MAJOR ARTICLE

Resurgence of Blackwater Fever in Long-Term European Expatriates in Africa: Report of 21 Cases and Review
Fabrice Bruneel,1 Bertrand Gachot,2 Michel Wolff,1 Bernard Re gnier,1 Martin Danis,3 Franc ois Vachon,1 a and the Corresponding Group
1

Clinique de Re animation des Maladies Infectieuses et Tropicales, Groupe Hospitalier BichatClaude Bernard, 2Ho pital de lInstitut Pasteur, 3 and Service de Parasitologie, Ho pital de la Pitie Salpe trie ` re, Paris

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Blackwater fever (BWF) is a severe clinical syndrome, characterized by intravascular hemolysis, hemoglobinuria, and acute renal failure that is classically seen in European expatriates chronically exposed to Plasmodium falciparum and irregularly taking quinine. BWF virtually disappeared after 1950, when chloroquine superseded quinine. We report 21 cases of BWF seen in France from 1990 through 1999 in European expatriates who lived in sub-Saharan Africa. All patients had macroscopic hemoglobinuria, jaundice, and anemia. Acute renal failure occurred in 15 patients (71%), 7 of whom required dialysis. The presumed triggers of BWF were halofantrine (38%), quinine (24%), meoquine (24%), and halofantrine or quinine (14%). Glucose-6-phosphate dehydrogenase (G6PD) activity was normal in the 14 patients who underwent this test. Low-level P. falciparum parasitemia was found in 8 patients. All 21 patients survived. Our data and 13 cases reported in the literature suggest a resurgence of classic BWF among Europeans living in Africa and a need to discuss attendant therapeutic implications. Acute hemoglobinuria with passage of black urine associated with recent or concurrent Plasmodium falciparum infection is a well-known clinical syndrome, rst described a century ago [1]. Acute hemoglobinuria indicates massive intravascular hemolysis and can be caused by a variety of factors in patients with P. falciparum infestation, including classic blackwater fever (BWF) as dened by the World Health Organization (WHO) on the basis of classic descriptions [2], overwhelming malaria with a high level of parasitemia [2, 3], glucose-6-phosphate dehydrogenase (G6PD) deciency induced hemolysis [4, 5], and other causes of hemolysis [4]. Unfortunately, the term BWF is commonly used to designate all of these conditions, a practice that leads to confusion and complicates analysis of the relevant literature. The introduction in 1950 of chloroquine for use instead of quinine was associated with a dramatic drop in the incidence of BWF [1, 6]. In recent years, the development of resistance to chloroquine has led to the reintroduction of quinine and the introduction of meoquine and halofantrine and has been associated with a reappearance of BWF [7, 8]. The objective of this article is to raise awareness among clinicians of the resurgence of BWF among long-term European expatriates in Africa, to discuss the potential pathogenic role of various aminoalcohol drugs, and to discuss therapeutic implications.

Received 21 March 2000; revised 21 August 2000; electronically published 2 April 2001.
a

The Corresponding Group members are listed at the end of the text.

Reprints or correspondence: Professeur Franc ois Vachon, Clinique de Re animation des Maladies Infectieuses et Tropicales, Ho pital BichatClaude Bernard, 46 rue Henri Huchard, 75877 Paris Cedex 18, France (francois.vachon@ bch.ap-hop-paris.fr). Clinical Infectious Diseases 2001; 32:113340 2001 by the Infectious Diseases Society of America. All rights reserved. 1058-4838/2001/3208-0003$03.00

