Haemolytic anaemia in an HIV-infected patient with severe falciparum malaria after treatment with oral artemether-lumefantrine.
ABSTRACT Intravenous (i.v.) artesunate is now the recommended first-line treatment of severe falciparum malaria in adults and children by WHO guidelines. Nevertheless, several cases of haemolytic anaemia due to i.v. artesunate treatment have been reported. This paper describes the case of an HIV-infected patient with severe falciparum malaria who was diagnosed with haemolytic anaemia after treatment with oral artemether-lumefantrine.The patient presented with fever, headache, and arthromyalgia after returning from Central African Republic where he had been working. The blood examination revealed acute renal failure, thrombocytopaenia and hypoxia. Blood for malaria parasites indicated hyperparasitaemia (6%) and Plasmodium falciparum infection was confirmed by nested-PCR. Severe malaria according to the laboratory WHO criteria was diagnosed. A treatment with quinine and doxycycline for the first 12 hours was initially administered, followed by arthemeter/lumefantrine (Riamet(®)) for a further three days. At day 10, a diagnosis of severe haemolytic anaemia was made (Hb 6.9 g/dl, LDH 2071 U/l). Hereditary and autoimmune disorders and other infections were excluded through bone marrow aspiration, total body TC scan and a wide panel of molecular and serologic assays. The patient was treated by transfusion of six units of packed blood red cell. He was discharged after complete remission at day 25. At present, the patient is in a good clinical condition and there is no evidence of haemolytic anaemia recurrence.This is the first report of haemolytic anaemia probably associated with oral artemether/lumefantrine. Further research is warranted to better define the adverse events occurring during combination therapy with artemisinin derivatives.
- [Show abstract] [Hide abstract]
ABSTRACT: Within 24 hr after oral administration of the antimalarial artesunate to rats on Day 10 or 11 postcoitum (pc), there is depletion of embryonic erythroblasts (EEbs), leading to embryo malformation and death. The proximate agent is dihydroartemisinin (DHA), the primary metabolite. We investigated the causes of EEb depletion by evaluating effects of DHA on EEbs in whole embryo culture (WEC). Rat embryos cultured starting on Day 9 pc were treated with 1 or 7 μM DHA for 24 hr starting after 19 hr of culture (∼Day 10 pc) and for 2 to 12 hr starting after 43 hr of culture (∼Day 11 pc). DHA effects indicating the depletion of EEbs were paling of the visceral yolk sac and reductions in visible blood cells, H&E-stained normal (Type II or III) EEbs, and dividing (BrdU-stained) EEbs. DHA-induced abnormal cell division was indicated by increases in symmetric and asymmetric binuclear cells. DHA-induced apoptosis was indicated by increases in TUNEL- and Caspase-3-positive cells and EEbs with fragmented nuclei. In addition, although the overall number of EEbs was decreasing, DHA caused increases in the numbers of circulating early-stage (Type I or earlier) EEbs that could not be accounted for by cell division, suggesting the release of new, less sensitive erythroblasts from the yolk sac. In summary, treatment of Day 10 or 11 pc rat embryos with DHA in WEC resulted in defective and arrested cell division in EEbs followed by apoptosis, suggesting a mechanism for their depletion after artesunate treatment in vivo.Birth Defects Research Part B Developmental and Reproductive Toxicology 01/2014; · 1.97 Impact Factor
- [Show abstract] [Hide abstract]
ABSTRACT: Background. Parenteral artesunate is recommended as first-line therapy for severe malaria. While its efficacy is firmly established, data on safety are still incomplete. Delayed hemolysis has been described in hyperparasitemic non-immune travelers but it is unknown if African children are equally at risk.Methods. Children aged six to 120 months with severe malaria were followed up after treatment with parenteral artesunate in Lambaréné, Gabon, and Kumasi, Ghana. The primary outcome was incidence of delayed hemolysis on Day 14.Results. 72 children contributed complete data sets necessary for primary outcome assessment. Delayed hemolysis was detected in 5 children (7%), with one child reaching a nadir in hemoglobin of 2.8 g/dl. Patients with delayed hemolysis had higher parasite counts on admission (geometric mean parasite densities (GMPD) 306,968/µl vs. 92,642/µl, p=0.028) and were younger (median age: 24 months vs. 43 months, p=0.046) than the rest of the cohort. No correlation with sickle cell trait or glucose-6-phosphate-dehydrogenase deficiency was observed.Conclusions. Delayed hemolysis is a frequent and relevant complication in hyperparasitemic African children treated with parenteral artesunate for severe malaria. Physicians should be aware of this complication and consider prolonged follow-up.Trial registration. Pan-African Clinical Trials Registry: PACTR201102000277177 (www.pactr.org).The Journal of Infectious Diseases 12/2013; · 5.85 Impact Factor
