Emerging Infectious Diseases Volume 17 Issue 5

2011·6.2 MB·English

by  CDC

Peer-Reviewed Journal Tracking and Analyzing Disease Trends pages 769–962
EDITOR-IN-CHIEF
D. Peter Drotman
Managing Senior Editor EDITORIAL BOARD
Polyxeni Potter, Atlanta, Georgia, USA
Dennis Alexander, Addlestone Surrey, United Kingdom
Senior Associate Editor Timothy Barrett, Atlanta, GA, USA
Brian W.J. Mahy, Bury St. Edmunds, Suffolk, UK Barry J. Beaty, Ft. Collins, Colorado, USA
Associate Editors Martin J. Blaser, New York, New York, USA
Paul Arguin, Atlanta, Georgia, USA Christopher Braden, Atlanta, GA, USA
Charles Ben Beard, Ft. Collins, Colorado, USA Arturo Casadevall, New York, New York, USA
Ermias Belay, Atlanta, GA, USA Kenneth C. Castro, Atlanta, Georgia, USA
David Bell, Atlanta, Georgia, USA Louisa Chapman, Atlanta, GA, USA
Corrie Brown, Athens, Georgia, USA Thomas Cleary, Houston, Texas, USA
Charles H. Calisher, Ft. Collins, Colorado, USA Vincent Deubel, Shanghai, China
Michel Drancourt, Marseille, France Ed Eitzen, Washington, DC, USA
Paul V. Effl er, Perth, Australia Daniel Feikin, Baltimore, MD, USA
David Freedman, Birmingham, AL, USA Kathleen Gensheimer, Cambridge, MA, USA
Peter Gerner-Smidt, Atlanta, GA, USA Duane J. Gubler, Singapore
Stephen Hadler, Atlanta, GA, USA Richard L. Guerrant, Charlottesville, Virginia, USA
Nina Marano, Atlanta, Georgia, USA Scott Halstead, Arlington, Virginia, USA
Martin I. Meltzer, Atlanta, Georgia, USA David L. Heymann, London, UK
David Morens, Bethesda, Maryland, USA Charles King, Cleveland, Ohio, USA
J. Glenn Morris, Gainesville, Florida, USA
Keith Klugman, Atlanta, Georgia, USA
Patrice Nordmann, Paris, France
Takeshi Kurata, Tokyo, Japan
Tanja Popovic, Atlanta, Georgia, USA
S.K. Lam, Kuala Lumpur, Malaysia
Didier Raoult, Marseille, France
Stuart Levy, Boston, Massachusetts, USA
Pierre Rollin, Atlanta, Georgia, USA
John S. MacKenzie, Perth, Australia
Ronald M. Rosenberg, Fort Collins, Colorado, USA
Marian McDonald, Atlanta, Georgia, USA
Dixie E. Snider, Atlanta, Georgia, USA
John E. McGowan, Jr., Atlanta, Georgia, USA
Frank Sorvillo, Los Angeles, California, USA
Tom Marrie, Halifax, Nova Scotia, Canada
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Philip P. Mortimer, London, United Kingdom
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J. Todd Weber, Stockholm, Sweden Fred A. Murphy, Galveston, Texas, USA
Henrik C. Wegener, Copenhagen, Denmark Barbara E. Murray, Houston, Texas, USA
P. Keith Murray, Geelong, Australia
Founding Editor
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Emerging Infectious Diseases • www.cdc.gov/eid • Vol. 17, No. 5, May 2011
May 2011
On the Cover Molecular Epidemiology of
Stelios Faitakis (b. 1976) Oropouche Virus, Brazil .............................800
Kakerlaken sind die Zukunft (2009) H. Baldez Vasconcelos et al.
Mixed media on canvas (260 cm × 190 cm) Genotypes II–IV derived from genotype I, which was
Courtesy of Th e Breeder responsible for virus dispersal.
[email protected]
Athens
Severe Imported
Photo: Vivianna Athanasopoulou
Plasmodium falciparum Malaria,
France, 1996–2003 ......................................807
About the Cover p. 958 E. Seringe et al.
Travelers should be urged to take antimalarial
Perspective chemoprophylaxsis.
Vector-borne Infections .............................769
Plasmodium knowlesi Malaria in
R. Rosenberg and C.B. Beard
Children, Malaysia ......................................814
These infections are prominent contributors to B.E. Barber et al.
emerging diseases.
This parasite is the most common cause of malaria
among children in a deforested rural area.
