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Haemoglobinuric renal failure and typhoid fever
482 TRANSACTIONS OF THE ROYAL SOCIETY OF TROPICAL MED~CXNE AND HYGIENE (1988) 82, 482-484
Haemoglobinuric J. K. Onwubalii
renal failure University
and typhoid
of Nigeria Teaching Hospital,
Abstract
Three patients with typhoid fever, initially misdiagnosed, developed intravascular haemolysis, disseminatedintravascular coagulation, haemoglobmuria and acute renal failure. 2 of the patients were deficient in erythrocyte glucose-6-phosphate dehydrogenase; Pkmodium falcibanrm was nresent in the blood of the third. Among the indigenous population of endemic areas, typhoid fever is the likely diagnosis in any pyrexial illness associatedwith haemoglobinuric renal failure.
fever P.M.B.
01129, Enugu, Nigeria
every 8 h), cimetidine and antacids were commenced. 24 h later, he had 2 brief generalized seizures and lapsed into coma. Peritoneal dialysis was initiated, but he died 12 h later. Salmonella &phi was isolated from 2 blood culture bottles. Autopsy confirmed extensive typhoid enteritis. The kidneys showed marked tubule cell necrosis with numerous haemoglobin casts, moderate interstitial nephritis and focal arteriolar occlusion by fibrin thrombi. Case 2
Introduction
It is not always appreciated that typhoid fever is the most common infective cause of acute renal failure among adults in tropical Africa (ADU et al., 1976). In endemic areas, where resources are low and microbiology services inadequate, doctors often have only clinical acumen to guide them in early recognition of this disease.Sadly, the diagnosis is sometimesmissed or delayed, with disastrous consequences, because somepatients may present unusual features (WICKS et al., 1971; OSUNTOKUN et al., 1972) or develop less well recognized complications such as renal failure (LWANGA 81 WING, 1970).
This paper describes 3 patients with some unusual features of typhoid fever in whom the disease was initially misdiagnosed and consequently complicated by massive intravascular haemolysis and haemoglobinuric acute renal failure. Its purpose is to emphasize the need for clinicians in the tropics to suspect typhoid fever in any patient developing this clinical syndrome.
A 22-year-old student was admitted into a private hospital-with 2 weeks’ history of fever and headache. He had nvrexia (385°C). tachvcardia. tender heDatomegaly (i cm) and a white blood cell count (WBC) of 3.9 x lO’/litre (Table). A blood fihn was negative for malaria. His urine contained protein, blood and excess urobilinogen, but no cells or organisms. His red blood cells were deficient in glucosel6-phosphate dehvdroeenase (G6PD). He was treated with blood trar~fusi’on, chloroquine, ampicillin (500 mg every 6 h) and folic acid for haemolysis induced by “infection”. On day 4, he became confused, developed vomiting and was referred. At the University of Nigeria Teaching Hospital (UNTH) he was drowsy, febrile, oliguric and jaundiced. Abdominal tenderness, melaena, haemoglobinuria and proteinuria were noted, and he bled from venepuncture sites. Laboratory investigation (Table) showed evidence of intravascular haemolysis, consumption coagulopathy and axotaemia. Fresh blood transfusions, intravenous (iv) chloramphenicol (1 g
A 35year-old driver was admitted into a district hospital for fever, rigors and dry cough of 3 weeks’ duration. He had pyrexia (39”C), tender hepatomegaly (5 cm), splenomegaly (2 cm), anaemia, leucocytosis, thrombocytopenia and mild axotaemia (Table). Blood culture, and blood film for malaria parasites, were negative, but a chest X-ray showed slight elevation of the rieht dome of the dianhratzm. He was treated for presu&d amoebic liver abscesswith blood transfusion, chloroquine, metronidaxole and ampiclox (1 g every 6 h). 3 d later, pyrexia was less, but he developed vomiting, melaena and muscle twitching, and was referred. Evaluation at UNTH revealed pyrexia (40”(Z), delirium. iaundice. coffee-grounds vomit, a distended, ‘tender abdomen, hepatosplenomegaly and oliguria. Investigation (Table) showed G6PD deficiency with evidence of intravascular haemolysis and coagulopathy, worsening axotaemia and mild hepatitis. He was treated with fresh blood transfusion, iv chloramphenicol(750 mg) and ampicillin (2 g) every 6 h, and vitamin K. An ultrasound scan showed large, unobstructed kidneys, coils of distended, thickened bowel, but no liver abscess.Peritoneal dialysis was commenced and yielded blood-stained dialysate. He be~es;opnrogressivelyinaccessible and died 48 h after Blood and stool cultures, and a Widal test result obtained later, were positive for S. typhi. Permission for autopsy was refused by the family. Case 3
