Download Recurrence of blackwater fever: triggering of

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Tropical Medicine and International Health
volume 3 no 8 pp 632–639 august 1998
Recurrence of blackwater fever: triggering of relapses by
different antimalarials
Jef Van den Ende1,2, Guy Coppens3, Tom Verstraeten2, Tine Van Haegenborgh1, Katrien Depraetere2,
Alfons Van Gompel1, Erwin Van den Enden1, Jan Clerinx1, Robert Colebunders1,2, Willy E. Peetermans4 and
Wilfried Schroyens5
1
2
3
4
5
Institute of Tropical Medicine, Antwerp, Belgium
Department of Tropical Medicine, University Hospital Antwerp, Edegem, Belgium
Department of Clinical Microbiology, University Hospital, KU Leuven, Leuven, Belgium
Department of Internal Medicine, University Hospital, KU Leuven, Leuven, Belgium
Department of Haematology, University Hospital Antwerp, Edegem, Belgium
Summary
Five cases of blackwater fever (BWF) are described, all of whom had a history of recent quinine therapy. In
two cases a second haemolytic crisis was induced by halofantrine, in one case also a third. Increasing
frequency of this syndrome with its dramatic clinical presentation is to be expected as imported P.
falciparum infection, parasite resistance to chloroquine and the use of quinine and other related
antimalarials become more frequent.
keywords Malaria, blackwater fever, antimalarials
correspondence Dr J. Van den Ende, Institute of Tropical Medicine, Nationalestraat 155, 2000 Antwerp,
Belgium
Introduction
Numerous definitions of blackwater fever (BWF) and its cause
have been proposed and discussed by various authors (Findlay
1949; Ross 1962; Bruce-Chwatt & Bruce-Chwatt 1980; James
& Christophers 1992; Knochel & Moore 1993). There are
widespread descriptions of cases with fever, jaundice and
haemoglobinuria or passing black urine throughout the
history of medicine, dating as far back as to Hippocrates. Case
reporting started mainly around 1820; by 1850 cases were
reported from almost all continents. BWF has been associated
with P. falciparum infections since 1920 (Plehn 1920), and was
recorded even in induced Plasmodium infections for the
treatment of syphilitics (James & Christophers 1922). It is
likely that many cases of BWF in the past were due to other
diseases or conditions such as glucose-6-phosphate
dehydrogenase deficiency (G-6-PD) and leptospirosis.
The possible aetiological role of quinine was recognized in
1937 (Stephens 1937). Recently mefloquine and halofantrine
have been recognized as possible triggers, although classical
drug-induced haemolysis was not excluded in these cases
(Vachon et al. 1992; Danis et al. 1993; Mojon et al. 1994), and
the exact pathogenic role of the parasite and the antimalarial
drugs remains unclear.
632
A diagnosis of BWF should be considered in a person
living in a malarious area in the presence of
haemoglobinuria, a dramatic fall in haemoglobin and a thick
film showing no or very few parasites. In most cases it is
possible to trace a history of successive malaria attacks, often
inadequately treated (Maegraith 1948). Massive haemolysis
in one or several waves is common: several million red blood
cells (RBC) per mm3 can be destroyed in 24 h. The first urine
is often red, then dark brown. Blood urea nitrogen is elevated,
overt renal failure can be present. Sometimes a polyuric phase
follows recovery from anuria. Methaemalbuminaemia is
frequent and indicative of the severity of the haemolysis
(Tietz 1990; Dacie & Lewis 1991). Liver function
abnormalities appear early in many cases; acute epigastric
discomfort, nausea and vomiting can be present. Jaundice
affected 33 of 46 (71%) fatal cases of BWF in the British West
African Colonies in the period 1941–43 (Findlay 1949).
Vascular collapse is possible, followed by death of 20–30% of
the patients (Bruce-Chwatt & Bruce-Chwatt 1980).
Blackwater fever should be distinguished from very severe
malaria with hyperparasitaemia, where massive haemolysis
and liver failure contribute to jaundice. Other causes of
intravascular haemolysis must be excluded (Delacollette et al.