Synopses
Travel-related Dengue Virus
Intravenous Artesunate for
Infection, the Netherlands,
Severe Malaria in Travelers, Europe .........771
2006–2007....................................................821
T. Zoller et al.
G.G.G. Baaten et al.
Patients should be monitored for hemolysis for up to 6
weeks after resolution of parasitemia. p. 852 Short-term travelers to dengue-endemic areas are at
substantial risk.
Experimental Infection of
Lessons Learned about
Amblyomma aureolatum Ticks
Pneumonic Plague Diagnosis,
with Rickettsia rickettsii.............................829
Democratic Republic of the Congo ...........778
M.B. Labruna et al.
E. Bertherat et al.
Transmission through amplifi er hosts may support
Effi cient frontline management and diagnostic
maintenance in disease-endemic areas.
strategy are essential.
p. 859
Genotypic Profi le of
Research
Streptococcus suis Serotype 2
Evolution of New Genotype of and Clinical Features of Infection
West Nile Virus in North America ..............785 in Humans, Thailand ..................................835
A.R. McMullen et al. A. Kerdsin et al.
Understanding this genotype is essential for Sequence types 1 and 104 can cause sepsis, but only
identifying effects on human health. type 1 commonly causes meningitis.
Transstadial Transmission of Babesiosis in Lower Hudson Valley,
Francisella tularensis holarctica in New York, USA ............................................843
Mosquitoes, Sweden ..................................794 J.T. Joseph et al.
J.O. Lundström et al. Cases were associated with tick bites and receipt of
Disease may originate from infection at the larval blood products.
stage.
Emerging Infectious Diseases • www.cdc.gov/eid • Vol. 17, No. 5, May 2011
Experimental Oral Transmission
of Atypical Scrapie to Sheep .....................848
M.M. Simmons et al. May 2011
Peripheral tissue infectivity is undetectable by current
914 Dengue Incidence among Hospitalized
surveillance screening methods.
Patients, United States
J.A. Streit et al.
Historical Review
917 Detection and Characterization of Human
Evidence of Tungiasis in Hepatitis E Virus Strains, Czech Republic
P. Vasickova et al.
Pre-Hispanic America ................................855
V. Maco et al. 920 Genetic Characterization of West Nile Virus
Lineage 2, Greece, 2010
Artifacts and writings indicate the disease was
A. Papa et al.
endemic among Peruvians for at least 14 centuries.
Another Dimension
Dispatches
923 The Crab Hole Mosquito Blues
863 Human Intraocular Filariasis Caused by
K.M. Johnson et al.
