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Resurgence of Blackwater Fever CID 2001:32 (15 April) 1133

M A J O R A R T I C L E

Resurgence of Blackwater Fever in Long-TermEuropean Expatriates in Africa: Report of 21Cases and Review

Fabrice Bruneel,1 Bertrand Gachot,2 Michel Wolff,1 Bernard Regnier,1 Martin Danis,3 Francois Vachon,1

and the Corresponding Groupa

1Clinique de Reanimation des Maladies Infectieuses et Tropicales, Groupe Hospitalier BichatClaude Bernard, 2Hopital de lInstitut Pasteur,

and 3Service de Parasitologie, Hopital de la Pitie Salpetriere, Paris

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 fal-

ciparum 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 BWF virtually disappeared after 1950, when chloroquine superseded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%), mefloquine (24%), and halofantrine or quinine (14%). Glucose-6-phosphatedehydrogenase

(G6PD) activity was normal in the 14 patients who underwent this test. Low-level P. falciparumparasitemia 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 as-

sociated with recent or concurrent Plasmodium falcipa-rum infection is a well-known clinical syndrome, first

described a century ago [1]. Acute hemoglobinuria in-

dicates massive intravascular hemolysis and can be

caused by a variety of factors in patients with P. falci-

parum infestation, including classic blackwater fever

(BWF) as defined by the World Health Organization

(WHO) on the basis of classic descriptions [2], over-

whelming malaria with a high level of parasitemia [2, 3],

glucose-6-phosphate dehydrogenase (G6PD) deficiency

induced hemolysis [4, 5], and other causes of hemolysis

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 Francois Vachon, Clinique de Re-

animation des Maladies Infectieuses et Tropicales, Hopital 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

[4]. Unfortunately, the term BWF is commonly used

to designate all of these conditions, a practice that leadsto confusion and complicates analysis of the relevant

literature.

The introduction in 1950 of chloroquine for use in-

stead of quinine was associated with a dramatic drop in

the incidence of BWF [1, 6]. In recent years, the devel-

opment of resistance to chloroquine has led to the rein-

troduction of quinine and the introduction of meflo-

quine 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 expatriatesin Africa,

to discuss the potential pathogenic role of variousamino-alcohol drugs, and to discuss therapeutic implications.

PATIENTS AND METHODS

Definitions. We defined BWF on the basis of the

1990 WHO description: severe, acute intravascular he-

molysis with hemoglobinuria and a dramatic fall in

hemoglobin value, but scant or absent parasitemia, that

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1134 CID 2001:32 (15 April) Bruneel et al.

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, mefloquine) were

taken in an irregular fashion for prophylaxis and treatment [2].

Consequently, 2 cases of BWF in Africans were excluded.

Tropical splenomegaly syndrome was defined as chronic sple-

nomegaly with asthenia and mild anemia that occurs in a pa-

tient living in an area of high malarial endemicity, with at least3 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-Salpetriere hospitals); 5

of these 14 cases have already been reported in letters [7, 8].

The remaining 7 cases were recruited by clinicians of the Cor-

responding 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 retrospec-

tively for information on medical history, physical findings, 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 de-

hydrogenase levels). Thick and thin peripheral blood smears

also were done. Data from the following tests were available

for only some patients: direct antiglobulin; G6PD deficiency;

amino-alcohol-dependent antibodies to RBCs; and infectiousdisease detection. Antibodies to P. falciparum were sought with

an indirect immunofluorescent 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 CentreNationalde Reference pour les MaladiesdImportation(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 Pvalues !.05 were considered significant.

Literature review. MEDLINE was searched for studies

mentioning BWF and published from January 1989 through

December 1999. Among the studies thus retrieved, we selected

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 de-

veloped 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), Cam-

eroon (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 ex-

perienced several episodes of malaria. None used regular pro-

phylactic 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( ) or suspected ( ) falciparum malaria. The mediannp 8 np 13

time from the last amino-alcohol dose to onset of BWF was

24 hours (range, 5120 ha).

Background epidemiological data. During the study pe-

riod, 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 in-

cidences of BWF and malaria in relation to quinine, halofan-trine, and mefloquine were significant.

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 Simplified Acute Physiology

Score II [15] for these 16 patients was . All 2136.8 13.0

patients presented with macroscopic hemoglobinuria, fatigue,

jaundice, and a characteristic slate-gray skin color. Moderate

hypotension the required dopamine therapy occurred in 2 pa-

tients. Thirteen patients (62%) had nausea, often with vom-

iting, and 5 (24%) had diarrhea. Splenomegaly was present in

14 patients (67%), hepatomegaly in 11 (52%), and hepatos-

plenomegaly in 9 (43%). Ten patients (48%) had evidence of

minor neurological dysfunction.