PATIENTS AND METHODS Denitions. We dened BWF on the basis of the 1990 WHO description: severe, acute intravascular hemolysis with hemoglobinuria and a dramatic fall in hemoglobin value, but scant or absent parasitemia, that
Resurgence of Blackwater Fever CID 2001:32 (15 April) 1133

occurred in a patient (a European expatriate) who had lived in an area of malarial endemicity for several years, during which amino-alcohol drugs (quinine, halofantrine, meoquine) were taken in an irregular fashion for prophylaxis and treatment [2]. Consequently, 2 cases of BWF in Africans were excluded. Tropical splenomegaly syndrome was dened as chronic splenomegaly with asthenia and mild anemia that occurs in a patient living in an area of high malarial endemicity, with at least 3 of the 4 following criteria: (1) massive splenomegaly, (2) high titers of malarial antibodies, (3) high titers of total serum IgM, and (4) a dramatic clinical response to antimalarial agents [9, 10]. Patients. Twenty-one patients were included in our study from 1990 through 1999. Fourteen were recruited by 2 units (the BichatClaude Bernard and Pitie -Salpe trie ` re hospitals); 5 of these 14 cases have already been reported in letters [7, 8]. The remaining 7 cases were recruited by clinicians of the Corresponding Group, at 43 French hospital departments, who were asked to report any cases of BWF during the same period. Clinical data. Medical records were reviewed retrospectively for information on medical history, physical ndings, the course of the disease, its treatment, any complications, and the outcome. Laboratory investigations. Blood tests were done for all or most patients to determine the following: hemoglobin level; leukocyte and platelet counts; routine biochemistry values; and liver function (including bilirubin, haptoglobin, and lactate dehydrogenase levels). Thick and thin peripheral blood smears also were done. Data from the following tests were available for only some patients: direct antiglobulin; G6PD deciency; amino-alcohol-dependent antibodies to RBCs; and infectious disease detection. Antibodies to P. falciparum were sought with an indirect immunouorescent assay for the intra-erythrocytic form of P. falciparum (negative at 1:32 dilution). Treatment. Antimalarial agents, blood transfusions, and symptomatic treatments were administered at the discretion of the attending physicians. Usually, amino-alcohol drugs were rapidly withdrawn when it was suspected that they had triggered the BWF. Background epidemiological data. Epidemiological data on malaria cases seen during our study period in French nationals who had been expatriates in Africa for 6 consecutive months at the time malaria was diagnosed were obtained from the Centre National de Re fe rence pour les Maladies dImportation (CNRMI) [11, 12]. Statistics. Data are reported as means SE or as medians (ranges). Categorical variables were compared with the Fishers exact test. Two-sided P values !.05 were considered signicant. Literature review. MEDLINE was searched for studies mentioning BWF and published from January 1989 through December 1999. Among the studies thus retrieved, we selected
1134 CID 2001:32 (15 April) Bruneel et al.

those reporting the classic form of BWF in white long-term expatriates.

RESULTS Epidemiology. The most relevant data are listed in table 1. All 21 patients were white long-term expatriates in Africa who either were sent to France for treatment of BWF or developed BWF shortly after coming to France. Only 5 (24%) were women. Duration of residence in Africa was 18.1 8.9 years (range, 437 years). The country of residence was the Central African Republic (8 patients), Ivory Coast (4), Cameroon (2), Guinea (2), or Gabon, Congo, Burkina, Benin, or Republic of Togo (1 patient each). Three patients (14%) had experienced 1 prior episode of BWF. All 21 patients had experienced several episodes of malaria. None used regular prophylactic medication. Seven patients (33%) had preexisting tropical splenomegaly. All 21 patients were treated with an amino-alcohol drug before the onset of BWF, for proven (n p 8) or suspected (n p 13) falciparum malaria. The median time from the last amino-alcohol dose to onset of BWF was 24 hours (range, 5120 ha). Background epidemiological data. During the study period, 17,248 malaria cases imported to France were reported to the CNRMI [11, 12]. Table 2 details the cases of falciparum malaria and BWF among French adult expatriates to Africa reported in France. To provide a more accurate picture of BWF in France during the study period, we added to our 21 cases 2 French cases that have been reported elsewhere [13, 14], yielding a total of 23 cases. No comparisons between the incidences of BWF and malaria in relation to quinine, halofantrine, and meoquine were signicant. Clinical features at admission. Sixteen patients required initial admission to an intensive care unit for a median period of 12 days (range, 463 days). The Simplied Acute Physiology Score II [15] for these 16 patients was 36.8 13.0. All 21 patients presented with macroscopic hemoglobinuria, fatigue, jaundice, and a characteristic slate-gray skin color. Moderate hypotension the required dopamine therapy occurred in 2 patients. Thirteen patients (62%) had nausea, often with vomiting, and 5 (24%) had diarrhea. Splenomegaly was present in 14 patients (67%), hepatomegaly in 11 (52%), and hepatosplenomegaly in 9 (43%). Ten patients (48%) had evidence of minor neurological dysfunction. Laboratory features. The plasma haptoglobin level (available for 15 patients) was 15.0 10.0 mg/dL (normal range, 97.0258.0 mg/dL), the leukocyte count (17 patients) was 7.2 3.8 103 cells/mm3, and the conjugated and unconjugated bilirubin levels (13 patients) were 6.3 12.6 mg/dL and 4.6 2.8 mg/dL, respectively. Peripheral blood lms were done for all patients: 4 patients