Dirofi laria sp. Nematode, Brazil
D. Otranto et al.
Letters
867 Human Intraocular Filariasis Caused by
p. 868
Pelecitus sp. Nematode, Brazil
928 Plasmodium vivax in Bred Cynomolgus
O. Bain et al.
Monkeys, China
870 Linguatula serrata Tongue Worm in Human
929 Imported Dengue Virus Serotype 3, Yemen
Eye, Austria
to Italy, 2010
M. Koehsler et al.
931 Strongyloidiasis in Man 75 Years after
873 Rickettsia rickettsii Transmission by a
Initial Exposure
Lone Star Tick, North Carolina
E.B. Breitschwerdt et al. 932 Anaplasma phagocytophilum Infection in
Ticks, China–Russia Border
876 Tick-Borne Encephalitis Virus, Kyrgyzstan
B.J. Briggs et al. 934 Japanese Encephalitis, Tibet, China
880 Probable Non–Vector-borne Transmission 936 Babesia sp. EU1 Infection in a Forest
of Zika Virus, Colorado Reindeer, the Netherlands
B.D. Foy et al. 938 Dengue Virus Serotype 4, Roraima State,
p. 881
883 Tick-Borne Relapsing Fever Borreliosis, Brazil
Rural Senegal 940 Novel Phlebovirus in Febrile Child, Greece
P. Parola et al.
941 Toscana Virus in Blood Donors, France,
886 Novel Bluetongue Virus Serotype, Kuwait 2007
S. Maan et al.
943 Quinine-Resistant Malaria in Traveler
890 Spotted Fever Group Rickettsiae in Ticks, Returning from French Guiana, 2010
Germany
945 Kyasanur Forest Disease Virus Alkhurma
C. Silaghi et al.
Subtype in Ticks, Saudi Arabia
893 Bartonella spp. in Feral Pigs, Southeastern
947 West Nile Virus Infection, Assam, India
United States
A.W. Beard et al. 948 Rare Rotavirus Strains in Children with
Severe Diarrhea, Malaysia
896 Rickettsia parkeri in Gulf Coast Ticks,
Southeastern Virginia 950 Avian Malaria Deaths in Parrots, Europe
C.L. Wright et al. 952 Fatal Human Case of Western Equine
899 Test for Lyme Disease and Anaplasmosis Encephalitis, Uruguay
in a Serosurvey of Dogs, Maine 954 Widespread Availability of Artemisinin
P.W. Rand et al. Monotherapy, United States
903 Phylogenetic Analysis of West Nile Virus 955 Yersinia pestis DNA Sequences in Late
Isolates, Italy, 2008–2009 Medieval Skeletal Finds, Bavaria (response)
G. Rossini et al.
907 Genomic Characterization of Nipah Virus, About the Cover
West Bengal, India
V.A. Arankalle et al. 958 And therefore I have sailed the seas and
910 Chikungunya Virus, Southeastern France come / To the holy city of Byzantium
M. Grandadam et al. Etymologia
799 Francisella tularensis
Emerging Infectious Diseases • www.cdc.gov/eid • Vol. 17, No. 5, May 2011
Vector-borne Infections
Ronald Rosenberg and C. Ben Beard
Infections with vector-borne pathogens are a major A corollary of this ability to bridge environments occurs
source of emerging diseases. The ability of vectors to bridge when animals or humans move the pathogen from one
spatial and ecologic gaps between animals and humans vector-capable region to another. The introduction of West
increases opportunities for emergence. Small adaptations Nile virus into the United States in 1999 was a dramatic
of a pathogen to a vector can have profound effects on the
example, as was the recent introduction of Usutu virus to
rate of transmission to humans.
Europe from Africa in migrating birds (2). The potential for
vector-borne zoonotic transmission to adapt to vector-borne
This issue of Emerging Infectious Diseases highlights human-to-human transmission is exemplifi ed historically
the role of arthropod vectors in the origin and by dengue virus and Plasmodium spp., and more recently
dissemination of emerging pathogens. As Woolhouse and by Zika virus (3) and probably P. knowlesi (4).
Gaunt have pointed out (1), a substantial proportion of Third, the complexity of vector transmission offers the
human pathogens are zoonotic and vector-borne, and they pathogen increased opportunities to evolve. In almost no
infect a substantial proportion of the world’s population. instances is the arthropod simply a vessel for transmission.
Vector-borne pathogens also are prominent contributors Usually, the pathogen must move from the gut to the feeding
to emerging disease. There are 3 principal reasons for this apparatus to be transmitted. Mechanisms range from the
infl uence. relatively simple, as with the plague bacillus, Yersinia
First, most major classes of pathogens have evolved pestis, to the elaborately intricate, as with parasites in the
agents that are capable of being transmitted by blood-feeding genera Plasmodium and Leishmania. In these examples,
arthropods: viruses (e.g., yellow fever virus, Rift Valley the pathogen replicates in some fashion, which makes
fever virus), rickettsiae (Rickettsia rickettsii, R. typhi), it dependent on an invertebrate host physiology much
bacteria (Borrelia burgdorferi, Francisella tularensis), different from what it will encounter in its various vertebrate
protozoa (genera Plasmodium and Leishmania), and hosts. As a consequence, epidemic emergence can result
helminths (Onchocerca volvulus, Wuchereria bancrofti). from enhanced transmission independent of increased
Fungi seem to be the only category not represented. pathogenicity to humans. This is especially true of the
Second, vectors bridge barriers that would prevent arthropod-borne viruses (arboviruses) that infect humans,
transmission by direct contact among humans and especially all of which are RNA viruses and have high potential
between animals and humans. These barriers are not only mutability. A notable recent example is the chikungunya
spatial but behavioral and ecological. Transmission of virus epidemic that swept through the Indian Ocean region
yellow fever virus between arboreal monkeys and humans beginning in 2006 and which is believed to have infected
by mosquitoes is the classic example, but there are many >2 million persons. A single-nucleotide polymorphism
others; transmission of B. burgdorferi, the agent of Lyme (SNP) in the virus genome accelerated its replication in
disease, between evasive forest rodents and humans by the relatively common mosquito Aedes albopictus, usually
ticks is just as exemplary. In such cases, direct contact a poorer host than Ae. aegypti mosquitoes (5). There is
between feral host and human would rarely take place. also evidence that an SNP enabled Venezuelan equine
encephalitis virus to jump vectors, sparking the 1993
Author affi liation: Centers for Disease Control and Prevention, Fort epidemic in Mexico (6), and it might have been an SNP
Collins, Colorado, USA in West Nile virus that increased its virulence to birds and
infl uenced the shape of the epidemic in the United States
DOI: 10.3201/eid1705.110310
Emerging Infectious Diseases • www.cdc.gov/eid • Vol. 17, No. 5, May 2011 769
PERSPECTIVE
(7). In none of these examples was increased pathogenicity Dr Beard is chief of the Bacterial Diseases Branch, Division
to humans an apparent seminal factor in the epidemics. of Vector-Borne Diseases, Centers for Disease Control and
Complexity of epidemiology and adaptive plasticity Prevention, Fort Collins, Colorado. His research interests are
of pathogen and arthropod make the vector-borne diseases Lyme disease, plague, tularemia, and the infl uence of climate on
especially diffi cult to control, much less to eradicate. disease ecology.