A 48-year-old midwifery tutor was admitted into a Mission hosoital with a 10-d historv of withdrawd behaviour, fever and intermenstrual spotting. Shehad suffered 2 previous episodes of reactive withdrawal following bereavement. She was conscious but mute, pyrexial (39°C) with tachycardia and hypotension. Her haemoglobin concentration was 8.8 g/d& WBC 10.3 x lO’/litre, and a blood fihn contained numerous ring forms of Plusmodium falciparum. Acute malaria with depression was diagnosed and she received chloroquine, amitriptyline, vitamins and diaxepam. However, pyrexia persisted. Blood culture and Widal test, performed in a commercial labora-
483 Table-Clinical
and laboratory
data of 3 patients with typhoid
Age (years) and sex Initial clinical features
Week of illness on admission to UNTH Laboratory results in UNTH’ Haemoglobin, g/d1 Leucocyte count, X 109/litre Platelet count, X 10Vitre Reticulocytes % Malaria parasites G6PD activity of red cells Coomb’s test Blood urea, mg% (normal 15-35) Serum creatinine, mg% (normal 0.6-1.3) Serum bihrubin, mg% Fibrinogen degradation products Prothrombm time/control, set Positive culture of S. myphi Widal titres to S. zyphi :g Urine: volume (ml)124 h haemoglobin urobilinogen deposit
fever
Case 1
Case 2
Case 3
22 M fever, 38.5”C, pulse 104/n&l, BP 120170mm He. headache, hepatomegaly
35 M fever, 39°C. pulse %/m&l, BP 130/90 mm Hg, dry cough, hepatomegaly, splenomegaly 3’/z
48 F fever. 39°C. pulse 140/min, BP 80/60-140/100mm Hg, withdrawal, vaginal bleeding
(7.6) 7.2
(8.8) 5.1 g;.;r l3
12 negative deficient negative 162 4.5 4.6 positive 30112 blood
8 negative deficient negative (66) 206
10 positive normal negative [Yj) ‘9”” 2.1 g;;p
11640 l/160 250 oositive
11320 11320 187 positive increased WBC, casts
nil
K? 5.7 positive 1812 blood, stool
2i/2
nil 11640 l/320 35 positive increased RBC, WBC, casts
ND ND typhoid enteritis, interstitial nephritis,. . acute tuaular necrosis ‘Results from referring hospitals are given in parentheses. Abbreviations: G6PD, glucose-6-phosphatedehydrogenase; F, female; M, male; ND, not done; UNTH, University of Nigeria Teaching Hospital, Enugu. Autopsy
tory, were negative, but urine culture grew Escherichia coli. Ampicillin, gentamicin and celotaxime were
given iv. On day 8, her conscious level fluctuated, pyrexia persisted and oliguria was noted. She was referred. In UNTH, she was deeply unconscious, had widespread bleeding and episodes of hypotension associatedwith profuse sweating and spikes of fever. Investigation (Table) revealed evidence of intravascular haemolysis and coagulopathy, renal failure and hepatitis. Following the notification of positive Widal titres for S. ryphi, iv chloramphenicol(1 g every 8 h) was commenced. Peritoneal dialysis, fresh blood transfusion, vitamin K and cimetidine were also initiated. However, coma persisted until she died 5 d after admission. Permission for autopsy was refused. Discussion
These 3 patients died of typhoid fever complicated by intravascular haemolysis, disseminated coagulopathy, haemorrhage and haemoglobinuric renal failure. Although S. typhi was not isolated from case 3, the clinical illness and high antibody titres favour this diagnosis. 2 patients were G6PD deficient, a proportion that reflects the high incidence (25%) of this enzyme defect among Nigerians (GILLES & TAYLOR, 1961). In typhoid, renal failure usually develops in a setting of intravascular coagulopathy and haemolysis
in patients who are G6PD deficient (LWANGA & WING, 1970; ADU et al., 1976), although these complications and a haemolytic uraemic syndrome may also be seen in people with normal G6PD (BAKER et al., 1974). Non-haemolytic renal damage also occurs, mediated by an immune-complex glomerulonephritis, rhabdomyolysis with myoglobinuria, circulatory collapse or interstitial nephritis (reviewed by KIBUKAMUSOKE 81 COOVADIA, 1984). The concomitant presenceof P. fulcipawm infection in case 3 raised the possibility of blackwater fever. Although occasionally seen in young children, pregnant women and patients with sickle cell disease or G6PD deficiency, this syndrome rarely occurs among the adult population of holoendemic malarious areas (ROSS, 1932). Furthermore, no improvement was seenin this patient following parasite eradication with chloroquine. It has been our practice to treat patients with undiagnosed pyrexia with chloroquine, as a further diagnostic aid while awaiting laboratory confirmation, since chloroquine-resistant P. fulcipurum malaria was unknown in Nigeria until very recently (SALAKO & ADEROUNMU, 1987).
