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Further studies on the treatment of African histoplasmosis with ketoconazole
560
TRANSACTNXVS OFTHEROYALSOCIETY OFTROPICAL MEDICINE ANDHYGIENE
Further studies ketoconazole
on the treatment
(1989) 83, 560-562
of African histoplasmosis
with
D. C. W. Mabey’* and R. J. Hati ‘Medical Research Council Laboratories, Fajara, ‘0 epartment of Clinical Sciences, London School of Hygiene and Tropical Medicine
The Gambia;
Abstract
Five patients with African histoplasmosis were treated with ketoconazole. Three of these were children with disseminated diseaseand 2 were adults with localized cutaneous disease. Both patients with cutaneous disease responded to treatment, although one was lost to follow-up. Of the 3 children with disseminated disease, one was apparently cured, one responded well but subsequently relapsed, and one failed to respond in spite of having blood levels of ketoconazole within the therapeutic range. Further studies are needed to determine the optimum dosage and duration of treatment with ketoconazole for this condition. Introduction
The word histoplasmosis is used to describe two distinct conditions-classical or small form histoplasmosis (histoplasmosis capsulati) and African or large form histoplasmosis (histoplasmosis duboisii). The former is widely distributed throughout the old and new worlds and is caused by Histoplasma capsulatum var. caps&turn whose yeast forms in tissue are seldom larger than 5 w in diameter. The principle clinical manifestations of this type of histoplasmosis are respiratory, although chronic mucosal ulcers or adrenal disease as well as fulminating disseminated infection may occur (GOODWIN8z DES PREZ,1978). As the name suggeststhe African form is restricted to central and west Africa. It is causedby H. capsulatum var. duboisii which produces much larger yeast forms in tissues (8-12 w) and the commonest clinical features are skin or bone infection (COCKSHOTT & LUCAS, 19643 VANBREUSEGHEM,
1953).
The principle therapy for African histoplasmosis has been intravenous amphotericin B (COCKSHOTT& LUCAS, 1964; DROUHET,in press), although simple excision (DROUHET,in press) for localized lesions and oral sulphonamides (BROWN et al., 1974) have also been used with varying degrees of success. We have previously reported a caseof disseminated disease successfully treated with oral ketoconazole (MABEY et al., 1983). We report here the long-term follow up of this patient, and our experience in treating 4 further patients with this drug. Case Reports Case I
S.T., a female aged 4 years and weighing 13 kg, was the subject of a previous report (MABEY et al., 1983). She presented with painful swelling affecting the lower left femur. Biopsy showed multiple yeasts ‘Presentaddress:Departmentof Clinical Sciences,London Schoolof Hygieneand Tropical Medicine, Keppel Street, London, WClE 7HT, UK.
Fig. 1. Patient1 showing skinlesionstypicalof Africanhistoplasmosis. with the morphological appearanceof H. capsulatum var. duboisii. Six weeks after the biopsy generalized skin lesions characteristic of West African histoplasmosis were noted (Fig. 1). She was treated with a total of 293 mg of amphotericin B over 5 weeks with considerable improvement, after which shewas lost to follow-up for 14 months. When next seenshe was febrile and emaciated, with extensive generalized ulceration of the skin, and 5 long bones were involved, with a massiveabscessover the left tibia. Amophotericin B was resumed (a total of 405 mg being given over 16 weeks), after which the skin lesions had healed but the tibia continued to
561 discharge. Amphotericin was discontinued and treatment with ketoconazole was instituted (15 mg/kg/d). After 6 weeks there was no further discharge. Ketoconazole was continued at the samedosagefor 32 weeks, after which it was stopped. 6 weeks later there was painful swelling of the lower right fibula, with a purulent discharge containing yeasts of H. Treatment was restarted cabsulatum var. dub&i. (lb mg/kg) and continued for a further 11 months, after which time all lesions had healed and the natient was well. When last seen, one year after treatment was discontinued, she remamed asymptomatic. Case 2