Vaccines are unavailable for all but a few diseases;
and even when they are available, as for yellow fever,
References
prevention can be diffi cult to achieve. The yellow fever
epidemic that began in Uganda at the end of 2010 was the 1. Woolhouse M, Gaunt E. Ecological origins of novel pathogens. Crit
fi rst in that country in 20 years. Tools for treatment are Rev Microbiol. 2007;33:231–42. doi:10.1080/10408410701647560
nearly as scarce. Falling behind in the race to keep up with 2. Weissenböck H, Kolodziejek J, Url A, Lussy H, Rebel-Bauder B,
Nowotny N. Emergence of Usutu virus, an African mosquito-borne
developing resistance of P. falciparum to artemisinins is a
fl avivirus of the Japanese encephalitis virus group, central Europe.
specter that haunts malariologists, and treatment for visceral Emerg Infect Dis. 2002;8:652–6.
leishmaniasis remains too expensive and complicated to be 3. Duffy MR, Chen TH, Hancock WT, Powers AM, Kool JL, Lanciotti
widely practiced where it is most needed. RS, et al. Zika virus outbreak on Yap Island, Federated States of
Micronesia. N Engl J Med. 2009;360:2536–43. doi:10.1056/NEJ-
The constant development of pesticide resistance
Moa0805715
is even more worrisome than drug resistance because a 4. Cox-Singh J, Davis TM, Lee KS, Shamsul SS, Matusop A, Ratnam
pesticide can often be used to suppress vectors of many S, et al. Plasmodium knowlesi malaria in humans is widely distribut-
different pathogens. Even when pesticides are effi cacious, ed and potentially life threatening. Clin Infect Dis. 2008;46:165–71.
doi:10.1086/524888
their effectiveness is often compromised by human
5. de Lamballerie X, Leroy E, Charrel RN, Ttsetsarkin K, Higgs S,
behavior and vector biology, as is often seen in campaigns Gould EA. Chikungunya virus adapts to tiger mosquito via evolu-
against dengue. Changes in climate, land use, and transport tionary convergence: a sign of things to come? Virol J. 2008;5:33.
will affect rates of pathogen emergence in ways we poorly doi:10.1186/1743-422X-5-33
6. Brault AC. Changing patterns of West Nile virus transmission: al-
understand. Fortunately, there is a growing appreciation by
tered vector competence and host susceptibility. Vet Res. 2009;40:43.
scientists and by funding agencies (8) that characterizing doi:10.1051/vetres/2009026
factors that infl uence pathogen and disease emergence are 7. Brault AC, Powers AM, Ortiz D, Estrada-Franco JG, Navarro-Lopez
worthy goals for investigation, especially in those tropical R, Weaver SC. Venezuelan equine encephalitis emergence: enhanced
vector infection from a single amino acid substitution in the enve-
environments where rapid change is most likely to incubate
lope glycoprotein. Proc Natl Acad Sci U S A. 2004;101:11344–9.
new pathogens. doi:10.1073/pnas.0402905101
8. Katz RL, López LM, Annelli JF, Arthur RR, Carroll D, Chapman
LW, et al. U.S. Government engagement in support of global dis-
Dr Rosenberg is associate director for science in the Division ease surveillance. BMC Public Health. 2010;10(Suppl 1):S13.
of Vector-Borne Diseases, Centers for Disease Control and doi:10.1186/1471-2458-10-S1-S13
Prevention, Fort Collins, Colorado.