1995). These can be divided into red blood cell abnormalities
© 1998 Blackwell Science Ltd
Tropical Medicine and International Health
J. Van den Ende et al.
volume 3 no 8 pp 632–639 august 1998
Blackwater fever and antimalarials
and environmental conditions. Red blood cell abnormalities
can be either acquired (the Zieve syndrome, paroxysmal
nocturnal haemoglobinuria) or hereditary (spherocytosis, RBC
enzyme deficiencies such as glucose-6-phosphate
dehydrogenase deficiency (G6PD), haemoglobinopathies such
as sickle-cell disease). Environmental causes include
mechanical damage to RBC (march haemoglobinuria, sports
anaemia, macrovascular traumatic cardiac haemolytic
anaemia, microangiopathic haemolytic anaemia such as in
thrombotic thrombocytopenic purpura, the haemolytic
uraemic syndrome and diffuse intravascular coagulation),
immunohaemolytic haemolysis (allo-immune such as
transfusion reaction and erythroblastosis fetalis, auto-immune
with warm or cold autoantibodies or drug-induced haemolysis)
or directly toxic events (merely infectious such as severe
malaria, leptospirosis, Clostridium perfringens septicaemia,
but also snake and spider envenomation and traditional drugs).
The purpose of this paper is to illustrate the recurrence of
this severe syndrome and its possible association with
increased use of quinine and newer antimalarials. We also
want to warn clinicians of this complication of malaria,
especially as it is typically associated with a low or negative
parasite count.
Case reports
Case I
On October 2nd 1990, a 64-year-old Belgian Catholic nun
working in Mali presented with vomiting, fatigue and
anorexia. She denied any prophylactic medication for
malaria, but had been treating bouts of fever or fatigue with
small doses of quinine for two years, since she was aware of
parasite resistance to chloroquine. Initially she was given
quinine at a rate of 2 3 500 mg/day. On October 3rd she
reported red urine, fever up to 38.5 8C and an incipient
jaundice, followed on the next day by frank jaundice, fever,
nausea and dark urine. A thick film is reported to have shown
very rare trophozoites of P. malariae (diagnosis in Mali,
blood smear not available for confirmation). Laboratory
abnormalities included haemoglobin 6.2 g/dl, sedimentation
at a rate of 145 mm/h, urea 83.4 mg/dl (nl: 15–47), serum
creatinin 0.64 mg/dl (nl: 0.7–1.4), alkaline phosphatase 95 U/l
(nl: 21–92), conjugated bilirubin 3.19 mg/dl, non-conjugated
bilirubin 5.6 mg/dl, ALT (alanine amino transferase) 125
U/ml (nl , 40), AST (aspartate amino transferase) 145 U/l
(nl , 45) (Table 1). The patient was treated with intravenous
liquids, 4 3 500 mg quinine IM and 3 3 300 mg chloroquine
orally before repatriation and hospitalization on October 6th.
She was very pale and dyspnoeic at the slightest effort and
had a temperature of 38 8C. Auscultation revealed a few faint
crackles, the liver descended 2 cm below the costal margin,
and the spleen was not felt.
Key laboratory tests gave the following results:
haemoglobin 4.9 g/dl, lactate dehydrogenase 2040 IU/l, total
bilirubin 3.5 mg/dl, AST and ALT normal, haemoglobinuria
27 mg/l, urea 113 mg/dl and creatinin 1.8 mg/dl. A thick film
for malaria was negative, cultures of blood and urine
remained sterile. Further work-up for haemolysis revealed
Table 1 Most relevant data of the five cases, at presentation in Belgium
Case I
Case II
Case III
Case IV
Case V
Nationality
Sex
Age
Country of residence
Prophylaxis intake
Belgian
Female
64
Mali
none
Belgian
Female
54
Congo
none
Belgian
Male
67
Congo
none
Belgian
Female
39
West Africa
none
Presumed trigger
quinine
quinine
Thick film
Haemoglobin concentration (g/dl)
Total bilirubin (mg/dl)
Creatinin (mg/dl)
Anti P. falciparum antibodies (dilution)
Direct antiglobulin test, IgG
Direct antiglobulin test, complement
Cold agglutinins
Antimalarial treatment
Haemodialysis
negative
4.9
3.5
1.8
10 240
neg
neg
1/32, anti-I
halofantrine
no
quinine,
halofantrine*
negative
5
11.4
8.9
not reported
neg
neg
not reported
halofantrine
yes
Belgian
Female
53
Congo
chloroquine
proguanil
quinine
mefloquine?
