Journal of Infection (I992) z4, 67-7I
CASE REPORT Rhinocerebral
mucormycosis following bone marrow transplantation
D. S. Hyatt,* Y. M. Young,~: K. A. Haynes,* J. M. T a y l o r , t D. M. M c C a r t h y ~ a n d T. R. Rogers*
* Department of Medical Microbiology, Charing Cross and Westminster Medical School, I7 Horseferry Road, London S W I and t Department of Haematology, Charing Cross Hospital, Fulham Palace Road, London W6 8RF, U.K. Accepted for publication 27 June I99I Summary
Rhizopus oryzae was the causative organism in a fatal case of rhinocerebral and then pulmonary mucormycosis in a patient cured of her underlying leukaemia by bone marrow transplantation. We discuss the risk factors involved and the need for maintaining a high index of suspicion of fungal infection in the late post-transplant period.
Introduction Members of the order Mucorales (class Zygomycetes) are ubiquitous moulds which have been documented as opportunistic pathogens of man. T h e most common aetiological agent is Rhizopus oryzae. Invasive infection with these fungi is most commonly associated with uncontrolled diabetes mellitus (particularly if there is ketoacidosis), though infection in neutropenic cancer patients has been reported? We discuss here a patient who presented with the classical signs and symptoms of rhinocerebral and then pulmonary mucormycosis 6 months after an allogeneic bone marrow graft for chronic granulocytic leukaemia. This is the first time that this presentation of mucormycosis has been reported following bone marrow transplantation (BMT).
Case report A 39-year-old woman was admitted to Westminster Hospital in November I988 with an 8 days' history of headache, transient loss of sight, facial pain and numbness for which she had been treated with aspirin. Chronic granulocytic leukaemia had been diagnosed in February I988 and she had undergone B M T from her HLA-compatible sister in May of the same year. T h e initial transplant period was complicated by cutaneous graft-vs.host disease (GVHD) which was controlled with steroids. She was discharged home, well, on prednisolone (I5 mg daily), glibenclamide for steroid induced Present address: Department of Public Health Medicine, St Georges' Hospital, Blackshaw Road,
London SWw oRE, U.K. oi63-4453/92/oioo67+05 $03.00/0
© I992 The British Society for the Study of Infection 3-2
68
D. S. H Y A T T
ET AL.
diabetes (5 mg daily), cyclosporin A (I3O mg daily) and cotrimoxazole for prophylaxis of Pneumocystis carinii pneumonia (two tablets twice weekly). Physical examination on admission revealed she was afebrile, had facial swelling more on the left side than the right and decreased sensation in the distribution of the left trigeminal nerve. Other cranial nerves were intact. She had a black necrotic lesion on the left side of the palate (Plate I). Swabs of this area were taken on days I and 2 after admission and it was biopsied on the sixth day. T h e chest was clinically and radiologically clear. A peripheral total WBC was normal and the patient was not neutropenic. Her blood glucose level was raised at 22 mmol/6, though she was not keto-acidotic. Sliding-scale insulin treatment was started. During the next 48 h the necrotic lesion spread to cover most of the hard palate, and intravenous metronidazole, erythromycin and amphotericin B (I m g / k g / d a y ) were started. T h e patient was also given oral itraconazole (200 mg daily). On day 3 she became pyrexial (39 °C) and developed a nonproductive cough. Slight shadowing on the chest radiograph was noted which progressed to a 'whiteout' of both lung fields by day IO. Antibiotic therapy was changed to include sequentially ceftazidime, imipenem and netilmicin, with no clinical response. T h e palatal necrosis and facial pain also progressed over the same time and involvement of the gums was noted. By day 7 it became impossible for her to eat and parenteral nutrition was started. T h e patient died from respiratory failure I5 days after admission.