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Table 1.

Relevant data that concerns 21 cases of blackwater fever, at presentation in France.

Prior antimalarial Presumed treatment trigger Q, C, SP Q M H Q, C H Q, H, SP H Q, M, SP ,H Q, H, C Q Q ND H Q H, C Q, H Q, H Q Q, H, A Q NA M M M H H H or Q H H H or Q Q Q Q M H H H H H or Q M Q Q NA Direct Plasma creatinine G6PD antiglobulin level,e mg/dL deciency test result 4.5 3.4 ND 3.8 7.1 7.5 6.2 8.8 10.6 11.9 1.3 2.8 1.2 1.3 2.7 9.0 3.2 3.4 2.7 ND 1.5 4.9 3.3 No No No No ND ND No No ND No No No ND ND No No No No ND ND No NA Neg ND ND Neg Pos (Cpt/IgG) Pos (Cpt/IgG) Pos (Cpt/IgG) Pos (Cpt) Pos (Cpt) ND Pos (Cpt) Pos ND Pos (Cpt) ND Pos Neg ND Pos (Cpt/IgG) Pos (Cpt/IgG) Neg NA

Case no., reference 1 [8] 2 [8] 3 [8] 4 [7] 5 [7] 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21

Age, y 52 67 28 48 18 48 39 37 42 56 37 55 48 35 60 54 57 60 51 67 78

Year 1989 1990 1990 1990 1990 1992 1992 1993 1993 1994 1995 1996 1996 1996 1997 1997 1997 1997 1997 1997 1999 NA

Temp., C 40.0 40.0 39.0 38.5 38.0 38.2 37.8 39.3 37.5 39.0 37.0 39.7 39.5 39.1 36.0 37.0 37.0 39.5 38.4 39.0 37.3 38.4 1.1

Hemoglobin level,a g/dL 6.0 5.6 6.9 4.5 3.4 5.8 4.5 5.5 5.5 6.3 9.0 5.0 6.2 5.7 3.0 4.5 6.1 4.8 3.0 3.0 7.1 5.3 1.5

Platelet count,b Total bilirubin 103 cells/mm3 level,c mg/dL 37 116 ND 33 37 59 55 18 137 37 117 ND 47 106 103 46 ND 214 77 129 57 80 51 9.5 4.0 ND ND 11.2 5.5 4.0 4.9 6.3 3.9 3.9 33.6 4.2 7.3 4.1 10.3 0.5 3.7 42.6 11.3 5.9 9.3 10.7

LDH,d U/L 4805 ND ND ND 4523 7840 8540 ND 7870 1486 3800 5325 2579 2081 ND ND 660 6081 7000 ND 3336 4712 2531

Mean SE 49.4 14.1

NOTE. A, artemisinin; C, chloroquine; Cpt, complement; G6PD, glucose-6-phosphate dehydrogenase; H, halofantrine; LDH, lactate dehydrogenase; M, meoquine; NA, not applicable; ND, not determined; Neg, negative; Pos, positive; Q, quinine; SP , sulfadoxine-pyrimethamine; temp., temperature.
a b c d e

Normal range, 1318 g/dL. Normal range, 150400 103 cells/mm3. Normal range, 0.11.4 mg/dL. Normal range, !470 U/L. Normal range, 0.61.2 mg/dL.