C.T., a female aged 5 years, weighed 18 kg. She presented with painless cervical lymphadenopathy. A bioosv showed multiole veastswith the moruholoeical appearancesof H. capsuiatum var. duboisii.*3 moiths after biopsy, generalized painless lymphadenopathy developed. Treatment was started with intravenous amphoteritin B, 0.25 mg/kg/d, increasing by 1 mg daily. After her 12th dose (0.6 mg/kg) she suffered a rigor with fever? and this occurred after each of the next 3 doses in spite of reducing the dosageto 0.25 mg/kg. Blood urea was also raised at this time (7.5 mmol/litre), and treatment was discontinued. Six months later she was found to have massive cervical lymphadenopathy, with glands up to 5 cm in diameter, and glands greater than 2 cm diameter in both axillae and groins. Pus aspirated from a cervical gland contained numerous yeasts with the typical appearanceof H. capsulatum var. duboisii. Treatment was started with ketoconazole 10 mg/kg daily. This gave blood levels (2 h after the first dose) of 6.0 @ml, within the therapeutic range. After 10 months treatment with ketoconazole, the cervical and inguinal glands were less than 1 cm in diameter, but axillary glands of some 2 cm diameter remained. Treatment was discontinued since ketoconazole was no longer available, but restarted 3 months later. After a further year’s treatment, there were only shotty glands (< 1 cm) in the neck, axillae and groins, and treatment was discontinued. Six months later she remained in good health and no adenopathy was detected, but after a further 6 months a painless fluctuant swelling, 4 cmx2 cm, was noted on the right forearm (Fig. 2). Pus aspirated from this swelling contained numerous capsulated yeasts with the appearance of H. capsulatum var. duboisii. After a further 6 months treatment with ketoconazole this swelling remained unchanged.
continued for 3 months, after which time there was no change and it was discontinued. Three months later one swelling had discharged and was smaller (1 cm), but 2 lymph glands had appeared in the right posterior cervical triangle and one in the left supraclavicular region. Ketoconazole was restarted (12 mg/kg) and 2 months later the right-sided cervical swelling, which had become fluctuant, was aspirated. Pus contained yeasts of H. capsulatum var. duboisii. 7 months later the swellings were all larger (Fig. 3), although ketoconazole levels had been shown to be in the therapeutic range (12.8 @ml 2 h after dosing). Treatment with intravenous amphotericin B was therefore started, at a dose of 5 mg initially, increasing by 1 mg daily to a total of 1 mg/kg/d. After 6 weeks the swellings were all smaller, and amphoteritin was reduced to 1 mg/kg twice weekly, which was continued for 6 weeks. 4 months after treatment was stopped there was no detectable lymphadenopathy, and when last seen after a further 5 months no abnormality was found. Case 4
Y.K. was an adult male aged 50 years. Skin lesions had been present on his right upper arm for at least 3 years (Fig. 4). Biopsy showed a dermal Mammatory infiltrate with giant cells, some of which contained yeasts with the appearance of H. capsulatum var. duboisii.
He received ketoconazole 7 mg/kg; after 2 weeks there was considerable improvement. Lost to followup after 4 weeks treatment? he returned 9 months later with new lesions on his chest wall adjacent to those on his arm, which had returned to their original
Fig. 2. Patient 2. Cold abscesswhich appeared 12 months after treatment was stopped.
Case 3
G. J. was a male patient aged 10 years. He weighed 34 kg. He presented with a swelling on the back of the neck, present for 2 years. On examination there were two fluctuant painless swellings about 3 cm in diameter. Biopsy revealed numerous yeasts with the appearanceof H. capsulatum var. duboisii. Ketoconazole (6 mg/kg) was given for 5 months, after which time the swellings were unchanged. Increasing the dose to 12 mg/kg for a further month had no effect. Surgical removal was therefore attempted, but 4 weeks after this a firm swelling appeared along the operation scar and a gland of 2 cm diameter below it. Ketoconazole was restarted at a dose of 6 mg/kg and
Fig. 3. Patient 3 after unsuccessful treatment with ketoconazole.