Address for correspondence: Ronald Rosenberg, Division of Vector-
Borne Diseases, Centers for Disease Control and Prevention, Fort Collins,
CO 80521, USA; email: [email protected]
770 Emerging Infectious Diseases • www.cdc.gov/eid • Vol. 17, No. 5, May 2011
Intravenous Artesunate for Severe
Malaria in Travelers, Europe
Thomas Zoller, Thomas Junghanss, Annette Kapaun, Ida Gjørup, Joachim Richter,
Mats Hugo-Persson, Kristine Mørch, Behruz Foroutan, Norbert Suttorp, Salih Yürek, and Holger Flick
Multicenter trials in Southeast Asia have shown not registered for this indication, and the only commercially
better survival rates among patients with severe malaria, available product is not manufactured according to good
particularly those with high parasitemia levels, treated with manufacturing practice. Quinine has several adverse
intravenous (IV) artesunate than among those treated with effects (e.g., cardiotoxicity, hypotension, hypoglycemia,
quinine. In Europe, quinine is still the primary treatment for
and cinchonism), has a narrow therapeutic range, and must
severe malaria. We conducted a retrospective analysis for
be administered 3×/d by rate-controlled infusion (3,4). In
25 travelers with severe malaria who returned from malaria-
experienced hands, adverse effects can be minimized, but
endemic regions and were treated at 7 centers in Europe.
a major proportion of patients still experience moderate-to-
All patients survived. Treatment with IV artesunate rapidly
severe side effects.
reduced parasitemia levels. In 6 patients at 5 treatment
centers, a self-limiting episode of unexplained hemolysis The effi cacy and safety of artemisinins and their
occurred after reduction of parasitemia levels. Five patients derivatives in oral, rectal, and intramuscular dosage forms
required a blood transfusion. Patients with posttreatment have been widely studied (5–11). When administered
hemolysis had received higher doses of IV artesunate than intravenously, these drugs are useful for treatment of
patients without hemolysis. IV artesunate was an effective severe malaria because of their rapid parasite clearance,
alternative to quinine for treatment of malaria patients in apparent absence of clinically relevant side effects, and
Europe. Patients should be monitored for signs of hemolysis,
simplicity of administration (e.g., by bolus injection). Since
especially after parasitologic cure.
1992, several studies in Asia (5,6,8–10) and a recent study
of children in Africa (11) have shown better, or at least
Infection with Plasmodium falciparum malaria remains equivalent, survival rates for patients with severe malaria
a major risk for European travelers returning from treated with artesunate than for those treated with quinine.
malaria-endemic areas. World Health Organization (WHO) This fi nding applies particularly to patients with severe
guidelines recommend intravenous (IV) artesunate as fi rst- malaria and hyperparasitemia (10).
line therapy for severe malaria (1). However, quinine is still Systematic data are not available for safety and effi cacy
the primary treatment for severe non–multidrug-resistant P. of IV artesunate for treatment of severe P. falciparum
falciparum malaria in Europe (2) because IV artesunate is malaria outside disease-endemic areas. In the United
States, use of IV artesunate is monitored by the Centers
Author affi liations: Charité Universitätsmedizin, Berlin, Germany for Disease Control and Prevention (Atlanta, GA, USA)
(T. Zoller, N. Suttorp, S. Yürek, H. Flick); Universitätsklinikum under an investigational new drug protocol (12). In Europe,
Heidelberg, Heidelberg, Germany (T. Junghanss, A. Kapaun); artesunate manufactured by the Guilin Pharmaceutical
The State University Hospital, Copenhagen, Denmark (I. Gjørup); Factory No. 2 (Shanghai, People’s Republic of China),
Universitätsklinikum Düsseldorf, Düsseldorf, Germany (J. Richter); which was used in all major trials of artesunate in
Hospital of Helsingborg, Helsingborg, Sweden (M. Hugo-Persson); Southeast Aia and Africa (9–11), is used. TropNetEurop
Haukeland University Hospital, Bergen, Norway (K. Mørch); and (www.tropnet.net/about/contents/about_tropnet.html), a
Armed Forces Hospital, Berlin (B. Foroutan) European surveillance network for tropical diseases, has
been collecting data on artesunate use since 2005 (13).
DOI: 10.3201/eid1705.101229
Emerging Infectious Diseases • www.cdc.gov/eid • Vol. 17, No. 5, May 2011 771
SYNOPSIS
Severe malaria is rare outside disease-endemic regions. Serum or plasma samples were available for testing from
Thus, the limited numbers of patients in industrialized the time of artesunate treatment (patient 7), from the period
countries makes it diffi cult to conduct trials with suffi cient of posttreatment hemolysis (patients 6, 7, and 9), or from
statistical power to reproduce the survival benefi t for IV the convalescent phase (7 and 16 months; patients 6 and 9).