- [Show abstract] [Hide abstract]
ABSTRACT: In sub-Saharan Africa, artemisinin-based combination therapy (ACT) and injectable artesunate are the first-line treatments for uncomplicated and severe Plasmodium falciparum malaria, respectively. However, recent studies suggest that delayed anaemia is associated with these treatments in non-immune travellers. This paper aimed to assess the risk factors associated with delayed anaemia after falciparum malaria treatment with artemisinin-containing drugs in malaria-endemic populations.Malaria Journal 09/2014; 13(1):358. · 3.49 Impact Factor
CASE REPORTOpen Access
Haemolytic anaemia in an HIV-infected patient
with severe falciparum malaria after treatment
with oral artemether-lumefantrine
Angela Corpolongo*, Pasquale De Nardo, Piero Ghirga, Elisa Gentilotti, Rita Bellagamba, Chiara Tommasi,
Maria Grazia Paglia, Emanuele Nicastri and Pasquale Narciso
Intravenous (i.v.) artesunate is now the recommended first-line treatment of severe falciparum malaria in adults and
children by WHO guidelines. Nevertheless, several cases of haemolytic anaemia due to i.v. artesunate treatment
have been reported. This paper describes the case of an HIV-infected patient with severe falciparum malaria who
was diagnosed with haemolytic anaemia after treatment with oral artemether-lumefantrine.
The patient presented with fever, headache, and arthromyalgia after returning from Central African Republic where
he had been working. The blood examination revealed acute renal failure, thrombocytopaenia and hypoxia. Blood
for malaria parasites indicated hyperparasitaemia (6%) and Plasmodium falciparum infection was confirmed by
nested-PCR. Severe malaria according to the laboratory WHO criteria was diagnosed. A treatment with quinine and
doxycycline for the first 12 hours was initially administered, followed by arthemeter/lumefantrine (Riamet®) for a
further three days. At day 10, a diagnosis of severe haemolytic anaemia was made (Hb 6.9 g/dl, LDH 2071 U/l).
Hereditary and autoimmune disorders and other infections were excluded through bone marrow aspiration, total
body TC scan and a wide panel of molecular and serologic assays. The patient was treated by transfusion of six
units of packed blood red cell. He was discharged after complete remission at day 25. At present, the patient is in
a good clinical condition and there is no evidence of haemolytic anaemia recurrence.
This is the first report of haemolytic anaemia probably associated with oral artemether/lumefantrine. Further
research is warranted to better define the adverse events occurring during combination therapy with artemisinin
Keywords: Severe malaria, Artemisinin-based combination therapy (ACT), Haemolytic anaemia, Drugs and haemoly-
Artemisinins were discovered in 1971 from a herb,
Artemisia annua, known in the past for their activity
against intermittent fever . Now, artemisinin and its
derivatives have become essential components of arte-
misinin-based combination therapy (ACT) . Intrave-
nous (i.v.) artesunate is the recommended first-line
treatment of severe falciparum malaria in adults and
children, including cerebral malaria, because they pro-
duce rapid parasite/fever clearance, show fewer adverse
effects, and have not been associated with occurrence
of less resistance [3,4]. The World Health Organiza-
tion’s (WHO) up-to-date guidelines recommend arte-
sunate as the treatment of choice for adults and
children with severe malaria . However, quinine is
still the primary treatment for severe non-multidrug
resistant Plasmodium falciparum malaria in Europe
because i.v. artesunate is not registred for this indica-
tion. This paper describes the occurrence of a case of
haemolytic anaemia in an HIV-infected patient with
falciparum malaria treated with intravenous (i.v.) qui-
nine and doxycycline for the first 12 hours and then
* Correspondence: firstname.lastname@example.org
National Institute for Infectious Diseases “Lazzaro Spallanzani”, Via Portuense
292, 00149 Rome, Italy
Corpolongo et al. Malaria Journal 2012, 11:91
© 2012 Corpolongo et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative
Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and
reproduction in any medium, provided the original work is properly cited.