Laboratory features. The plasma haptoglobin level (avail-

able for 15 patients) was mg/dL (normal range,15.0 10.0

97.0258.0 mg/dL), the leukocyte count (17 patients) was3 cells/mm3, and the conjugated and unconju-7.2 3.8 10

gated bilirubin levels (13 patients) were mg/dL and6.3 12.6

mg/dL, respectively.4.6 2.8

Peripheral blood films were done for all patients: 4 patients

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Table 2. Falciparum malaria (FM) and blackwater fever in French adult expatriatesto Africa during 19901999 in France.

Treatment

used or

presumed

triggera

Declared

cases of FM,

no. (%)

Blackwater fever

Collected cases,b

no. (%)

Incidence per 100

cases of FM, %

Quinine 297 ( 33) Definite, 6 (26) ; including 3

possible cases, 9 (39)c

2.0; 3.0d

Halofantrine 478 (53) Definite, 9 (39); including 3

possible cases, 12 (52)c

1.9; 2.5d

Mefloquine 99 (11) Definite, 5 (22) 5.1

Chloroquine 27 (3) 0 0

Total 901 23 2.6

aIndicates treatment used (FM column) and presumed trigger (BWF column).

bPresent study and [13, 14].

cIn 3 cases the presumed trigger of BWF was quinine or halofantrine.

dThe first percentage includes only definite cases, the second, both definite 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 films

done before the administration of amino-alcohol drug therapywas initiated revealed a few (1%) erythrocytes parasitized

with P. falciparum trophozoites. In the 13 remaining cases,

results of blood films 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 halofantrine-

dependent antibodies in only 1 patient.A number of tests were done to eliminate differential diag-

noses. Test results for antibodies to HIV ( ), leptospirosisnp 8

( ), dengue virus ( ), hepatitis A ( ), cytomega-np 7 np 2 np 2

lovirus ( ), Mycoplasma species ( ), and hantavirusnp 2 np 2

( ) were all negative. Of the 8 patients tested for hepatitisnp 1

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 profile 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 he-

moglobin level dropped to a mean minimum value of 4.6

g/dL. Transfusions of packed RBCs were needed by 18 of1.2

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 En-

terococcus faecalis [ ], Escherichia coli [ ], or Pseu-np

2 np

1domonas aeruginosa [ ]). The remaining patient had 3np 1

infections: Klebsiella pneumoniae bacteremia, Candida albicans

infection of a peritoneal dialysis catheter, and E. coli throm-

bophlebitis. 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 hal-

ofantrine, 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 treat-ment 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 expatri-

ates 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 Eu-

ropean 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 first half of the 20th century

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Table 3. Relevant data in 13 cases of blackwater fever identified by a literature review.

Reference

Age in y,

sex

Country

of residence

Presumed

trigger Clinical feature(s)

Hemoglobin

level,a

g/dL

Total bilirubin

level,b

mg/dL

Plasma creatinine

level,c

mg/dL

Parasitem

(level at adm

[13] 41, M Mali H MH, nausea,

jaundice, fatigue

5.0 ND ND Neg

[16] 57, F Cameroon Mef or H MH, jaundice,

fatigue, fever

4.9 17.5 ND Pos (0.5%)

[17] 64, F Mali Q MH, nausea,

jaundice, fever

4.9 3.5 1.8 Neg

[17] 54, F Congo Q or H MH, jaundice, fatigue 5 11.4 8.9 Neg

[17] 53, F Congo Q or Mef MH, nausea,

jaundice, fever

5.2 68.5 4.4 Neg

[17] 67, M Congo Q MH 6.3 1.7 2.5 Neg

[17] 39, F Guinea Q or H MH, nausea, fever 3.5 ND Normal Neg

[14] 44, M Central Africa Q MH, jaundice, fever 3.9 40.0 Anuria Neg

[18] 49, F Central Africa Q then H MH, jaundice, fever 7.5, then 4.1 4.1 ND Neg, then Pos

[18] 59, F Ivory Coast Mef MH, jaundice, fever 4.8 ND ND Pos (!0.1%)

[18] 44, M Congo Q MH, jaundice 7.5 ND ND Neg

[18] 74, M Central Africa Q or H MH ND ND Transient anuria ND

[18] 44, M Angola Q MH, fever 5.4 ND 1.9 (anuria) Neg

NOTE. Cpt, complement; F, female; G6PD, glucose-6-phosphate dehydrogenase; H, halofantrine; HD, hemodialysis; M, male; Mef, mefloquine; MH, macrosc