negative
5.2
68.5
4.4
320
neg
pos
1/32, asp.
quinine, doxycycline
yes
quinine
halofantrine*
negative
3.5
not reported
normal
10 240*
pos
neg
1/8, anti-I *
halofantrine
no
negative
6.3
1.7
2.5
5120
pos
neg
1/16 anti-I
none
no
IgG, immunoglobulin G; asp, aspecific. *second episode.
© 1998 Blackwell Science Ltd
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J. Van den Ende et al. Blackwater fever and antimalarials
cold agglutinins anti-I 1/32 at 4 8C, slightly lowered osmotic
resistance as well as negative HAM test, polyvalent RAGT
test, sucroselyse and Donath-Landsteiner. Vitamin B 12, folic
acid and glucose-6-phosphate dehydrogenase were within the
normal range. Serology was negative for hepatitis B, surface
antigen, hepatitis A IgM antibodies and HIV antibodies.
Antibodies to Mycoplasma pneumoniae were 1/100 and to
P. falciparum 1/10240 were indirect immunofluorescence,
(IFAT). The chest X-ray was normal. Abdominal ultrasound
showed hepatosplenomegaly, thickening of the gallbladder
wall and a few small lymph nodes in the porta hepatis. An
echocardiographic examination detected some thickening of
the aortic valve without vegetations.
Four units of packed cells, halofantrine (3 3 500 mg/12 h,
once) and subcutaneous heparin to prevent thrombosis were
administered. One month later the patient was symptomfree, with haemoglobin at 12 mg/dl, while the sedimentation
rate was still 110 mm/h. Two months later the sedimentation
rate had dropped to 68 mm/h, and the IFAT to 1/5120. She
returned to Africa with 300 mg of chloroquine a week and
200 mg of proguanil a day as malaria prophylaxis.
Case II
A 54-year-old nurse who had been working for 14 years as a
laboratory assistant in Congo woke up with fever one night
(38.5 C) and took a tablet of quinine (500 mg), as she had
often done before. In the morning she took a second tablet
together with 200 mg of doxycycline. Except for some
nausea, she had no complaints, but noted that her urine was
very dark-coloured, ‘like coffee’. The fever dropped, but
because of nausea and fatigue she was treated with
intramuscular injections of quinine (3 3 600 mg/day). Only 4
injections were given. Jaundice appeared on day 3, hepatitis
was suspected and the patient was repatriated on day 7 after
onset of symptoms.
On admission we found severe anaemia and renal failure
(key laboratory values are shown in Table 2) and remarkable
jaundice. There was no splenomegaly or hepatomegaly, a
blood slide was negative, and other causes of severe
haemolysis were excluded: blood cultures remained sterile,
serology for other infectious causes was negative, no enzyme
deficiencies were found, Donath-Landsteiner and HAM test
were negative. The antiglobulin test (Coombs test) remained
negative throughout the hospital stay. No malaria treatment
was given. Haemodialysis was performed immediately after
admission and 4 days later. After a few days of polyuria
kidney function normalized gradually.
On the 17th day of admission the patient suddenly
developed fever. A blood slide showed P. falciparum
(0.0002% of parasitised RBC), halofantrine (1–3-2 tablets at
6-h intervals) was given and the fever disappeared on the
634
second day. One day later the urine was the colour of ‘red
port wine’ and haemoglobin suddenly dropped, both of
which were ascribed to the malaria recrudescence. After a
transfusion of four units of packed cells, Plasmodia parasites
were no longer seen on the blood smear, and renal function
and bilirubin level continued to normalize. With the second
cycle of halofantrine 7 days later (2 tablets three times daily
at 6-h intervals), the dark red urine reappeared, and an
association of BWF with halofantrine was suspected. Blood
smears remained negative, and the haemoglobinuria lasted
a few days. The haemoglobin decreased only slightly and
kidney function remained stable. The further clinical
evolution was uneventful.
