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TMIH287 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 633 Tropical Medicine and International Health volume 3 no 8 pp 632–639 august 1998 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 635 Tropical Medicine and International Health volume 3 no 8 pp 632–639 august 1998 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. References Bruce-Chwatt LJ & Bruce-Chwatt JM (1980) Health in tropical Africa during the colonial period. Malaria and yellow fever. Clarendon Press, Oxford. Dacie JV & Lewis SM (1991) Practical haematology. 7th, edn. Churchill Livingstone, p. 502. Danis M, Nozais JP, Paris L et al. (1993) Jan 23) Fièvre bilieuse hemoglobinurique après prise de mefloquine. Trois observations. Presse Médicale 22, 80. Delacollette C, Taelman H & Wery M (1995) An etiologic study of hemoglobinuria and blackwater fever in the Kivu Mountains, © 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 Zaire. Annales de la Société Belge de Médecine Tropicale 75, 51–63. Findlay GM (1949) Blackwater fever in West-Africa, 1941–45. II. Blackwater fever in African military personnel. Annals of Tropical Medicine and Parasitology 43, 213–224. Jaffe CH, Atkinson JP & Frank MM (1976) The role of complement in the clearance of cold agglutinin-sensitised erythrocytes in man. Journal of Clinical Investigation 58, 942–949. James SP & Christophers SR (1922) Malaria: serious cases; complications and sequelae. In The practice of medicine in the tropics, Vol. 2 (eds. W. Byam & RG. Archibald), Henry Frowde/Hodder & Stoughton, London, pp. 1599–1620. Knochel JP & Moore GE (1993) Rhabdomyolysis in Malaria. New England Journal of Medicine 329, 1206–1207. Lefrançois G, Le Bras J, Simmoneau M, Bouvet E, Vroklans M & Vachon F (1981) Anti-erythrocyte autoimmunisation during chronic falciparum malaria. The Lancet ii, 661–663. Maegraith BG (1948) Pathological processes in malaria and blackwater fever. Blackwell Scientific Publications, Oxford. Mojon M, Wallon M, Gravey A, Peaud PY, Sartre J & Peyron F (1994) Intravascular haemolysis following halofantrine intake. Transactions of the Royal Society of Tropical Medicine and Hygiene 88, 91. Peel SA, Bright P, Yount B, Handy J & Baric RS (1994) A strong © 1998 Blackwell Science Ltd association between mefloquine and halofantrine resistance and amplification, overexpression, and mutation in the P-glycoprotein gene homolog (pfmdr) of Plasmodium falciparum in vitro. American Journal of Tropical Medicine and Hygiene 51, 648–658. Plehn A (1920) Neue Untersuchungen über die Entstehungsweise des Schwarzwasserfiebers. Archiv für Schiffs- und Tropenkrankheiten 24, 321–326. Ross GR (1962) Blackwater fever in Southern Rhodesia in retrospect. Central African Journal of Medicine 8, 294–297. Rosse WF & Lauf PK (1970) Reaction of cold agglutinins with I antigen solubilised from human red cells. Blood 36, 777. Stein CM & Germany FM (1987) Drug-induced haemolysis masquerading as blackwater fever. Central African Journal of Medicine 33 (1), 22–24. Stephens JWW (1937) Blackwater fever: a historical survey and summary of observations made over a century, University Press, Liverpool. Tietz NW(ed.) (1990) Clinical guide to Laboratory tests. 2nd, edn. WB Saunders Co, Philadelphia, pp. 394–395. Vachon F, Fajac I, Gachot B, Coulaud JP & Charmot G (1992) Halofantrine and acute intravascular hemolysis. The Lancet 340, 909–910. Williams WJ, Beutler E, Erslev AJ & Lichtman MA (1990) Hematology, 4th. edn., McGraw-Hill, New York, pp. 677–78. 639