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Table 2. Falciparum malaria (FM) and blackwater fever in French adult expatriates to Africa during 19901999 in France.
Treatment used or presumed triggera Quinine Halofantrine Meoquine Chloroquine Total
a b c d

Declared cases of FM, no. (%) 297 (33) 478 (53) 99 (11) 27 (3) 901

Blackwater fever Collected cases, no. (%) Denite, 6 (26); including 3 possible cases, 9 (39)c Denite, 9 (39); including 3 c possible cases, 12 (52) Denite, 5 (22) 0 23
b

Incidence per 100 cases of FM, % 2.0; 3.0d 1.9; 2.5 5.1 0 2.6
d

Indicates treatment used (FM column) and presumed trigger (BWF column). Present study and [13, 14]. In 3 cases the presumed trigger of BWF was quinine or halofantrine. The rst percentage includes only denite cases, the second, both denite and possible cases.

had thin smears done in Africa and the remainder had both thin and thick smears done in France. In 8 cases, blood lms done before the administration of amino-alcohol drug therapy was initiated revealed a few (1%) erythrocytes parasitized with P. falciparum trophozoites. In the 13 remaining cases, results of blood lms were negative, but all but 1 were done after the beginning of amino-alcohol therapy. P. falciparum antibodies were sought in 12 patients, which included 6 with tropical splenomegaly. In all patients, the results of antibody titers were strongly positive (median, 11,392; range, 409648,600). Three patients had high titers of total serum IgM, and all of them had tropical splenomegaly. Seven patients were tested for amino-alcoholdependent antibodies to erythrocytes. The test showed halofantrinedependent antibodies in only 1 patient. A number of tests were done to eliminate differential diagnoses. Test results for antibodies to HIV (n p 8), leptospirosis (n p 7), dengue virus (n p 2), hepatitis A (n p 2), cytomegalovirus (n p 2), Mycoplasma species (n p 2), and hantavirus (n p 1) were all negative. Of the 8 patients tested for hepatitis C antibodies, 2 had positive results. Test results for hepatitis B surface antigen were positive for 1 of 8 patients. Two of 4 patients had antibodies to Epstein-Barr virus, with a prole that suggested reactivation. False-positive results were noted for 4 patients (for VDRL and IgM antibody to cardiolipin, leptospirosis, and cytomegalovirus). Treatment and outcome. During hospitalization the hemoglobin level dropped to a mean minimum value of 4.6 1.2 g/dL. Transfusions of packed RBCs were needed by 18 of the 21 patients; the median number of units given was 9.5 (range, 237 units). Of the 15 patients with acute renal failure, 6 required hemodialysis and 1 needed peritoneal dialysis. The urinalysis suggested acute tubular necrosis, but full recovery occurred in every case. Two patients required mechanical ven-

tilation. Nosocomial infections occurred in 5 patients. Four patients developed a lower urinary tract infection (due to Enterococcus faecalis [n p 2], Escherichia coli [n p 1], or Pseudomonas aeruginosa [n p 1]). The remaining patient had 3 infections: Klebsiella pneumoniae bacteremia, Candida albicans infection of a peritoneal dialysis catheter, and E. coli thrombophlebitis. Acute cholecystitis (acalculous in 3 cases) occurred in 4 patients, of whom 3 required surgery. Seven patients received quinine after the onset of BWF. In 5 of these 7 cases, the presumed trigger of the BWF was halofantrine, and in 2 of these 5, quinine treatment worsened the symptoms. In the 2 remaining cases, the trigger was quinine itself; the condition of 1 of these patients worsened after further quinine therapy. Three patients received steroid therapy. All the patients with tropical splenomegaly received long-term treatment with chloroquine after the BWF episode. All 21 patients survived. The median duration of hospitalization was 20 days (range, 593 days). DISCUSSION We report 21 cases of BWF in European long-term expatriates in Africa whose clinical presentations closely matched the classic descriptions of BWF published in the early 20th century [1, 2]. We found 13 similar cases in the literature that occurred during the same period; 6 of the patients were Italian, 5 were Belgian, and 2 were French (table 3) [13, 14, 1618]. These 34 cases reported during a 10-year period indicate a resurgence of BWF in European expatriates, since a review of the literature from the 30 previous years revealed only 5 comparable cases [19, 20]. Further evidence of a resurgence of BWF among European expatriates is that the current ratio of BWF cases over falciparum malaria cases (table 2) is comparable to that seen in similar populations during the rst half of the 20th century

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1136 CID 2001:32 (15 April) Bruneel et al.