Some unusual features in these patients - hepatomegaly, absenceof leucopenia, splenomegaly, rash or pulse disproportion (Table) - may have contributed to the initial misdiagnosis. These atypical features are not uncommon in endemic typhoid fever (OSUNTOKUN et al., 1972). Other common pyrexial illnesses in
484
the tropics, such as pneumonia, meningitis, amoebic liver diseaseand viral infections, occurring in patients with sickle cell diseaseor G6PD deficiency, or snake envenoming, may causeintravascular haemolysis and haemoglobinuric renal failure. These conditions can be distinguished clinically and by appropriate laboratory tests. Particular difficulty may be encountered with amoebic liver abscess,as in case2, in the absence of facilities for isotopic or ultrasonic diagnosis. The presence of marked leucocytosis, severe hepatic and intercostal tenderness (Durban’s sign), and the response to metronidaxole distinguish this condition from typhoid fever. Massive hagmolysis induced by drues (GILLES& TAYLOR. 1961) or herbal medicines (BAGEL& THOMAS,1987j in G6PD deficient persons may also lead to renal failure, but hyperpyrexia is unusual and a careful history should reveal the diagnosis. So, in any patient with pyrexia and haemoglobinuric renal failure in whom these conditions have been excluded, typhoid fever is the most likely diagnosis. I have frequently noted progression of typhoid fever, as in these cases, despite early therapy with modest doses of drugs, other than chloramphenicol, which have in vitro activity against the organism. Sadly, late introduction of chloramphenicol could not save these patients who had already developed severe complications of the disease. These observations emphasize the obduracy of S. typhi and the importance of early diagnosis and institution of chloramphenicol, in adequate dosage, in any pyrexial patient developing haemoglobinuric renal failure.
References
Adu, D., Anim-Addo, Y., Fob, A. K., Yeboah, E. D., Quartey, J. K. ,M. & Rjbeiro, B: F. (1976). Acute renal ~‘Ou~2m tropical Aft-ma. Bntssh Medacal Journal, I, Baker, S. ‘& Thomas, P. S. (1987). Herbal medicine precipitating massive haemolysis. Lancer, i, 1039-1040. Baker, N. M., Mills, A. E., Rachman, I. 81Thomas?J. E. P. (1974). Haemolytic-uraemic syndrome in typhoid fever. British Medical Jotanal,
ii, 84-87.
Gilles, H. M. & Taylor, B. G. (1961). The existence of glucose-6-phosphate dehydrogenase deficiency trait in Nigeria and its clinical implications. Annals of Tropical Medicine and Parasitology,
55, 64-68.
Kibukamusoke, J. W. & Coovadia, H. M. (1984). Nephropathy in typhoid fever. In: Tropical Nephrology, Kibukamusoke, J. W. (editor). Canberra: Citforge, pp. 306-312. Lwanga, D. & Wing, A. J. (1970). Renal complications associated with typhoid fever. East African Medical Journal, 47, 146-152. Osuntokun, B. O., Bademosi?O., Ogunremi, K. & Wright, S. G. (1972). Neuropsychtatric manifestations of typhoid fever in 959 patients. Archives of Neurology, 27, 7-13. Ross, G. R. (1932). Researches in blackwater fever. London Schoolof Hygiene and Tropical Medicine Memoir No. 6. Salako, L. A. & Aderounmu, A. F. (1987). In vitro chloroquine and mefloquine-resistant Plasmodium falcipawn in Nigeria. Lancet, i, 572-573. Wicks, A. C. B., Holmes, G. S. & Davidson, L. (1971). Endemic typhoid fever - a diagnostic pitfall. Quurter~ Journal of Medicine, 159, 341-354. Received 7 October 1987; accepted for publication 2 December I987
Haemoglobinuric J. K. Onwubalii
renal failure University
and typhoid
of Nigeria Teaching Hospital,
Abstract
Three patients with typhoid fever, initially misdiagnosed, developed intravascular haemolysis, disseminatedintravascular coagulation, haemoglobmuria and acute renal failure. 2 of the patients were deficient in erythrocyte glucose-6-phosphate dehydrogenase; Pkmodium falcibanrm was nresent in the blood of the third. Among the indigenous population of endemic areas, typhoid fever is the likely diagnosis in any pyrexial illness associatedwith haemoglobinuric renal failure.