Case III
A 53-year-old missionary nun had been working as a teacher
in Congo for 21 years. As prophylaxis for malaria she took
chloroquine 300 mg/week and proguanil 200 mg/day. Upon
her return to Belgium she developed fever with shivering,
interpreted as malaria. After 3 tablets of sulphadoxinpyrimethamin (Fansidar®) the fever dropped. Three days later
she took mefloquine (1.5 g once) against recurring fever.
Despite these antimalarials the fever did not disappear
completely.
Two weeks later a rectal antipyretic containing 50 mg of
quinine was administered and the patient was admitted to
the emergency ward because of persistent fever, somnolence,
vomiting, jaundice, abdominal discomfort and dark urine.
Physical examination revealed pale conjunctivae and
jaundice. Chest X-ray and abdominal ultrasound were
normal.
Key laboratory results and their evolution are summarized
Table 2 Evolution of salient laboratory results of case II
Thick film
Hb
Creatinine
Urea
LDH
AST
Tot. bil.
Dir. bil.
Urine
Treatment
22-Jan
9-Feb
11-Feb
16-Feb
00
05
08.9
231
948
030
011.4
06.26
normal
000.0002
010.6
002.3
090
211
017
003.3
001.78
normal
halofantrine
0006.2
0002.3
0137
2678
0117
0007.9
0002.27
port
009.3
001.8
070
783
007
002.4
001.2
normal
halofantrine
20-Feb
000
008.6
001.6
078
888
037
003.7
001.53
port
Hb; haemoglobin (g/dl). LDH; lactic dehydrogenase (IU/dl). Tot. bil.;
serum total bilirubin (mg/dl). Dir.bil.; serum direct bilirubin (mg/dl).
Thick film; parasites in thick film. AST; aspartate amino transferase
(IU/dl).
© 1998 Blackwell Science Ltd
Tropical Medicine and International Health
J. Van den Ende et al.
volume 3 no 8 pp 632–639 august 1998
Blackwater fever and antimalarials
Table 3 Evolution of salient laboratory results of case III
Parameter (normal values)
Week 1
Week 2
Week 3
Week 4
Week 5
Week 8
Week 11
Week 14
Haemoglobin g/dl (12–16)
Reticulocytosis % (0.2–2.0)
Haptoglobin g/l (1–3)
Free Hb in plasma mg/dl (0)
Bilirubin, direct mg/dl (0–0.5)
Bilirubin, total mg/dl (0.2–1.0)
Platelets, 109/l (1–3)
PT percentage (70–100)
d – dimer ng/ml (0–500)
Alk. phosph. IU/dl (40–120)
ASAT IU/dl (2–19)
ALAT IU/dl (5–24)
LDH IU/dl (80–240)
Creatinin mg/dl (0.55–1.1)
Cr. clearance ml/min (75–125)
.00005.2
.00000.1
.00000.1
.00870
.00036.6
.00068.5
.00015
.00023
.10000
.00106
.00243
.00072
.05350
.00004.4
0008.4
0000.2
0000.1
.008.7
.000.1
.001.3
.006
.016
.022
.014
.045
,500
.565
.022
.022
.428
.007.1
.007.2
.000.6
.002.8
0007.5
0008
005.6
004.2
.008.3
.005.1
.003.6
.000
0022.1
0030.2
0026
0028
0924
0071
0048
0043
1820
0009.6
0000
.011.2
.055
.056
,500
2068
.059
.083
.336
.007.1
0006.2
0344
0070
0002.57
0180
0068
1500
0031
0069
0266
0011.9
0017
1155
0006
0012
0252
0009.3
0029.8
000.75
001.44
151
800
049
068
543
003.1
019
.000.6
.217
.090
,500
.770
.025
.048
.161
.002.3
.027.3
LDH, lactic dehydrogenase; ASAT, aspartate amino transferase; ALAT, alanine amino transferase; Cr; clearance, clearance of serum creatinin.
in Table 3. Thick films for malaria remained negative. The
bloodsmear showed normal RBC morphology with
rouleaux-formation. Hepatitis B surface antigen and
antibodies against hepatitis A (IgM) and C, Epstein Barr
virus (IgM), cytomegalovirus (IgM) and Mycoplasma
pneumoniae were negative. Antibodies against P. falciparum
were present with a titre of 1/320 (indirect
immunofluorescence, IFAT). Repetitive blood cultures
remained sterile.