A 34-year-old man presented with a seven-day history of
fever, headache, and arthromyalgia after returning from
Central African Republic. He is Italian and he had been
working for governmental and non-governmental orga-
nizations for several years. His past medical history
included HIV infection known since October 2010 with
no anti-retroviral treatment. At admission on 18 July,
2011, the physical examination revealed prostration,
severe obesity (BMI 42), pallor, shallow tachypnoic
breathing, and hepato-splenomegaly. Blood examinations
showed acute renal failure (creatinine 3.29 mg/dl), anae-
mia (Hb 7.4 g/dl), thrombocytopaenia (PLT 17000), glu-
cose 88 mg/dl, AST 108 U/l, ALT 33 U/l, bilirubin total
2.9 mg/dl, bilirubin direct 1.5 mg/dl, albumin 2,5 g/dl,
G6PDH 16 U/gHb, hypoxia and metabolic acidosis (pH
7.35, pO2 62 mmHg, HCO3-16.5 mmol/l) (see Table
1). Polymerase Chain Reaction (PCR) and light micro-
scopy on peripheral blood smear detected P. falciparum
with a 6% parasitaemia. Severe malaria, according to
WHO criteria (hyperparasitaemia, metabolic acidosis,
renal impairment), was diagnosed .
The patient was initially treated with i.v. quinine load-
ing dose (20 mg/kg, 1500 mg) in combination with oral
doxycycline (100 mg) for the first 12 hours followed by
oral fixed-dose co-formulated artemether/lumefantrine
(Riamet®) for a further three days. At admission, the
blood test detected moderate-severe anaemia (Hb 7.4 g/
dl and HCT 22%) and a transfusion with one unit of
packed red blood cells (RBC) was prescribed. Because of
the persistence of the anaemia, the patient was trans-
fused with a further RBC transfusion on day 4 (Hb 6.7
g/dl and HCT 20%). Parasite clearance time was 72
hours. Renal and pulmonary functions immediately
improved but fever was still reported up to 28 July,
when the diagnosis of severe haemolytic anaemia was
performed (Hb 6.9 g/dl, haptoglobin < 7.19 mg/dl, reti-
culocytes 4.8%, LDH 2071 U/l). The patient was trans-
fused with an additional four packed blood transfusions
on two different days.
Direct and indirect anti-globulin tests, cold agglutinin
test, and auto-immune assays were all negative; PCR and
antibody detection for chikungunya, dengue, serology for
B19 Parvovirus, Leishmania species, Mycoplasma pneu-
moniae, Chlamydia pneumoniae, Mycobacterium tuber-
culosis complex, atypical mycobacteria, Salmonella typhi
and paratyphi, Trypanosoma spp., Toxoplasma gondii,
and Treponema pallidum were all negative; antigens of
Cryptococcus neoformans were not detectable; PCR and
peripheral blood smears for Plasmodium species were
Table 1 Laboratory data
Day 17Day 25
Potassium, mEq/l 3.54.9 3.6-5.5
Bilirubin total/direct, mg/dl2.9/1.51.4/0.71.6/0.6 1.9/0.8 < 1.2/0.3
108/33 32/2640/23 < 40
Haematocrit, %2224 201829 36-52
White blood cells, 103/mmc
17114 127 9815280-400
Neutrophils %75.541.1 23.1 31.636.640-75
Lymphocytes % 2042.7624941.220-51
CD4 cells/mmc (%)569 (23.2)(36-44)
Erythrocyte Sedimentation Rate, mm/hr122> 140> 140< 15
C-Reactive proteine mg/dl 214.7 < 0.6
Thick and thin smearsPosNeg, day 3Neg
PCR for Plasmodium falciparum
Pos Neg, day 3Neg
Coombs test direct/indirect neg/negneg/neg
Corpolongo et al. Malaria Journal 2012, 11:91
Page 2 of 4
persistently negative. Bone marrow aspiration was nega-
tive for infectious agents and lympho-proliferative dis-
eases. A total body CT scan reported splenomegaly. After
significant improvement of his clinical condition, the
patient was discharged on 12 August (Hb 9.6 g/dl). Five
weeks after discharge, haemoglobin, haematocrit, reticu-
locytes count were all within normal values (see Table 1).