artesunate observed in Southeast Asia (10). Nonetheless, Serologic testing was conducted by using standard
these patients may benefi t from the lower cardiotoxicity of gel card techniques (DiaMed, Cressier sur Morat,
artesunate than that of quinine and, because of more rapid Switzerland). Artesunate was diluted in 0.9% NaCl at
parasite clearance, from reduction of time spent in intensive a concentration of 1.0 mg/mL. Ex vivo antigens (urine)
care units, in-hospital treatment, decreased use of exchange were obtained from 2 patients receiving IV artesunate to
transfusion, and secondary complications. This fi nding is detect reactivity to artesunate metabolites. Serum samples
relevant for increased numbers of older persons who travel were tested for reactivity with artesunate solution or urine
abroad to malaria-endemic areas, despite relevant cardiac metabolites by using the indirect antiglobulin test and a
or other medical conditions associated with a several-fold drug-dependent–antibody test with the gel card technique
increased risk for complications and death caused by severe (17–19). Cumulative doses and treatment duration (days)
malaria (14). We report data for 25 patients with severe were compared between adult patients with and without
malaria who were treated with IV artesunate in 7 treatment signs of posttreatment hemolysis by using the Mann-
centers in areas to which malaria was not endemic. Whitney U test.
Study Characteristics Patient Characteristics
During January 2006–June 2010, we conducted a One child and 24 adults (mean ± SD age 44.1 ± 16.1
retrospective analysis of 25 patients from 7 treatment years; 14 male and 11 female patients) treated with IV
centers in Europe who were admitted to a hospital for artesunate for severe malaria during January 2006–June
P. falciparum malaria, which was classifi ed as severe 2010 were included in the study (online Appendix Table,
according to WHO criteria (15,16), and who received www.cdc.gov/EID/content/17/5/771-appT.htm). Eighteen
IV artesunate as the main antiparasitic therapy. The patients were travelers from Europe to malaria-endemic
hyperparasitemia level for patients in a region to which areas, and 7 patients were immigrants who returned from
malaria was not endemic was >5% (15). Patients treated at malaria-endemic countries after having visited friends
7 centers, 4 in Germany (2 in Berlin, 1 in Heidelberg, and and relatives. With the exception of patient 13, who was a
1 in Düsseldorf), and 1 each in Denmark (Copenhagen), short-term visitor to Germany from Chad, all other patients
Sweden (Helsingborg), and Norway (Bergen), participated who visited friends and relatives had permanently left their
in the study. The Berlin (Charité University Medical home countries for >5 years before becoming infected.
Center), Heidelberg, Düsseldorf, Bergen, and Copenhagen Hyperparasitemia (range 5%–51% parasitized
centers are tertiary care academic teaching hospitals; the erythrocytes) in 20 (80%) patients and cerebral malaria in
center in Helsingborg and the Armed Forces Hospital in 8 (32%) patients were the most common severe malaria-
Berlin are secondary care regional referral hospitals. The defi ning criteria observed. Seven patients (28%) had renal
second Berlin center and the Bergen center provided data failure, and 2 (8%) required hemodialysis. Respiratory
only for patients with posttreatment hemolysis; other failure caused by severe shock developed in 1 patient; this
centers provided data for all patients treated with IV patient required therapy with vasopressors and mechanical
artesunate. Anonymous treatment data were reported on ventilation for 6 days. Repeated chest radiographs did not
case-reporting forms for severe malaria (TropNetEurop). show pulmonary edema or pneumonia. Shock developed in
The study was reviewed and approved by the ethics 4 patients (patients 3, 4, 13, and 25); these patients required
committee of the Charité Hospital in Berlin. Artesunate vasopressor therapy.
was obtained from the Guilin Pharmaceutical Factory No.
2 and stored at room temperature in all centers, according Antimalarial Therapy
to the manufacturer’s instructions. Details on dosage, treatment duration, and concomitant
therapy are shown in the online Appendix Table. All but
Posttreatment Hemolysis 3 patients received IV artesunate as fi rst-line therapy.
Serum and plasma of 3 patients with unusual Therapy for patient 1 was changed to IV artesunate after
posttreatment hemolysis in Berlin and Heidelberg (patients complications (bradycardia) caused by the fi rst dose of
6, 7, and 9) were tested for drug-induced autoantibodies, quinine. Therapy for patients 10 and 13 was 1 dose of
which react in the absence of the drug or its metabolites with artemether/lumefantrin or IV quinine, respectively, before
erythrocytes, and for drug-dependent antibodies, which transfer to a treatment center to avoid a delay in treatment
react only in the presence of the drug or its metabolites. initiation.
