/publications/atoz/9789241549127/en/.

    • Search Google Scholar
    • Export Citation
  • 4.

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

    • Search Google Scholar
    • Export Citation
  • 5.

    Caramello P, Balbiano R, De Blasi T, Chiriotto M, Deagostini M, Calleri G, 2012. Severe malaria, artesunate and haemolysis. J Antimicrob Chemother 67: 20532054.

    • Search Google Scholar
    • Export Citation
  • 6.

    Kreeftmeijer-Vegter AR, van Genderen PJ, Visser LG, Bierman WF, Clerinx J, van Veldhuizen CK, de Vries PJ, 2012. Treatment outcome of intravenous artesunate in patients with severe malaria in The Netherlands and Belgium. Malar J 11: 102.

    • Search Google Scholar
    • Export Citation
  • 7.

    Kano S, 2010. Artemisinin-based combination therapies and their introduction in Japan. J Infect Chemother 16: 375382.

  • 8.

    Zoller T, Junghanss T, Kapaun A, Gjorup I, Richter J, Hugo-Persson M, Morch K, Foroutan B, Suttorp N, Yurek S, Flick H, 2011. Intravenous artesunate for severe malaria in travelers, Europe. Emerg Infect Dis 17: 771777.

    • Search Google Scholar
    • Export Citation
  • 9.

    Rehman K, Lotsch F, Kremsner PG, Ramharter M, 2014. Haemolysis associated with the treatment of malaria with artemisinin derivatives: a systematic review of current evidence. Int J Infect Dis 29: 268273.

    • Search Google Scholar
    • Export Citation
  • 10.

    Raffray L, Receveur MC, Beguet M, Lauroua P, Pistone T, Malvy D, 2014. Severe delayed autoimmune haemolytic anaemia following artesunate administration in severe malaria: a case report. Malar J 13: 398.

    • Search Google Scholar
    • Export Citation
  • 11.

    Rolling T, Agbenyega T, Issifou S, Adegnika AA, Sylverken J, Spahlinger D, Ansong D, Lohr SJ, Burchard GD, May J, Mordmuller B, Krishna S, Kremsner PG, Cramer JP, 2014. Delayed hemolysis after treatment with parenteral artesunate in African children with severe malaria—a double-center prospective study. J Infect Dis 209: 19211928.

    • Search Google Scholar
    • Export Citation
  • 12.

    Rolling T, Wichmann D, Schmiedel S, Burchard GD, Kluge S, Cramer JP, 2013. Artesunate versus quinine in the treatment of severe imported malaria: comparative analysis of adverse events focussing on delayed haemolysis. Malar J 12: 241.

    • Search Google Scholar
    • Export Citation
  • 13.

    Centers for Disease Control and Prevention (CDC), 2013. Published reports of delayed hemolytic anemia after treatment with artesunate for severe malaria—worldwide, 2010–2012. MMWR 62: 58.

    • Search Google Scholar
    • Export Citation
  • 14.

    Paczkowski MM, Landman KL, Arguin PM; Centers for Disease Control and Prevention (CDC), 2014. Update on cases of delayed hemolysis after parenteral artesunate therapy for malaria—United States, 2008 and 2013. MMWR 63: 753755.

    • Search Google Scholar
    • Export Citation
  • 15.

    Lee J, Krajden S, Graham C, Boggild AK, Pavenski K, Keystone JS, Kain KC, 2015. Severe delayed hemolysis associated with regulated parenteral antimalarial drug. Emerg Infect Dis 21: 164166.

    • Search Google Scholar
    • Export Citation
  • 16.

    Shokoples SE, Ndao M, Kowalewska-Grochowska K, Yanow SK, 2009. Multiplexed real-time PCR assay for discrimination of Plasmodium species with improved sensitivity for mixed infections. J Clin Microbiol 47: 975980.

    • Search Google Scholar
    • Export Citation
  • 17.

    Committee to Advise on Tropical Medicine and Travel (CATMAT), 2014. Canadian Recommendations for the Prevention and Treatment of Malaria. Ottawa, Canada: Public Health Agency of Canada, 135. Available at: http://publications.gc.ca/collections/collection_2014/aspc-phac/HP40-102-2014-eng.pdf.

    • Search Google Scholar
    • Export Citation
  • 18.

    Haldar K, Mohandas N, 2009. Malaria, erythrocytic infection, and anemia. Hematology Am Soc Hematol Educ Program 2009: 8793.

  • 19.

    Price RN, Simpson JA, Nosten F, Luxemburger C, Hkirjaroen L, ter Kuile F, Chongsuphajaisiddhi T, White NJ, 2001. Factors contributing to anemia after uncomplicated falciparum malaria. Am J Trop Med Hyg 65: 614622.

    • Search Google Scholar
    • Export Citation
  • 20.

    Jaureguiberry S, Ndour PA, Roussel C, Ader F, Safeukui I, Nguyen M, Biligui S, Ciceron L, Mouri O, Kendjo E, Bricaire F, Vray M, Angoulvant A, Mayaux J, Haldar K, Mazier D, Danis M, Caumes E, Thellier M, Buffet P; French Artesunate Working Group, 2014. Postartesunate delayed hemolysis is a predictable event related to the lifesaving effect of artemisinins. Blood 124: 167175.

    • Search Google Scholar
    • Export Citation
  • 21.

    Gu HM, Warhurst DC, Peters W, 1986. Hemolysis induced by artemisinin and its derivatives in vitro. Zhongguo Yao Li Xue Bao 7: 269272.

  • 22.

    De Nardo P, Oliva A, Giancola ML, Ghirga P, Mencarini P, Bibas M, Nicastri E, Antinori A, Corpolongo A, 2013. Haemolytic anaemia after oral artemether-lumefantrine treatment in a patient affected by severe imported falciparum malaria. Infection 41: 863865.

    • Search Google Scholar
    • Export Citation

Author Notes

* Address correspondence to Stan Houston, Department of Medicine/Public Health, University of Alberta, 1-131 Clinical Sciences Building, 11350 83 Avenue, Alberta, Canada T6G 2G3. E-mail: shouston@ualberta.ca

Authors' addresses: Marthe Charles, Department of Medical Microbiology, University of Alberta, Alberta, Canada, E-mail: marthe@ualberta.ca. Jeffery M. Patterson, Division of Hematology, University of Alberta, Alberta, Canada, E-mail: jefferyp@ualberta.ca. Leyla Asadi, Department of Medicine, University of Alberta, Alberta, Canada, E-mail: lasadi@ualberta.ca. Stan Houston, Department of Medicine/Public Health, University of Alberta, Alberta, Canada, E-mail: shouston@ualberta.ca.

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