Blood grouping before transfusion was problematic: the
RBC were A-antigen positive while the serum test gave a
pattern of group ‘O’. The direct antiglobulin test was slightly
positive due to fixation of complement on the patient’s RBC,
without IgG. It became negative after one week.
Further investigation revealed the presence of a broad
thermal range IgM-panagglutinin with maximal activity at
room temperature and 30 8C in a titre of 1/32. It was
impossible to attribute a specificity to this cold agglutinin.
The Donath-Landsteiner test was negative and RBC-enzyme
deficiency excluded for G-6-PD, pyruvatekinase,
glutathionreductase and hexokinase. Negative osmotic
fragility test, sucrolyse test and Ham test excluded intrinsic
deformations of the RBC.
Initial treatment consisted of quinine, doxycycline,
cefotaxime, supportive intravenous fluid and oxygen. Within
the first week after admission the patient developed diffuse
intravascular coagulation and adult respiratory distress
syndrome (ARDS), requiring treatment with fresh frozen
plasma, anticoagulation therapy with low molecular weight
heparin and mechanical ventilation for 4 days. Acute renal
failure necessitated haemodialysis.
© 1998 Blackwell Science Ltd
The further course was complicated by catheter sepsis,
gastric ulcer bleeding, deep venous thrombosis of the left
femoral vein, nosocomial bilateral pneumonia and tubular
dysfunction with loss of salt and acidosis. After 13 weeks of
hospitalization, the patient left with persistent anaemia
(Hb 5 7 g/dl) and persistent renal dysfunction (serum
creatinin 5 2.5 mg/dl). The slow normalization of
haemoglobin (over 3 1/2 months) despite repeated blood
transfusions with packed cells was explained by blood loss
from gastric ulcers. The renal function improved gradually
over a period of about 10 months with the aid of a lowsodium diet, NaHCO3 and CaCO3 3 g/day, until stabilization
of the creatinin clearance at 50 ml/min.
Case IV
A 67-year-old priest who had been living in Congo for
40 years and presented with high fever and perspiration on
December 25th 1994 was given halofantrine 500 mg three
times at 6-h intervals. The fever disappeared initially but
returned two weeks later, and the patient was given another
1500 mg of halofantrine. Irregular bouts of fever persisted
and were treated with quinine 3 3 500 mg/day 5 weeks after
the first symptoms. On the next day, dark urine developed
and quinine was stopped immediately.
Eleven days later, the patient was hospitalized in Congo,
given 2 units of whole blood and chloramphenicol against
suspected concomitant typhoid fever. Eight weeks after the
first symptoms, the patient was transferred to Belgium. On
admission, he complained of pain in both the right and the
left upper quadrant. His aspect was pale and jaundiced; a
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J. Van den Ende et al. Blackwater fever and antimalarials
slight systolic murmur was noticeable at the apex, the tip of
the spleen was palpable. A polyuria of 6.5 l/day was noted.
Key laboratory results were haemoglobin 6.3 g/dl,
haematocrit 18.5%, leucocytes 8.4 3 109/l with normal
differential count, thrombocytes 179 3 109/l, plasma
haemoglobin 19.7 mg/dl, lactate dehydrogenase 876 IU/l,
glutamyltransferase 73 IU/l, other liver enzymes normal,
total bilirubin 1.7 mg/dl, urea 68 mg/dl, creatinin 2.5 mg/dl.