fever P.M.B.
01129, Enugu, Nigeria
every 8 h), cimetidine and antacids were commenced. 24 h later, he had 2 brief generalized seizures and lapsed into coma. Peritoneal dialysis was initiated, but he died 12 h later. Salmonella &phi was isolated from 2 blood culture bottles. Autopsy confirmed extensive typhoid enteritis. The kidneys showed marked tubule cell necrosis with numerous haemoglobin casts, moderate interstitial nephritis and focal arteriolar occlusion by fibrin thrombi. Case 2
Introduction
It is not always appreciated that typhoid fever is the most common infective cause of acute renal failure among adults in tropical Africa (ADU et al., 1976). In endemic areas, where resources are low and microbiology services inadequate, doctors often have only clinical acumen to guide them in early recognition of this disease.Sadly, the diagnosis is sometimesmissed or delayed, with disastrous consequences, because somepatients may present unusual features (WICKS et al., 1971; OSUNTOKUN et al., 1972) or develop less well recognized complications such as renal failure (LWANGA 81 WING, 1970).
This paper describes 3 patients with some unusual features of typhoid fever in whom the disease was initially misdiagnosed and consequently complicated by massive intravascular haemolysis and haemoglobinuric acute renal failure. Its purpose is to emphasize the need for clinicians in the tropics to suspect typhoid fever in any patient developing this clinical syndrome.
A 22-year-old student was admitted into a private hospital-with 2 weeks’ history of fever and headache. He had nvrexia (385°C). tachvcardia. tender heDatomegaly (i cm) and a white blood cell count (WBC) of 3.9 x lO’/litre (Table). A blood fihn was negative for malaria. His urine contained protein, blood and excess urobilinogen, but no cells or organisms. His red blood cells were deficient in glucosel6-phosphate dehvdroeenase (G6PD). He was treated with blood trar~fusi’on, chloroquine, ampicillin (500 mg every 6 h) and folic acid for haemolysis induced by “infection”. On day 4, he became confused, developed vomiting and was referred. At the University of Nigeria Teaching Hospital (UNTH) he was drowsy, febrile, oliguric and jaundiced. Abdominal tenderness, melaena, haemoglobinuria and proteinuria were noted, and he bled from venepuncture sites. Laboratory investigation (Table) showed evidence of intravascular haemolysis, consumption coagulopathy and axotaemia. Fresh blood transfusions, intravenous (iv) chloramphenicol (1 g
A 35year-old driver was admitted into a district hospital for fever, rigors and dry cough of 3 weeks’ duration. He had pyrexia (39”C), tender hepatomegaly (5 cm), splenomegaly (2 cm), anaemia, leucocytosis, thrombocytopenia and mild axotaemia (Table). Blood culture, and blood film for malaria parasites, were negative, but a chest X-ray showed slight elevation of the rieht dome of the dianhratzm. He was treated for presu&d amoebic liver abscesswith blood transfusion, chloroquine, metronidaxole and ampiclox (1 g every 6 h). 3 d later, pyrexia was less, but he developed vomiting, melaena and muscle twitching, and was referred. Evaluation at UNTH revealed pyrexia (40”(Z), delirium. iaundice. coffee-grounds vomit, a distended, ‘tender abdomen, hepatosplenomegaly and oliguria. Investigation (Table) showed G6PD deficiency with evidence of intravascular haemolysis and coagulopathy, worsening axotaemia and mild hepatitis. He was treated with fresh blood transfusion, iv chloramphenicol(750 mg) and ampicillin (2 g) every 6 h, and vitamin K. An ultrasound scan showed large, unobstructed kidneys, coils of distended, thickened bowel, but no liver abscess.Peritoneal dialysis was commenced and yielded blood-stained dialysate. He be~es;opnrogressivelyinaccessible and died 48 h after Blood and stool cultures, and a Widal test result obtained later, were positive for S. typhi. Permission for autopsy was refused by the family. Case 3