Table 3.

Relevant data in 13 cases of blackwater fever identied by a literature review.

Direct G6PD antiglobulin deciency test HD Outcome ND No No ND No No ND No ND No ND ND ND Pos Neg Neg Neg Pos (Cpt) Pos (IgG) Pos (IgG) Pos Neg Pos ND ND ND No Survived No Survived No Survived Yes Survived Yes Survived No Survived No Survived Yes Died No Survived No Survived No Survived No Survived Yes Survived

Age in y, Reference sex [13] [16] [17] [17] [17] [17] [17] [14] [18] [18] [18] [18] [18] 41, M 57, F 64, F 54, F 53, F 67, M 39, F 44, M 49, F 59, F 44, M 74, M 44, M

Country of residence Mali Cameroon Mali Congo Congo Congo Guinea

Presumed trigger H Mef or H Q Q or H Q or Mef Q Q or H

Clinical feature(s) MH, nausea, jaundice, fatigue MH, jaundice, fatigue, fever MH, nausea, jaundice, fever MH, nausea, jaundice, fever MH MH, nausea, fever MH, jaundice, fever MH, jaundice, fever MH, jaundice, fever MH, jaundice MH MH, fever

Hemoglobin level,a g/dL 5.0 4.9 4.9

Total bilirubin Plasma creatinine level,b mg/dL level,c mg/dL ND 17.5 3.5 11.4 68.5 1.7 ND 40.0 4.1 ND ND ND ND ND ND 1.8 8.9 4.4 2.5 Normal Anuria ND ND ND Transient anuria 1.9 (anuria)

Parasitemia (level at admission) Neg Pos (0.5%) Neg Neg Neg Neg Neg Neg Neg, then Pos (!0.1%) Pos (!0.1%) Neg ND Neg

MH, jaundice, fatigue 5 5.2 6.3 3.5 3.9 7.5, then 4.1 4.8 7.5 ND 5.4

Central Africa Q Central Africa Q then H Ivory Coast Congo Angola Mef Q Q

Central Africa Q or H

NOTE. Cpt, complement; F , female; G6PD, glucose-6-phosphate dehydrogenase; H, halofantrine; HD, hemodialysis; M, male; Mef, meoquine; MH, macroscopic hemoglobinuria; ND, not determined; Neg, negative; Pos, positive; Q, quinine.
a b c

Normal range, 1318 g/dL. Normal range, 0.11.4 mg/dL. Normal range, 0.61.2 mg/dL.