A thick film for malaria was negative on several occasions;
IFAT for P. falciparum was 1/5120. Urinalysis gave
haemoglobinuria 2.7 mg/l, sediment negative. Other causes
of severe haemolysis were excluded: blood cultures
remained sterile, serology for other infectious causes was
negative, no enzyme deficiencies were found, DonathLandsteiner and HAM test were negative. The direct
antiglobulin test was slightly positive for IgG, negative for
IgA and complement. Cold agglutinins were positive at 1:16,
with an anti-I specificity. Abdominal ultrasound showed a
splenomegaly of 16 cm, sludge in the gallbladder, thickening
of the gallbladder wall and hyperechogenicity of the renal
cortex.
Malaria treatment was discontinued and another 2 units
of packed cells were given. Ofloxacin was substituted for
chloramphenicol. Anaemia, polyuria, splenomegaly and
renal function gradually resolved.
Case V
A 39-year-old female anthropologist who had been working
in West Africa for 14 years, had suffered several malarial
episodes in the past which were treated with quinine,
mefloquine, halofantrine and pyrimethamin-sulphadoxin
(Fansidar®) without serious complications. On March 14th
1995 she developed fever and diarrhoea in Guinea-Conakry
and was treated with loperamide and with Quinimax®
3 3 200 mg/day for 7 days. By March 27th, she had another
bout of fever and diarrhoea. A thick film was positive for
malaria, the species was not identified. All symptoms
receded quickly with quinine at 3 3 500 mg/day for 3 days
followed by doxycycline 1 3 200 mg/day for 5 days. Nine
days after the start of the quinine therapy the fever suddenly
recurred, this time with dark red urine. Two days later she
was hospitalized in the capital with frank jaundice,
persisting fever and severe anaemia. After transfusion with
one unit of fresh whole blood the patient was transferred to
Dakar, Senegal, where she was given Quinimax® IV, 3 3 400
mg/day for 3 days, followed by one intramuscular injection
of artemether and a transfusion of two more units of fresh
blood.
After transfer to Belgium and upon admission April 9th,
she was extremely anaemic (Hb 3.5 g/dl) with signs of
frank haemolysis and haemoglobinuria, and with a positive
636
direct antiglobulin test showing ‘warm’ anti-erythrocyte
IgG autoantibodies with broad specificity but without
reaction with anti-IgA and anti-complement. A thick film
was negative, other causes of haemolysis were excluded.
Kidney function was normal throughout the observation
period (Table 1). The diagnoses of BWF or auto-immune
haemolytic anaemia were considered. Further transfusions
were given.
Fever rose again by April 15th. Notwithstanding a
negative thick film, halofantrine 1500 mg was administered.
No frank haemolysis ensued. During the two months’
follow-up period, haemoglobin levels increased and serum
IgM and malarial antibody levels decreased. The patient
returned to Guinea-Conakry on a chemoprophylactic
regimen of proguanil 200 mg/day and chloroquine 300
mg/week. Her fever recurred once more and was treated with
halofantrine and doxycycline without any adverse reaction.
On September 25th 1995, the patient took halofantrine
again for fever and muscle pain without an attempt to a
parasitological diagnosis. The next day the fever persisted,
she passed dark urine, and a transfusion of one unit of blood
was given (without haemoglobin level determination). On
the 27th another two units of blood and one injection of
artemisinin were administrated in Conakry. On the 28th the
patient returned to Belgium, where on admission she was
afebrile. A clinical examination showed jaundice and
hepatomegaly of 4 fingers below the costal margin.
Key laboratory values were haemoglobin 10.7 g/dl,
leukocytes 4.4 3 109/l with normal differential count,
thrombocytes 64 3 109/l, plasma haemoglobin 545 mg/l,
lactate dehydrogenase 1713 IU/l, other liver enzymes
normal, total bilirubin 3.2 mg/dl, direct bilirubin 1.1 mg/dl,
urea 90 mg/dl, creatinine 1.7 mg/dl. A thick film for malaria
was negative on several occasions; IFAT for P. falciparum
was 1/10240. Urinalysis revealed haemoglobinuria
4 mg/l, . 100.000 bacteria, K. pneumoniae and E. coli.