562
Fig. 4. Patient 4 at presentation.
Discussion We have described the treatment with oral ketoconazole of 5 patients with African histoplasmosis. The 2 patients in whom diseasewas localized to the skin appeared to respond satisfactorily, although one was lost to follow-up. The 3 children with disseminated diseasehad a less predictable response. One was apparently cured by ketoconazole, one was cured but relapsed after treatment was discontinued, and the last showed no responsein spite of prolonged treatment and adequate blood levels, but subsequently responded to amphotericin B. In view of this heterogeneity it is difficult to make recommendations on the optimum dosageor duration of treatment, which will need to await further studies on larger numbers of patients. However, ketoconazole has some potential advantages over existing therapy with amphotericin B. It can be given asoutpatient treatment and it is lesstoxic than amphotericin despite the important but rare side effects of hepatitis and blockade of androgen biosynthesis (CLISSOLD, 1987). Another study of ketoconazolein this infection was reported by DROUHET & DUPONT (1983): who described the results of treatment of 4 patients with African histoplasmosis. They found that one patient was cured at follow-up 34 months after starting therapy, but the other 3 relapsed. Two of the latter had widely disseminated infections, which reinforces the view that ketoconazole is less effective in widespread disease, but may be useful in patients with localized lesions. Treatment of someforms of classical infections, as with the African forms, have responded less well. It is possible that the. newer triazole antifungal itraconazole may be more active against both forms of histoplasmosis and early reports of its use in treatment of the classical small form infections have been encouraging (NEGRONI et al., 1987). References Brown, K. G. E., Molesworth, B. D., Boerrighter, F. G. G. & Tozer, R. A. (1974). Disseminated histoplasmosis duboisii in Malawi. Partial response to sulphonamide/ trimethoprim combination. East African Medical Journal. 51. 584-590. Clissold, S. P. (1987). Safety in clinical practice. In: Ketoconazole Todq. A Review of Clinical Experience, F-r, H. E. (ednor). Manchester: Adrs Press, pp.
Fig. 5. Patient 5 at presentation.
appearance. Ketoconazole was given (7 mg/kg) for 6 weeks, after which both lesions had healed. Case 5
M.M:, a female aged 37 years. Lesions due to large form mstoplasmosis on her scalp and forehead had been present for 4 years (Fig. 5). Ketoconazole (8 mg/kg) was given for 6 weeks, after which there was someimprovement; subsequently she was lost to follow-up.
Cockshottt. W. P. & Lucas, A. 0. (1964). Histoplasmosis duborsn. Quarter& Journal of Medicine, 33, 223-238. Drouhet, E. (in press). African Histoplasmosis in Tropical Fungal Infections. Clinical Tropical Medicine and Communicable Diseases Series. London: Bailliere Tindall. Drouhet, E. & Dupont, B. (1983). Laboratory and clinical assessment of ketoconazole in deep-seated mycoses. Am&an Journal of Medicine, 74, lB, 3047. Goodwin, R. A. & Des Prez, R. M. (1978). Histoplasmosis. American Review of Respiratory Diseases, 117, 929-956. Mabey, D. C. W., Ajdnkiewicz, A. B. & Hay, R. J. (1983). Treatment of African histoplasmosis with ketoconazole. Transactions of the Royal Society of Tropical Medicine and Hygiene, 77, 219-221.