Pos, positive; Q, quinine.a

Normal range, 1318 g/dL.b

Normal range, 0.11.4 mg/dL.c

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 figure 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 diseasessuch as classic BWF. These data suggest that the incidence of

BWF in French expatriates and probably in European expatri-

ates 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 amino-

alcohol drugs mefloquine (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 mefloquine

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 mefloquine were the only presumed

triggers in 26.5% (9) of 34 cases and 17.5% (6) of 34 cases,

respectively, a finding 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, ; quinine-mefloquine, ; ornp 1 np 1

quinine-halofantrine, ) [17, 18]. These 5 cases supportnp 3

the theory that there is cross-reactivity between the 3 amino-

alcohol 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 mech-

anisms. 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 confirm this possibility.

BWF is one of the complications that results from chronicexposure to P. falciparum. It is important to recognize it because

its treatment is highly specific. The first 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

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 hemo-

globinuria 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 spleno-megaly 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 re-

mains unclear, since G6PD deficiency was not found in any of

the 20 tested patients. This is not surprising, since the incidence

of G6PD deficiency is extremely low among Europeans. G6PD

deficiency 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 deficiency,

but a high frequency of G6PD deficiency among them is highlyunlikely. 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 pos-

sible cause of a positive direct antiglobulin test. For the re-

maining 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 reflects nonspecific binding of Igs as-

sociated with malaria-induced polyclonal hypergammaglobuli-

nemia [17]. Another hypothetical factor is drug-induced he-

molysis [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 sep-

ticemia [5], leptospirosis [4, 5], and hantavirus infection [4]. Of

our 21 patients, 3 had viral hepatitis and 2 had reactivated Ep-

stein-Barr virus infection, which cannot explain the occurrence

of BWF.The exact pathogenesis of classic BWF remains unclear, and

it is still difficult 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 im-

mune lysis of RBCs sensitized by quinine, halofantrine, or me-

floquine in patients chronically exposed to P. falciparum [7].

Although it is good clinical practice to seek evidence of G6PD

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Resurgence of Blackwater Fever CID 2001:32 (15 April) 1139

deficiency 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 mor-

tality rate associated with BWF was generally in the 25%30%range in the early 20th century [1, 2]. This dramatic improve-

ment 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 ther-

apy during a BWF episode. The presumed trigger should be

withdrawn immediately. Nevertheless, antimalarial treatment is

required for patients with parasitemia and/or preexisting trop-

ical splenomegaly. Because there is probably cross-reactivity

between quinine, halofantrine, and mefloquine, 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,

mefloquine, 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 meflo-

quine is given as presumptive treatment for malaria in Euro-

pean long-term expatriates to Africa.

In conclusion, our study and literature review clearly suggest

a resurgence of classic BWF in European long-term expatriatesin Africa. Not only quinine but also halofantrine and meflo-

quine can induce BWF. Moreover, the reports of recurrences,

sometimes triggered by different amino-alcohol drugs, suggest

cross-reactivity between these related drugs. Therefore, the cur-

rent resurgence of BWF may suggest the need for caution in

administering these 3 amino-alcohol drugs to patients who are

at risk for BWF.

CORRESPONDING GROUP

M. Arsac (Centre Hospitalier Regional dOrleans); L. Brin-quin (Hopital dInstruction des Armees Val de Grace, Paris);

V. Caudwell (Hopital Broussais, Paris); J. P. Coulaud, J. Le Bras,

and O. Bouchaud (Hopital BichatClaude Bernard, Paris); J.

Delmont (Hopital Felix Houphouet-Boigny, Marseille); C. Ga-

binski (Hopital Saint-Andre, Bordeaux); F. Janbon, O. Jonquet,

and J. J. Beraud (Centre Hospitalo Universitaire de Montpel-

lier); M. F. Mamzer-Bruneel (Hopital Necker-Enfants Malades,

Paris); J. D. Tempe (Hopital Hautepierre, Strasbourg, France);

F. Bricaire and M. M. Thiebault (Hopital de la Pitie Salpetri ere,

Paris); and M. Wysocki (Institut Mutualiste Montsouris, Paris).

Acknowledgments

We thank Antoinette Wolfe and Annabel Vicente for pro-

viding technical support, Jean-Christophe Lucet for statistical

assistance, and Fabrice Legros for supplying data from theCNRMI clinical database.

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