A 48-year-old midwifery tutor was admitted into a Mission hosoital with a 10-d historv of withdrawd behaviour, fever and intermenstrual spotting. Shehad suffered 2 previous episodes of reactive withdrawal following bereavement. She was conscious but mute, pyrexial (39°C) with tachycardia and hypotension. Her haemoglobin concentration was 8.8 g/d& WBC 10.3 x lO’/litre, and a blood fihn contained numerous ring forms of Plusmodium falciparum. Acute malaria with depression was diagnosed and she received chloroquine, amitriptyline, vitamins and diaxepam. However, pyrexia persisted. Blood culture and Widal test, performed in a commercial labora-
483 Table-Clinical
and laboratory
data of 3 patients with typhoid
Age (years) and sex Initial clinical features
Week of illness on admission to UNTH Laboratory results in UNTH’ Haemoglobin, g/d1 Leucocyte count, X 109/litre Platelet count, X 10Vitre Reticulocytes % Malaria parasites G6PD activity of red cells Coomb’s test Blood urea, mg% (normal 15-35) Serum creatinine, mg% (normal 0.6-1.3) Serum bihrubin, mg% Fibrinogen degradation products Prothrombm time/control, set Positive culture of S. myphi Widal titres to S. zyphi :g Urine: volume (ml)124 h haemoglobin urobilinogen deposit
fever
Case 1
Case 2
Case 3
22 M fever, 38.5”C, pulse 104/n&l, BP 120170mm He. headache, hepatomegaly
35 M fever, 39°C. pulse %/m&l, BP 130/90 mm Hg, dry cough, hepatomegaly, splenomegaly 3’/z
48 F fever. 39°C. pulse 140/min, BP 80/60-140/100mm Hg, withdrawal, vaginal bleeding
(7.6) 7.2
(8.8) 5.1 g;.;r l3
12 negative deficient negative 162 4.5 4.6 positive 30112 blood
8 negative deficient negative (66) 206
10 positive normal negative [Yj) ‘9”” 2.1 g;;p
11640 l/160 250 oositive
11320 11320 187 positive increased WBC, casts
nil
K? 5.7 positive 1812 blood, stool
2i/2
nil 11640 l/320 35 positive increased RBC, WBC, casts
ND ND typhoid enteritis, interstitial nephritis,. . acute tuaular necrosis ‘Results from referring hospitals are given in parentheses. Abbreviations: G6PD, glucose-6-phosphatedehydrogenase; F, female; M, male; ND, not done; UNTH, University of Nigeria Teaching Hospital, Enugu. Autopsy
tory, were negative, but urine culture grew Escherichia coli. Ampicillin, gentamicin and celotaxime were
given iv. On day 8, her conscious level fluctuated, pyrexia persisted and oliguria was noted. She was referred. In UNTH, she was deeply unconscious, had widespread bleeding and episodes of hypotension associatedwith profuse sweating and spikes of fever. Investigation (Table) revealed evidence of intravascular haemolysis and coagulopathy, renal failure and hepatitis. Following the notification of positive Widal titres for S. ryphi, iv chloramphenicol(1 g every 8 h) was commenced. Peritoneal dialysis, fresh blood transfusion, vitamin K and cimetidine were also initiated. However, coma persisted until she died 5 d after admission. Permission for autopsy was refused. Discussion
These 3 patients died of typhoid fever complicated by intravascular haemolysis, disseminated coagulopathy, haemorrhage and haemoglobinuric renal failure. Although S. typhi was not isolated from case 3, the clinical illness and high antibody titres favour this diagnosis. 2 patients were G6PD deficient, a proportion that reflects the high incidence (25%) of this enzyme defect among Nigerians (GILLES & TAYLOR, 1961). In typhoid, renal failure usually develops in a setting of intravascular coagulopathy and haemolysis
in patients who are G6PD deficient (LWANGA & WING, 1970; ADU et al., 1976), although these complications and a haemolytic uraemic syndrome may also be seen in people with normal G6PD (BAKER et al., 1974). Non-haemolytic renal damage also occurs, mediated by an immune-complex glomerulonephritis, rhabdomyolysis with myoglobinuria, circulatory collapse or interstitial nephritis (reviewed by KIBUKAMUSOKE 81 COOVADIA, 1984). The concomitant presenceof P. fulcipawm infection in case 3 raised the possibility of blackwater fever. Although occasionally seen in young children, pregnant women and patients with sickle cell disease or G6PD deficiency, this syndrome rarely occurs among the adult population of holoendemic malarious areas (ROSS, 1932). Furthermore, no improvement was seenin this patient following parasite eradication with chloroquine. It has been our practice to treat patients with undiagnosed pyrexia with chloroquine, as a further diagnostic aid while awaiting laboratory confirmation, since chloroquine-resistant P. fulcipurum malaria was unknown in Nigeria until very recently (SALAKO & ADEROUNMU, 1987).