Negroni, R., Pahnieri, P., Koren, F., Tiraboschi, I. N. & Galimberti, R. (1987). Oral treatment of paracoccidioidomycosis and histoplasmosis“th itraconazole in hnm~4~-S$zvews of Znfectwus Daseases, 9, supplement 1, Vanbreuseghem?R. (1953). Histoplasma duboisii and African histoplasmosis. Mycologicl, 45, 803-816. Received accepted
14 Februaty 1989; revised 15 March publication 15 March 1989
for
1989;
TRANSACTNXVS OFTHEROYALSOCIETY OFTROPICAL MEDICINE ANDHYGIENE
Further studies ketoconazole
on the treatment
(1989) 83, 560-562
of African histoplasmosis
with
D. C. W. Mabey’* and R. J. Hati ‘Medical Research Council Laboratories, Fajara, ‘0 epartment of Clinical Sciences, London School of Hygiene and Tropical Medicine
The Gambia;
Abstract
Five patients with African histoplasmosis were treated with ketoconazole. Three of these were children with disseminated diseaseand 2 were adults with localized cutaneous disease. Both patients with cutaneous disease responded to treatment, although one was lost to follow-up. Of the 3 children with disseminated disease, one was apparently cured, one responded well but subsequently relapsed, and one failed to respond in spite of having blood levels of ketoconazole within the therapeutic range. Further studies are needed to determine the optimum dosage and duration of treatment with ketoconazole for this condition. Introduction
The word histoplasmosis is used to describe two distinct conditions-classical or small form histoplasmosis (histoplasmosis capsulati) and African or large form histoplasmosis (histoplasmosis duboisii). The former is widely distributed throughout the old and new worlds and is caused by Histoplasma capsulatum var. caps&turn whose yeast forms in tissue are seldom larger than 5 w in diameter. The principle clinical manifestations of this type of histoplasmosis are respiratory, although chronic mucosal ulcers or adrenal disease as well as fulminating disseminated infection may occur (GOODWIN8z DES PREZ,1978). As the name suggeststhe African form is restricted to central and west Africa. It is causedby H. capsulatum var. duboisii which produces much larger yeast forms in tissues (8-12 w) and the commonest clinical features are skin or bone infection (COCKSHOTT & LUCAS, 19643 VANBREUSEGHEM,
1953).
The principle therapy for African histoplasmosis has been intravenous amphotericin B (COCKSHOTT& LUCAS, 1964; DROUHET,in press), although simple excision (DROUHET,in press) for localized lesions and oral sulphonamides (BROWN et al., 1974) have also been used with varying degrees of success. We have previously reported a caseof disseminated disease successfully treated with oral ketoconazole (MABEY et al., 1983). We report here the long-term follow up of this patient, and our experience in treating 4 further patients with this drug. Case Reports Case I
S.T., a female aged 4 years and weighing 13 kg, was the subject of a previous report (MABEY et al., 1983). She presented with painful swelling affecting the lower left femur. Biopsy showed multiple yeasts ‘Presentaddress:Departmentof Clinical Sciences,London Schoolof Hygieneand Tropical Medicine, Keppel Street, London, WClE 7HT, UK.
Fig. 1. Patient1 showing skinlesionstypicalof Africanhistoplasmosis. with the morphological appearanceof H. capsulatum var. duboisii. Six weeks after the biopsy generalized skin lesions characteristic of West African histoplasmosis were noted (Fig. 1). She was treated with a total of 293 mg of amphotericin B over 5 weeks with considerable improvement, after which shewas lost to follow-up for 14 months. When next seenshe was febrile and emaciated, with extensive generalized ulceration of the skin, and 5 long bones were involved, with a massiveabscessover the left tibia. Amophotericin B was resumed (a total of 405 mg being given over 16 weeks), after which the skin lesions had healed but the tibia continued to
561 discharge. Amphotericin was discontinued and treatment with ketoconazole was instituted (15 mg/kg/d). After 6 weeks there was no further discharge. Ketoconazole was continued at the samedosagefor 32 weeks, after which it was stopped. 6 weeks later there was painful swelling of the lower right fibula, with a purulent discharge containing yeasts of H. Treatment was restarted cabsulatum var. dub&i. (lb mg/kg) and continued for a further 11 months, after which time all lesions had healed and the natient was well. When last seen, one year after treatment was discontinued, she remamed asymptomatic. Case 2