Other causes of severe haemolysis were excluded. The
direct antiglobulin test was positive for IgG and negative for
C3d. After washing of red blood cells the antiglobulin test
was negative with all sera. Cold agglutinins were positive at
1:8, with an anti-I specificity. A search for specific
antibodies induced by proguanil, chloroquine and
halofantrine was negative. Abdominal ultrasound was
negative, clinically suspected hepatomegaly could not be
confirmed.
Artemisinin IM, 2 3 80 mg was given on Sept. 28th,
followed by 80 mg once daily for 4 days. Doxycycline, 100
mg/day was given for 7 days. Two more units of blood were
administered. During the following months, all parameters
gradually returned to normal, except for P. falciparum
antibodies, which increased temporarily. The patient
preferred not to return to an endemic country.
© 1998 Blackwell Science Ltd
Tropical Medicine and International Health
J. Van den Ende et al.
volume 3 no 8 pp 632–639 august 1998
Blackwater fever and antimalarials
Discussion
Transient polyclonal cold agglutinins, frequently seen
with a broad array of infections (Mycoplasma, Epstein
Barr virus, measles, malaria …), have mostly an anti-I or
anti-i specificity. (Rosse & Lauf 1970; Lefrançois et al.
1981). In four of the five cases cold agglutinins were
detected at a low titre; in three of these cases the
specificity was anti-I or anti-i. Haemolysis is unlikely to
be attributed to an auto-immune phenomenon caused by
cold agglutinins.
Diagnosis
In all five cases, sufficient clinical evidence for the diagnosis of
BWF was obtained: a recent stay in a malarious country,
evidence of P. falciparum infection, irregular treatment with
quinine, absent or very low parasitaemia, dramatic
haemolysis and haemoglobinuria.
Other causes of intravascular haemolysis were formally
excluded by various tests, or unlikely. A spectacular direct
lysis of RBC by the P. falciparum parasite would only be
explained in cases of malaria with a high parasitaemia. In
our 5 cases, parasites were scanty or absent. Mechanical
damage of RBC in the circulation was excluded by absence of
typical RBC deformities. Moreover, none of our patients
presented with symptoms or signs of DIC at the time of
haemolytic crisis.
Mechanism of haemolysis
The mechanism of haemolysis in these cases, as in other cases
of BWF, remains unclear. The direct antiglobulin test was
positive in cases III, IV and V, but it is not clear if it could
explain fully the intravascular haemolysis (Table 1).
d
In case III, the initially slightly positive direct
antiglobulin test with anticomplement specificity was
probably due to the aspecific cold agglutinin that
partially activated complement on the RBC during
blood sample transport below 37 8C. A positive direct
antiglobulin test with only anticomplement specificity is
suggestive of drug-induced haemolysis, with formation
of a drug antibody target cell complex (ternary
complex). The direct antiglobulin test became negative
within one week during further quinine therapy. This is a
strong argument against this mechanism as the cause of
the massive haemolysis.
d
In case IV the direct antiglobulin test was slightly
positive for IgG and interpreted as a non-specific binding
of IgG associated with malaria induced polyclonal
hypergammaglobulinaemia. This non-specific binding of
IgG does not explain the massive intravascular
haemolysis, either.
d
Case V was found with a transient positive direct
antiglobulin test for IgG auto-antibodies with broad
specificity. The test became negative one week after the
first hospitalization, thereby weakening the probability
of autoimmune haemolytic anaemia as a possible
diagnosis. Moreover, acute intravascular haemolysis
would be unusual for an autoimmune haemolytic
anaemia.
© 1998 Blackwell Science Ltd
The titre of the cold agglutinins (maximum 1/32) is too
low to explain a severe haemolytic anaemia. In cold
agglutinin autoimmune haemolytic anaemia serum titres
are commonly 1/10000 or higher. (Williams et al. 1990).
Haemolysis due to cold agglutinins is merely
extravascular through opsonization of RBC by the early
stages of complement (C3/C3bi) and their removal from
the circulation by hepatic and, to a lesser extent, splenic
macrophages. (Jaffe et al. 1976).
One would wonder if transfusion-related haemolysis could
have played a role in these cases. But firstly, all patients
developed dark urine before transfusion. Secondly, in case II
the close temporal relationship between administration of
halofantrine and black urine in the second and the third
episode make a role for the former transfusions unlikely.