The patient is now in good clinical condition and back to
his daily working life with no evidence of haemolytic
Written informed consent was obtained from the
patient for publication of this case report.
There are multiple causes of haemolytic anaemia, and
the clinical presentation can differ depending on the
etiology. Haemolysis may be extravascular due to auto-
immune disorders or to hereditary spherocytosis, intra-
vascular (e.g. associated to insertion of prosthetic
cardiac valves, G6PDH deficiency, thrombotic thrombo-
cytopenic purpura or disseminated intravascular coagu-
lation), or intramedullary-related due to pernicious
anaemia and thalassemia major. The haemolytic disorder
can be hereditary as in case of G6PDH deficiency ,
haemoglobinopathies and RBC membrane abnormalities,
or acquired, as in the case of immune disorders ,
exposure to toxic chemicals and drugs , paroxysmal
nocturnal haemoglobinuria , traumatic and microan-
giopathic haemolysis, hypersplenism or infections .
In this report, hereditary and auto-immune disorders
were excluded. Infectious agents other than malaria
were searched for with a wide panel of molecular and
serologic assays and through bone marrow examination.
All the results were negative. CT scan and bone marrow
analysis excluded lymphoproliferative disorders. Malaria
was treated with i.v. quinine and doxycycline for the
first 12 hours only, followed by Riamet®for 72 hours.
At day 10 a diagnosis of severe haemolytic anaemia was
established and it was treated by transfusion with six
units of packed red blood cells. The duration of haemo-
lysis was 15 days. The patient was discharged on 12
August after complete remission from severe malaria
and haemolytic anaemia.
There are few cases described in literature of haemoly-
tic anaemia during or after treatment with i.v. artesunate
alone or combined with mefloquine. Yasouka et al
reported the case of a Nigerian male with severe P. falci-
parum malaria initially treated with mefloquine. After
one day of treatment, because of the worsening clinical
condition of the patient and the increase of the parasitae-
mia, therapy with i.v. artesunate was initiated. Parasite
clearance was obtained within 20 hours after the first
administration of artesunate, but fever persisted for a
further seven days and haemolytic anaemia was observed,
requiring blood transfusion . Yoshizawa et al
described the case of a young woman with P. falciparum
malaria who was successfully treated with i.v. artesunate,
but showed worsening anaemia after artesunate adminis-
tration . Itoda et al observed severe haemolytic anae-
mia and jaundice on day 11 after i.v. artesunate
administration in a 68-year-old Japanese woman affected
by severe malaria . Recently, Zoller et al reported a
series of 25 travellers with severe malaria treated with i.v.
artesunate. Among them, six patients developed haemo-
lytic anaemia week after treatment possibily related to
artesunate or had persistent signs of haemolytic activity
until six weeks after the first dose of i.v. artesunate .
In this case series, patients with post-treatment haemoly-
sis had received a higher cumulative dose of i.v. artesu-
nate and were treated for longer periods.
This appears to the first reported case of haemolytic
anaemia after treatment with oral fixed-dose co-formu-
lated artemether/lumefantrine. The observation supports
the hypothesis that haemolysis might occur as a conse-
quence of artemether treatment. Efficacy and safety pro-
files of i.v. artesunate and ACT should be prospectively
evaluated, and patients should be monitored for signs of
haemolysis after parasitological cure.