C.T., a female aged 5 years, weighed 18 kg. She presented with painless cervical lymphadenopathy. A bioosv showed multiole veastswith the moruholoeical appearancesof H. capsuiatum var. duboisii.*3 moiths after biopsy, generalized painless lymphadenopathy developed. Treatment was started with intravenous amphoteritin B, 0.25 mg/kg/d, increasing by 1 mg daily. After her 12th dose (0.6 mg/kg) she suffered a rigor with fever? and this occurred after each of the next 3 doses in spite of reducing the dosageto 0.25 mg/kg. Blood urea was also raised at this time (7.5 mmol/litre), and treatment was discontinued. Six months later she was found to have massive cervical lymphadenopathy, with glands up to 5 cm in diameter, and glands greater than 2 cm diameter in both axillae and groins. Pus aspirated from a cervical gland contained numerous yeasts with the typical appearanceof H. capsulatum var. duboisii. Treatment was started with ketoconazole 10 mg/kg daily. This gave blood levels (2 h after the first dose) of 6.0 @ml, within the therapeutic range. After 10 months treatment with ketoconazole, the cervical and inguinal glands were less than 1 cm in diameter, but axillary glands of some 2 cm diameter remained. Treatment was discontinued since ketoconazole was no longer available, but restarted 3 months later. After a further year’s treatment, there were only shotty glands (< 1 cm) in the neck, axillae and groins, and treatment was discontinued. Six months later she remained in good health and no adenopathy was detected, but after a further 6 months a painless fluctuant swelling, 4 cmx2 cm, was noted on the right forearm (Fig. 2). Pus aspirated from this swelling contained numerous capsulated yeasts with the appearance of H. capsulatum var. duboisii. After a further 6 months treatment with ketoconazole this swelling remained unchanged.
continued for 3 months, after which time there was no change and it was discontinued. Three months later one swelling had discharged and was smaller (1 cm), but 2 lymph glands had appeared in the right posterior cervical triangle and one in the left supraclavicular region. Ketoconazole was restarted (12 mg/kg) and 2 months later the right-sided cervical swelling, which had become fluctuant, was aspirated. Pus contained yeasts of H. capsulatum var. duboisii. 7 months later the swellings were all larger (Fig. 3), although ketoconazole levels had been shown to be in the therapeutic range (12.8 @ml 2 h after dosing). Treatment with intravenous amphotericin B was therefore started, at a dose of 5 mg initially, increasing by 1 mg daily to a total of 1 mg/kg/d. After 6 weeks the swellings were all smaller, and amphoteritin was reduced to 1 mg/kg twice weekly, which was continued for 6 weeks. 4 months after treatment was stopped there was no detectable lymphadenopathy, and when last seen after a further 5 months no abnormality was found. Case 4
Y.K. was an adult male aged 50 years. Skin lesions had been present on his right upper arm for at least 3 years (Fig. 4). Biopsy showed a dermal Mammatory infiltrate with giant cells, some of which contained yeasts with the appearance of H. capsulatum var. duboisii.
He received ketoconazole 7 mg/kg; after 2 weeks there was considerable improvement. Lost to followup after 4 weeks treatment? he returned 9 months later with new lesions on his chest wall adjacent to those on his arm, which had returned to their original
Fig. 2. Patient 2. Cold abscesswhich appeared 12 months after treatment was stopped.
Case 3
G. J. was a male patient aged 10 years. He weighed 34 kg. He presented with a swelling on the back of the neck, present for 2 years. On examination there were two fluctuant painless swellings about 3 cm in diameter. Biopsy revealed numerous yeasts with the appearanceof H. capsulatum var. duboisii. Ketoconazole (6 mg/kg) was given for 5 months, after which time the swellings were unchanged. Increasing the dose to 12 mg/kg for a further month had no effect. Surgical removal was therefore attempted, but 4 weeks after this a firm swelling appeared along the operation scar and a gland of 2 cm diameter below it. Ketoconazole was restarted at a dose of 6 mg/kg and
Fig. 3. Patient 3 after unsuccessful treatment with ketoconazole.