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[1]. For instance, the incidence of BWF per 100 cases of malaria was about 1% (0.7%1.2%) among West African Command personnel during 19411943 [6]. During our study period, the incidence of BWF per 100 cases of malaria was about 2.6% (table 2). However, this gure may be an overestimation, since it has been suggested that 50% of malaria cases go unreported [12], whereas high reporting rates are the rule for severe diseases such as classic BWF. These data suggest that the incidence of BWF in French expatriates and probably in European expatriates is comparable to that noted before 1945. We feel that this resurgence can be ascribed to the reintroduction of quinine (starting in 1986) and to the introduction of the related aminoalcohol drugs meoquine (1987) and halofantrine (1988) in response to the development of chloroquine resistance in P. falciparum in Central and West Africa. Moreover, the dramatic decrease in the incidence of BWF when chloroquine superseded quinine in 1950 [1, 8, 9] and the reemergence of BWF following the reintroduction of quinine and introduction of meoquine and halofantrine both strongly suggest that amino-alcohol drugs play a role in the etiology of BWF. Quinine was the only presumed trigger in 29.5% of cases (10 of 34). In 26.5% (9 of 34) another amino-alcohol drug was taken with quinine, and the trigger may have been either or both. Halofantrine and meoquine were the only presumed triggers in 26.5% (9) of 34 cases and 17.5% (6) of 34 cases, respectively, a nding that strongly indicates that both of these agents should be considered capable of triggering BWF. This effect is consistent with their chemical similarity with quinine [17]. Of great interest are the cases of 5 patients (2 in our study) who each had 2 episodes of BWF, triggered by different drugs (halofantrine-quinine, n p 1 ; quinine-meoquine, n p 1 ; or quinine-halofantrine, n p 3 ) [17, 18]. These 5 cases support the theory that there is cross-reactivity between the 3 aminoalcohol drugs. Moreover, the clinical and laboratory features of BWF were the same no matter which drug was the trigger; this suggests that the 3 drugs precipitate BWF by similar mechanisms. Taken in aggregate, these data suggest that these 3 related amino-alcohol drugs are major contributors to classic BWF, although a study with a control group would be needed to conrm this possibility. BWF is one of the complications that results from chronic exposure to P. falciparum. It is important to recognize it because its treatment is highly specic. The rst clue is a history of a prolonged stay in an area where malaria is endemic. Second, the presentation of BWF is strikingly different from that of severe imported falciparum malaria, in which macroscopic hemoglobinuria is exceedingly rare [21], coma is common, anemia is initially mild, and the platelet count is very low [2, 3]. Nevertheless, this rare presentation must be distinguished
1138 CID 2001:32 (15 April) Bruneel et al.

early from BWF since severe malaria necessitates immediate intravenous injection of a loading dose of quinine. Therefore, in a long-term European expatriate chronically exposed to P. falciparum, the presence of macroscopic hemoglobinuria should suggest BWF as the most likely diagnosis and should prompt questions about recent use of amino-alcohol drug therapy. In 11 patients tropical splenomegaly was probably present before the BWF episode. Although tropical splenomegaly differs from BWF, it is associated with many factors that increase the risk of BWF, a fact that explains the high proportion of patients with tropical splenomegaly in our study. In our European patients, the mechanism of hemolysis remains unclear, since G6PD deciency was not found in any of the 20 tested patients. This is not surprising, since the incidence of G6PD deciency is extremely low among Europeans. G6PD deciency may substantially contribute to hemolysis in cases of BWF that occur in non-European populations, however [4, 5]. In our study 14 patients were not tested for G6PD deciency, but a high frequency of G6PD deciency among them is highly unlikely. The direct antiglobulin test was positive at admission for 17 of the 25 tested patients. However, we believe it is unlikely that this fully explained the massive intravascular hemolysis. In our study, 6 of the 11 patients with positive test results had preexisting tropical splenomegaly, which is a well-known possible cause of a positive direct antiglobulin test. For the remaining 5 patients, direct antiglobulin test results were only slightly positive and became negative within 36 days, results that suggest an autoimmune mechanism was not the sole cause of the massive hemolysis. A transiently positive result of a direct antiglobulin test in the context of BWF probably reects nonspecic binding of Igs associated with malaria-induced polyclonal hypergammaglobulinemia [17]. Another hypothetical factor is drug-induced hemolysis [22]. Quinine can induce immune thrombocytopenia and hemolysis with the presence of multiple quinine-dependent antibodies [23]. In our study, only 1 patient was positive for halofantrine-induced antibodies. Infectious diseases that have been reported to contribute to anemia and jaundice include septicemia [5], leptospirosis [4, 5], and hantavirus infection [4]. Of our 21 patients, 3 had viral hepatitis and 2 had reactivated Epstein-Barr virus infection, which cannot explain the occurrence of BWF. The exact pathogenesis of classic BWF remains unclear, and it is still difcult to determine the respective contributions to BWF of malariogenic conditions, amino-alcohol treatment, and human behaviors [1]. The mechanism of the massive hemolytic response in the absence of high parasitemia may involve immune lysis of RBCs sensitized by quinine, halofantrine, or meoquine in patients chronically exposed to P. falciparum [7]. Although it is good clinical practice to seek evidence of G6PD