AC, PDN, RB, EN collected and collated case information and details and
obtained consent. All authors participated in drafting the medical part of the
manuscript. MGP performed the PCR amplification and
immunohistochemistry. PG and EG were involved in literature search. All
authors read and approved the final manuscript.
The authors declare that they have no competing interests.
Received: 30 December 2011 Accepted: 27 March 2012
Published: 27 March 2012
1. Kano S: Artemisinin-based combination therapies and their introduction
in Japan. J Infect Chemother 2010, 16:375-382.
2. Hsu E: The history of qing hao in the Chinese materia medica. Trans R
Soc Trop Med Hyg 2006, 100:505-508.
3.Dondorp A, Nosten F, Stepniewska K, Day N, White N: South East Asian
Quinine Artesunate Malaria Trial (SEAQUAMAT) group. Artesunate versus
quinine for treatment of severe falciparum malaria: a randomised trial.
Lancet 2005, 366:717-725.
4.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: Artesunate versus quinine in the treatment of severe falciparum
malaria in African children (AQUAMAT): an open label, randomised trial.
Lancet 2010, 376:1647-1657.
5.World Health Organization: Guidelines for the treatment of malaria. 2nd
edition Geneva: The Organization; 2010.
6. Beutler E, Duparc S, G6PD Deficiency Working Group: Glucose-6-phosphate
dehydrogenase deficiency and antimalarial drug development. Am J
Trop Med Hyg 2007, 77:779-789.
Corpolongo et al. Malaria Journal 2012, 11:91
Page 3 of 4
7. Zeerleder S: Autoimmune haemolytic anaemia - a practical guide to
cope with a diagnostic and therapeutic challenge. Neth J Med 2011,
Garratty G: Immune hemolytic anemia associated with drug therapy.
Blood Rev 2010, 24:143-145.
Madkaikar M, Gupta M, Jijina F, Ghosh K: Paroxysmal nocturnal
haemoglobinuria: diagnostic tests, advantages, & limitations. Eur J
Haematol 2009, 83:503-511.
Kwaan HC: Infection and anemia. Infect Disord Drug Targets 2011, 11:40-44.
Yasouka C, Yasuoka A, Yamamoto Y, Genka I, Hatabu T, Kohno S, Oka S,
Kano S: A case of falciparum malaria successfully treated with
intravenous artesunate. Kansenshogaku Zasshi 2001, 75:822-825.
Yoshizawa S, Hike K, Kimura K, Matsumoto T, Furuya N, Takeda K, Kano S,
Yamaguchi K: A case of falciparum malaria successfully treated with
intravenous artesunate. Kansenshogaku Zasshi 2002, 76:888-892.
Itoda I, Yasunami T, Kikuki K, Yamaura H, Totsuka K, Yoshinaga K,
Teramura M, Mizoguchi H, Hatabu T, Kano S: Severe falciparum malaria
with prolonged haemolytic anemia after successful treatment with
intravenous artesunate. Kansenshogaku Zasshi 2002, 76:600-603.
Zoller T, Junghanss T, Kapaun A, Gjørup I, Richter J, Hugo-Persson M,
Mørch K, Foroutan B, Suttorp N, Yürek S, Flick H: Intravenous artesunate
for severe malaria in travelers, Europe. Emerg Infect Dis 2011, 17:771-777.
Cite this article as: Corpolongo et al.: Haemolytic anaemia in an HIV-
infected patient with severe falciparum malaria after treatment with
oral artemether-lumefantrine. Malaria Journal 2012 11:91.
Submit your next manuscript to BioMed Central
and take full advantage of:
• Convenient online submission
• Thorough peer review
• No space constraints or color figure charges
• Immediate publication on acceptance
• Inclusion in PubMed, CAS, Scopus and Google Scholar
• Research which is freely available for redistribution
Submit your manuscript at
Corpolongo et al. Malaria Journal 2012, 11:91
Page 4 of 4