562
Fig. 4. Patient 4 at presentation.
Discussion We have described the treatment with oral ketoconazole of 5 patients with African histoplasmosis. The 2 patients in whom diseasewas localized to the skin appeared to respond satisfactorily, although one was lost to follow-up. The 3 children with disseminated diseasehad a less predictable response. One was apparently cured by ketoconazole, one was cured but relapsed after treatment was discontinued, and the last showed no responsein spite of prolonged treatment and adequate blood levels, but subsequently responded to amphotericin B. In view of this heterogeneity it is difficult to make recommendations on the optimum dosageor duration of treatment, which will need to await further studies on larger numbers of patients. However, ketoconazole has some potential advantages over existing therapy with amphotericin B. It can be given asoutpatient treatment and it is lesstoxic than amphotericin despite the important but rare side effects of hepatitis and blockade of androgen biosynthesis (CLISSOLD, 1987). Another study of ketoconazolein this infection was reported by DROUHET & DUPONT (1983): who described the results of treatment of 4 patients with African histoplasmosis. They found that one patient was cured at follow-up 34 months after starting therapy, but the other 3 relapsed. Two of the latter had widely disseminated infections, which reinforces the view that ketoconazole is less effective in widespread disease, but may be useful in patients with localized lesions. Treatment of someforms of classical infections, as with the African forms, have responded less well. It is possible that the. newer triazole antifungal itraconazole may be more active against both forms of histoplasmosis and early reports of its use in treatment of the classical small form infections have been encouraging (NEGRONI et al., 1987). References Brown, K. G. E., Molesworth, B. D., Boerrighter, F. G. G. & Tozer, R. A. (1974). Disseminated histoplasmosis duboisii in Malawi. Partial response to sulphonamide/ trimethoprim combination. East African Medical Journal. 51. 584-590. Clissold, S. P. (1987). Safety in clinical practice. In: Ketoconazole Todq. A Review of Clinical Experience, F-r, H. E. (ednor). Manchester: Adrs Press, pp.
Fig. 5. Patient 5 at presentation.
appearance. Ketoconazole was given (7 mg/kg) for 6 weeks, after which both lesions had healed. Case 5
M.M:, a female aged 37 years. Lesions due to large form mstoplasmosis on her scalp and forehead had been present for 4 years (Fig. 5). Ketoconazole (8 mg/kg) was given for 6 weeks, after which there was someimprovement; subsequently she was lost to follow-up.
Cockshottt. W. P. & Lucas, A. 0. (1964). Histoplasmosis duborsn. Quarter& Journal of Medicine, 33, 223-238. Drouhet, E. (in press). African Histoplasmosis in Tropical Fungal Infections. Clinical Tropical Medicine and Communicable Diseases Series. London: Bailliere Tindall. Drouhet, E. & Dupont, B. (1983). Laboratory and clinical assessment of ketoconazole in deep-seated mycoses. Am&an Journal of Medicine, 74, lB, 3047. Goodwin, R. A. & Des Prez, R. M. (1978). Histoplasmosis. American Review of Respiratory Diseases, 117, 929-956. Mabey, D. C. W., Ajdnkiewicz, A. B. & Hay, R. J. (1983). Treatment of African histoplasmosis with ketoconazole. Transactions of the Royal Society of Tropical Medicine and Hygiene, 77, 219-221.
Negroni, R., Pahnieri, P., Koren, F., Tiraboschi, I. N. & Galimberti, R. (1987). Oral treatment of paracoccidioidomycosis and histoplasmosis“th itraconazole in hnm~4~-S$zvews of Znfectwus Daseases, 9, supplement 1, Vanbreuseghem?R. (1953). Histoplasma duboisii and African histoplasmosis. Mycologicl, 45, 803-816. Received accepted
14 Februaty 1989; revised 15 March publication 15 March 1989
for
1989;