Some unusual features in these patients - hepatomegaly, absenceof leucopenia, splenomegaly, rash or pulse disproportion (Table) - may have contributed to the initial misdiagnosis. These atypical features are not uncommon in endemic typhoid fever (OSUNTOKUN et al., 1972). Other common pyrexial illnesses in
484
the tropics, such as pneumonia, meningitis, amoebic liver diseaseand viral infections, occurring in patients with sickle cell diseaseor G6PD deficiency, or snake envenoming, may causeintravascular haemolysis and haemoglobinuric renal failure. These conditions can be distinguished clinically and by appropriate laboratory tests. Particular difficulty may be encountered with amoebic liver abscess,as in case2, in the absence of facilities for isotopic or ultrasonic diagnosis. The presence of marked leucocytosis, severe hepatic and intercostal tenderness (Durban’s sign), and the response to metronidaxole distinguish this condition from typhoid fever. Massive hagmolysis induced by drues (GILLES& TAYLOR. 1961) or herbal medicines (BAGEL& THOMAS,1987j in G6PD deficient persons may also lead to renal failure, but hyperpyrexia is unusual and a careful history should reveal the diagnosis. So, in any patient with pyrexia and haemoglobinuric renal failure in whom these conditions have been excluded, typhoid fever is the most likely diagnosis. I have frequently noted progression of typhoid fever, as in these cases, despite early therapy with modest doses of drugs, other than chloramphenicol, which have in vitro activity against the organism. Sadly, late introduction of chloramphenicol could not save these patients who had already developed severe complications of the disease. These observations emphasize the obduracy of S. typhi and the importance of early diagnosis and institution of chloramphenicol, in adequate dosage, in any pyrexial patient developing haemoglobinuric renal failure.
References
Adu, D., Anim-Addo, Y., Fob, A. K., Yeboah, E. D., Quartey, J. K. ,M. & Rjbeiro, B: F. (1976). Acute renal ~‘Ou~2m tropical Aft-ma. Bntssh Medacal Journal, I, Baker, S. ‘& Thomas, P. S. (1987). Herbal medicine precipitating massive haemolysis. Lancer, i, 1039-1040. Baker, N. M., Mills, A. E., Rachman, I. 81Thomas?J. E. P. (1974). Haemolytic-uraemic syndrome in typhoid fever. British Medical Jotanal,
ii, 84-87.
Gilles, H. M. & Taylor, B. G. (1961). The existence of glucose-6-phosphate dehydrogenase deficiency trait in Nigeria and its clinical implications. Annals of Tropical Medicine and Parasitology,
55, 64-68.
Kibukamusoke, J. W. & Coovadia, H. M. (1984). Nephropathy in typhoid fever. In: Tropical Nephrology, Kibukamusoke, J. W. (editor). Canberra: Citforge, pp. 306-312. Lwanga, D. & Wing, A. J. (1970). Renal complications associated with typhoid fever. East African Medical Journal, 47, 146-152. Osuntokun, B. O., Bademosi?O., Ogunremi, K. & Wright, S. G. (1972). Neuropsychtatric manifestations of typhoid fever in 959 patients. Archives of Neurology, 27, 7-13. Ross, G. R. (1932). Researches in blackwater fever. London Schoolof Hygiene and Tropical Medicine Memoir No. 6. Salako, L. A. & Aderounmu, A. F. (1987). In vitro chloroquine and mefloquine-resistant Plasmodium falcipawn in Nigeria. Lancet, i, 572-573. Wicks, A. C. B., Holmes, G. S. & Davidson, L. (1971). Endemic typhoid fever - a diagnostic pitfall. Quurter~ Journal of Medicine, 159, 341-354. Received 7 October 1987; accepted for publication 2 December I987