Finally, in cases IV and V the second appearance of dark
urine might have been provoked or enhanced by the previous
transfusions. These might also have contributed to the
positive direct antiglobulin test. But the first presentation
with dark urine in the absence of former transfusion, and the
further history make a substantial causal role of transfusion
in these cases highly unlikely.
d
Trigger
Although all five patients have a history of quinine intake as a
possible trigger for haemolysis, case II had a second and a
third haemolytic crisis, and case V had a second haemolytic
crisis apparently provoked by halofantrine. In case III it is
possible that mefloquine triggered the BWF syndrome,
although it is very unlikely, given the delay.
Recently mefloquine and halofantrine have been considered
as triggers of BWF. (Vachon et al. 1992; Danis et al. 1993)
This may not be so surprising since these three aminoalcohols display some similarity in their chemical formulas
(Figure 1), and cross-resistance has been shown in vitro
between amino-alcohols (Peel et al. 1994). The first case
described by Vachon had a positive antiglobulin test, in the
other cases results of the direct antiglobulin test were not
reported. One could wonder if all these cases fit the original
description of BWF, and if some of them do not represent a
classical drug-induced haemolysis. (Stein & Germany 1987)
637
Tropical Medicine and International Health
volume 3 no 8 pp 632–639 august 1998
J. Van den Ende et al. Blackwater fever and antimalarials
HO
CH
CH2
CH2
N
CH
CH2
CH3O
N
Quinine
H
H
HO
N
C
Treatment
N
CF3
CF3
Mefloquine
HO
CH
CH2
CH2
N[(CH2)3CH3]2
Cl
F3C
after World War II the campaign for the global eradication of
malaria resulted in a temporary and relative control of
malaria endemicity. Decreased efforts for malaria control in
many areas of the world, resistance of mosquitoes to DDT
and of the parasite to chloroquine provoked a worldwide
revival of malaria. Perhaps we see more BWF because we see
more malaria (in the Institute of Tropical Medicine, we had 7
positive thick films for malaria in 1957, 5 in 1967, 12 in 1977,
229 in 1987 and 267 in 1997). Secondly, in that period quinine
was restricted to seriously ill patients. The widespread advent
of chloroquine resistance made treatment with quinine or
newer antimalarials such as mefloquine and halofantrine
more popular, also as a presumptive treatment for minor
symptoms.
Cl
Case II gives a strong argument that antimalarial treatment is
necessary, besides supportive therapy: we documented a
relapse of malaria while withholding (on purpose)
antimalarial treatment. No consensus exists concerning
adequate medical treatment for BWF. Although it has never
been proven, some authorities advocate avoidance of quinine
as treatment of BWF. (James & Chistophers 1922).
The observation of severe haemolysis provoked by
mefloquine and halofantrine warns against these drugs as
treatment in BWF. In most cases chloroquine is excluded as a
curative treatment by the likelihood of chloroquine
resistance. Further studies are needed to elucidate whether
artemisinin or tetracycline could be helpful. The problems
with ABO typing in case III should be emphasized when
clinicians consider transfusions or (partial) exchange
transfusion for this condition. Careful cross-matching is
imperative.
Halofantrine
Figure 1 Structure of Quinine, Mefloquine and Halofantrine.
Was the development of halofantrine-induced haemolysis
in case II and V an isolated drug-induced phenomenon, or
was there a physiopathological link with the original
haemolytic mechanism, triggered by quinine? In all three
haemolytic crises of case II, the direct antiglobulin test was
negative, whereas in classical drug-induced haemolysis the
antiglobulin test is unequivocally positive. (Dacie & Lewis
1991) In case V the direct antiglobulin test was only
temporarily positive.
Recurrence of BWF
The absence of BWF from the literature and from our wards
for decades is noteworthy. We see two explanations: firstly,
638
Acknowledgements
We are indebted to Prof. Dr Salama, bloodbank VirchowKlinikum, Berlin, Germany, for the testing for specific
antibodies induced by antimalarials.
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