772 Emerging Infectious Diseases • www.cdc.gov/eid • Vol. 17, No. 5, May 2011
Artesunate for Malaria in Travelers, Europe
Patients 3–8, 15, 16, 18, and 19 received the dosing Patient 11, who was treated in Helsingborg, received
regimen for artesunate initially recommended by WHO (16): IV artesunate for 7 days. On day 15, laboratory parameters
after an initial dose of 2.4 mg/kg, therapy was continued were indicative of secondary hemolysis. The reticulocyte
with 1.2 mg/kg every 12 hours and then 1.2 mg/kg every count was within reference limits initially and was near the
24 hours. Patients 9–13 and 19–25 received artesunate, 2.4 upper reference value during secondary hemolysis. Patient
mg/kg/dose. Therapy for all but 6 patients was changed 23, who was treated in Bergen, had a similar episode of
to oral artemether/lumefantrine or atovaquone/proguanil recurring and intense hemolysis after 4 days of treatment
after rapid clinical improvement and ability to swallow on with IV artesunate, beginning on day 15, which required
days 3–4 of treatment. Different batches of artesunate were readmission to the center and blood transfusion. Results of
used in the Berlin and Heidelberg treatment centers. Batch the Coombs test were repeatedly negative, G6PD defi ciency
information was not available from centers in Helsingborg, was ruled out, and reticulocytes values were 2.3× the upper
Copenhagen, and Bergen and the second center in Berlin. reference value.
Six patients in whom posttreatment hemolysis occurred Other patients showed patterns of persisting hemolysis.
were treated for 4 years. Patient 7 was discharged from the hospital in Berlin 14
days after the fi rst dose of IV artesunate (treatment duration
Effi cacy 7 days) with a hemoglobin level of 8.2 g/dL, which was
In all patients with hyperparasitemia, parasite load was stable for 10 days. On day 32, this patient was readmitted
reduced ≈1 log after 24–36 hours. All but 1 patient were to the University Hospital in Heidelberg with a hemoglobin
10
free of parasites 36 hours–134 hours after the initial dose of level of 6.1 g/dL and signs of hemolysis (LDH 805 U/L).
artesunate. Parasite clearance was delayed (158 hours) in 1 The patient received 2 units of packed erythrocytes and
patient (patient 7). In this patient, infection with HIV was was discharged 3 days later in good clinical condition.
diagnosed (CD4 count 382 cells/μL). Mean ± SD parasite Hemolytic activity decreased over the next 10 days.
clearance time was 81.2 ± 35.4 hours for all patients treated
with IV artesunate as fi rst-line drug, who had an initial
parasitemia levels >1% and for whom data were available
(patients 2–12, 14, and 20–24), and 78.9 ± 29.5 hours for
patients not infected with HIV.
Tolerability
IV artesunate was generally well tolerated; there was
no evidence of hemodynamic, cardiac, or allergic adverse
reactions. Six patients from 5 treatment centers showed
unusual hemolytic anemia, which recurred after clearance
of parasites and was diagnosed 14–31 days after the fi rst
dose of IV artesunate (patients 6, 11, and 23) or persisted
after the end of treatment until the end of the fourth week
after the fi rst dose of IV artesunate (patients 7, 9, and 25).
Laboratory fi ndings and typical patterns of hemolysis are
shown in the Table and the Figure.
Patient 6 was treated with artesunate and doxycycline;
she had malaria-related hemolysis and an initial hemoglobin
level of 11.3 g/dL. This patient was discharged in good
clinical condition on day 10 (hemoglobin level 7.7 g/
dL, which had been stable for the past 4 days) and had a
decreased lactate dehydrogenase (LDH) level (317 U/L).
On day 15, this patient was readmitted because of severe
anemia caused by recurring hemolysis (hemoglobin 5.7 g/
dL, LDH 1,437 U/L). Glucose-6-phosphate dehydrogenase
(G6PD) defi ciency and antibody-mediated hemolysis were Figure. Typical patterns of hemolysis in 2 travelers with severe
excluded as causes (negative result for Coombs test). The malaria treated with intravenous artesunate, Europe, January
2006–June 2010. A) Patient 6 with recurring hemolysis. B) Patient 9
reticulocyte count was high (10.2%). After receiving 2
with persisting hemolysis. LDH, lactate dehydrogenase. * indicates
units of packed erythrocytes, the hemoglobin level of this
blood transfusion. Gaps between symbols indicate periods when
patient remained stable. samples were not obtained.