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deciency and amino-alcoholdependent antibodies, these 2 causes seem to be exceedingly rare in white Europeans. Despite the initial severity of the disease, there were no deaths among our 21 patients, and only one of the other 13 patients died. Another recent study of patients with BWF that was less severe than in our patients also showed that the prognosis was favorable: the mortality rate was 2% [5]. In contrast, the mortality rate associated with BWF was generally in the 25%30% range in the early 20th century [1, 2]. This dramatic improvement in prognosis may be explained by advances in medical care, most notably the availability of initial intensive care and of hemodialysis. There is no consensus with regard to antimalarial drug therapy during a BWF episode. The presumed trigger should be withdrawn immediately. Nevertheless, antimalarial treatment is required for patients with parasitemia and/or preexisting tropical splenomegaly. Because there is probably cross-reactivity between quinine, halofantrine, and meoquine, appropriate antimalarial agents may include sulfadoxine-pyrimethamine, artemisinin derivatives, and atovaquone-proguanil [24, 25]. In a recent study in Thailand, BWF did not occur during treatment with artemisinin derivatives alone [26]. After a BWF episode, it is reasonable to refrain from the administration of quinine, meoquine, or halofantrine because of the risk of recurrence. Consequently, other molecules should be used for prophylaxis and curative treatment. More generally, the risk of BWF should be taken into account when quinine, halofantrine, or meoquine is given as presumptive treatment for malaria in European long-term expatriates to Africa. In conclusion, our study and literature review clearly suggest a resurgence of classic BWF in European long-term expatriates in Africa. Not only quinine but also halofantrine and meoquine can induce BWF. Moreover, the reports of recurrences, sometimes triggered by different amino-alcohol drugs, suggest cross-reactivity between these related drugs. Therefore, the current resurgence of BWF may suggest the need for caution in administering these 3 amino-alcohol drugs to patients who are at risk for BWF.

F. Bricaire and M. M. Thiebault (Ho pital de la Pitie Salpe trie ` re, Paris); and M. Wysocki (Institut Mutualiste Montsouris, Paris).

Acknowledgments

We thank Antoinette Wolfe and Annabel Vicente for providing technical support, Jean-Christophe Lucet for statistical assistance, and Fabrice Legros for supplying data from the CNRMI clinical database.