Emerging Infectious Diseases • www.cdc.gov/eid • Vol. 17, No. 5, May 2011 773
SYNOPSIS
Table. Laboratory test results for 6 patients with posttreatment hemolysis who had been treated with intravenous artesunate for severe
malaria, Europe, January 2006–June 2010*
Levels Levels Levels at
at first at end of diagnosis of
Initial examination treatment Day of hemolysis
Patient parasitemia Hb, LDH, Treatment Parasite Hb, LDH, diagnosis of Hb, LDH,
no. level, % g/dL U/L duration, d clearance, d g/dL U/L hemolysis† g/dL U/L Other test results
6 30 11.3 765 7 4 7.7 317 15 5.7 1,437 Coombs negative,
reticulocytes 10.2%,
G6PD deficiency ruled
out
7 20 13.2 1,359 7 7 8.2 NA 32‡ 6.1 805 None
9 30 13.4 1,033 4 5 7.6 650 19‡ 5.3 672 None
11 4 13.4 904 7 2 9.8 311 15 7.8 660 Standard reticulocyte
count
23 9 15.5 490 4 2 11.1 571 15 5.7 1,489 Reticulocytes >2(cid:117) upper
reference value,
haptoglobin <0.1g/L,
Coombs negative
25 10 14.2 570 3 NA 7.8 454 16‡ 5.8 444 Reticulocytes 3(cid:117) upper
reference value,
haptoglobin <0.08 g/L
(day 14), G6PD
deficiency ruled out
*Hb, hemoglobin; LDH, lactate dehydrogenase; G6PD, gluose-6-phosphate dehydrogenase; NA, not available.
†After first dose of artesunate.
‡Patients had persistent hemolytic activity after the end of malaria treatment.
Patient 9 was treated in Heidelberg and received who had prolonged posttreatment hemolysis. Presence of
IV artesunate for 3 days, followed by oral artemether/ drug-dependent antibodies in serum or plasma of patients
lumefantrine for another 3 days, and was parasite free was investigated by using as test substrates an artesunate
after 96 hours. Intense and persisting hemolysis resulted solution and urine (artesunate metabolites) of patients
in a hemoglobin level of 5.6 g/dL on day 8 (LDH 633 receiving artesunate therapy; antibodies were not detected.
U/L). This patient received 2 units of packed erythrocytes,
and hemoglobin level increased to 7.9 g/dL. On day 19, Clinical Outcome
hemoglobin level decreased to 5.3 g/dL because of persistent All patients survived and all complications related
hemolysis (LDH 672 U/L); he was again given transfusions to severe malaria resolved at time of hospital discharge
of packed erythrocytes. Hemolytic activity decreased after for all but 1 patient. Patient 2 had a more severe clinical
day 22, and LDH levels returned to reference values on course (respiratory and renal failure), and required further
day 46. Patient 25 showed a similar pattern of persistent rehabilitation and physiotherapy because of critical illness
hemolysis, which gradually decreased after day 21, after (neuropathy) that developed while he received prolonged
malaria therapy. intensive care and immobilization. Unusual hemolysis in 6
In multiple repeat thin blood fi lms used to determine patients resolved spontaneously during weeks 3–6 after the
parasitemia levels, no abnormalities in erythrocyte fi rst dose of IV artesunate.
morphology were observed. To identify causes of
posttreatment hemolysis, cumulative doses of IV Conclusions
artesunate and treatment durations were compared among Data from large multicenter trials on use of parenteral
all adult patients. Patients with posttreatment hemolysis artesunate are limited to malaria-endemic regions,
had received higher doses of IV artesunate than patients particularly Southeast Asia. We report data on use of
without observed hemolysis (mean ± SD cumulative dose parenteral artesunate for patients with severe malaria
12.8 ± 3.3 mg/kg vs. 7.6 ± 2.9 mg/kg; p = 0.006 in all adult outside malaria-endemic areas, who were treated according
patients) and were treated for longer periods (mean ± SD to intensive care standards in Europe. In these patients,
5.8 ± 1.6 days vs. 3.6 ± 1.7 days; p = 0.038). treatment with IV artesunate was effective and induced
rapid parasite clearance. The only other report of a series
Immunohematologic Tests of patients treated with IV artesunate for severe malaria
Free indirect antibodies against globulin were not outside malaria-endemic areas was from Norway; outcomes
detected in serum or plasma from 3 patients (patients 6, for 9 patients were good, and adverse reactions related to
7, and 9) at the Berlin and Heidelberg treatment centers IV artesunate were not observed (21).
774 Emerging Infectious Diseases • www.cdc.gov/eid • Vol. 17, No. 5, May 2011