References
1. Bruce-Chwatt LJ. Quinine and the mystery of blackwater fever. Acta Leidensia 1987; 55:18196. 2. Severe and complicated malaria. World Health Organization, Division of Control of Tropical Diseases. Trans R Soc Trop Med Hyg 1990; 84(Suppl 2):165. 3. Mate-Kole MO, Yeboah ED, Affram RK, et al. Blackwater fever and acute renal failure in expatriates in Africa. Renal Failure 1996; 18:52531. 4. Delacollette C, Taelman H, Wery M. An etiologic study of hemoglobinuria and blackwater fever in the Kivu mountains, Zaire. Ann Soc Belg Med Trop 1995; 75:5163. 5. Chau TTH, Day NPJ, Chuong LV, et al. Blackwater fever in Southern Vietnam: a prospective descriptive study of 50 cases. Clin Infect Dis 1996; 23:127481. 6. Findlay GM. Blackwater fever in West Africa, 194145. I. Blackwater fever in European military personnel. Ann Trop Med Parasitol 1949; 43:14054. 7. Vachon F, Fajac I, Gachot B, et al. Halofantrine and acute intravascular hemolysis. Lancet 1992; 340:90910. 8. Danis M, Nozais JP, Paris L, et al. Fie ` vre bilieuse he moglobinurique apre ` s prise de me oquine: 3 observations. Presse Med 1993; 22:80. 9. White NJ. Malaria. In: Cook CG, ed. Mansons tropical diseases. 20th ed. London: WB Saunders, 1996:1087164. 10. Zingman BS, Viner BL. Splenic complications in malaria: case report and review. Clin Infect Dis 1993; 16:22332. 11. Goyet F, Legros F, Belkaid M, et al. Note sur le paludisme dimportation en France de 1993 a ` 1995. Bull Soc Pathol Exot 1997; 90:2579. 12. Legros F, Danis M, and Eurosurveillance editorial board. Surveillance du paludisme dans les pays de lunion Europe enne. Eurosurveillance 1998; 3:457. 13. Mojon M, Wallon M, Gravey A, Peaud PY, Sartre J, Peyron F. Intravascular haemolysis following halofantrine intake. Trans R Soc Trop Med Hyg 1994; 88:91. 14. Lesieur O, Duddefant P, Courtiade B, Haglund P. Blackwater fever: a fatal case. Intensive Care Med 1997; 23:1188. 15. Le Gall JR, Lemeshow S, Saulnier F. A new simplied acute physiology score (SAPS II) based on a European/North American multicenter study. JAMA 1993; 270:295763. 16. Orlando G, Isabella L, Atzori C, Cargnel A. Blackwater fever after halofantrine. Lancet 1996; 347:14089. 17. Van den Ende J, Coppens G, Verstraeten T, et al. Recurrence of blackwater fever: triggering of relapses by different antimalarials. Trop Med Int Health 1998; 3:6329. 18. Bisof Z, Marocco S, Monteiro G, Marsiaj M. Acute intravascular haemolysis (blackwater fever) after antimalarial treatment. Trop Med Int Health 1999; 4:723. 19. Dukes DC, Sealey BJ, Forbes JI. Oliguric renal failure in blackwater fever. Am J Med 1968; 45:899903. 20. Baumelou A, Salmon O, Dhainaut JF, et al. Formes graves du paludisme dimportation a propos de trois acce ` s pernicieux et dune e ` vre bilieuse he moglobinurique. Sem Hop Paris 1979; 55:17058. 21. Hocqueloux L, Bruneel F, Chevret S, et al. Prognostic factors of severe

Downloaded from http://cid.oxfordjournals.org/ by guest on April 29, 2013

CORRESPONDING GROUP M. Arsac (Centre Hospitalier Re gional dOrle ans); L. Brinquin (Ho pital dInstruction des Arme es Val de Gra ce, Paris); V. Caudwell (Ho pital Broussais, Paris); J. P. Coulaud, J. Le Bras, and O. Bouchaud (Ho pital BichatClaude Bernard, Paris); J. Delmont (Ho pital Fe lix Houphouet-Boigny, Marseille); C. Gabinski (Ho pital Saint-Andre , Bordeaux); F. Janbon, O. Jonquet, and J. J. Be raud (Centre Hospitalo Universitaire de Montpellier); M. F. Mamzer-Bruneel (Ho pital Necker-Enfants Malades, Paris); J. D. Tempe (Ho pital Hautepierre, Strasbourg, France);

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imported malaria in adults [abstract 1853]. In: Program and abstracts of the 39th Interscience Conference on Antimicrobial Agents and Chemotherapy (San Francisco). Washington, DC: American Society for Microbiology, 1999:730. 22. Stein CM, Germany FM. Drug-induced haemolysis masquerading as blackwater fever. Cent Afr J Med 1987; 33:224. 23. Gottschall JL, Neahring B, McFarland JG, Wu GG, Weitekamp LA, Aster RH. Quinine-induced immune thrombocytopenia with hemolytic uremic syndrome: clinical and serological ndings in nine patients and review of literature. Am J Hematol 1994; 47:2839.

24. White N. The treatment of malaria. N Engl J Med 1996; 335:8006. 25. Looareesuwan S, Wilairatana P, Charlermarut K, Rattanapong Y, Caneld CJ, Hutchinson DBA. Efcacy and safety of atovaquone/proguanil compared with meoquine for treatment of acute Plasmodium falciparum malaria in Thailand. Am J Trop Med Hyg 1999; 60:52632. 26. Price R, Van Vugt M, Phaipun L, et al. Adverse effects in patients with acute falciparum malaria treated with artemisinin derivatives. Am J Trop Med Hyg 1999; 60:54755.

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