Mycology and microbiology T h e palatal swabs taken on days i and 2 after admission were cultured on Sabouraud's dextrose agar at 30 °C. Candida albicans was isolated from both swabs after 24 h incubation. White cottony colonies were also present on one plate. Lactophenol cotton blue examination of these colonies revealed the broad aseptate hyphae, terminal sporangia and rhizoids (root-like anchors) located directly beneath clumped sporangiophores characteristic of Rhizopus spp. This isolate was sent to the U K Mycological Reference Laboratory, Public Health Laboratory Service, Colindale, London and identified as R. oryzae. This organism has been entered into the U K National Collection of Pathogenic Fungi as R. oryzae N C P F 2712. Histological examination of invasive mucormycotic lesions characteristically shows coagulative and haemorrhagic necrosis, aseptate hyphae, vascular thrombosis and neutrophilic infiltration. 2 Microscopic examination of the hard-palate biopsy specimen from this patient confirmed invasive infection with both R. oryzae and C. albicans, although only limited neutrophil infiltration was seen (Plate 2). Pleural fluid was cultured for bacteria, fungi and viruses; no organisms were isolated. Culture of urine, buffy coat and respiratory secretion specimens for cytomegalovirus and other viruses were negative, as was immunofluorescence for respiratory syncytial virus.
Journal of Infection
Plate I
Plate i. Hard palate showing infarcted area secondary to fungal invasion of blood vessels.
D. S. HYATT ET AL.
(Facing p. 68)
Journal of Infection
Plate 2
q
Place x. Section of palatal biopsy showing broad aseptate hyphae of Rhizopus oryzae and small pSeudofi~pha~ of Candida albicans. Magnification x 400. Stain haematoxylin and eosin.
D. S. HYATT ET AL.
Rhinocerebral mucormycosis
69
Discussion
M u c o r m y c o s i s is almost exclusively a disease of i m m u n o c o m p r o m i s e d hosts. 1 M a n y of the k n o w n risk factors associated with its d e v e l o p m e n t such as administration of corticosteroids and severe neutropenia are present in the p o s t - B M T patient population, in w h o m this infection is likely to b e c o m e increasingly recognised. O u r patient was not neutropenic b u t was also not yet fully i m m u n o c o m p e t e n t , she was only 6 months post-transplant and had mild G V H D ; full i m m u n e reconstitution does not occur for at least 12 months postB M T and is delayed further when G V H D occurs. H e r diabetes mellitus secondary to steroid treatment and concurrent candidial infection m a y also have c o n t r i b u t e d to the development of invasive mucormycosis. A further risk factor for the development of m u c o r m y c o s i s is desferrioxamine therapy for iron overload. Desferrioxamine acts as a siderophore for R. oryzae, a and both its presence and the presence of iron enhance the pathogenicity of this organism by serving as a growth factor. O u r patient was not keto-acidotic and it was therefore unlikely that increased availability of iron (which is associated with this state) was operating as a risk factor. Primary p u l m o n a r y m u c o r m y c o s i s has been reported p o s t - B M T . 1'2 Infection begins with fever and p u l m o n a r y infiltrates, which persist despite antifungal therapy. Dissemination is common. H o w e v e r , rhinocerebral m u c o r m y c o s i s is usually associated with poorly controlled diabetes mellitus. Spores of the fungus are inhaled, begin to germinate and then hyphal invasion of the nasal sinus a n d / o r palate occurs. This is rapidly followed b y spread of the infection to the adjacent paranasal sinuses and possibly to the retro-orbital area and finally to the brain. This accounts for the classical s y m p t o m s seen here of headache, loss of vision and dysfunction of the cranial nerves. Substantial clearing of invasive hyphae has been reported with i m p r o v e d control of diabetes alone, 4 t h o u g h this is rare. Neutrophils seem to play a large role in defence against this infection; neutropenia is a major risk factor, and the presence of neutrophil-rich exudates surrounding hyphae has been associated with the resolution of experimental lesions. 5 Diabetic neutrophils are persistently abnormal; they display impaired chemotaxis and nitroblue tetrazolium reduction, and have disturbances of glycolytic processes. All these factors contribute to their observed reduction in microbicidal efficiency. 6 Similar defects have been demonstrated in neutrophils from patients receiving steroids. 7 In contrast to classical lesions of invasive mucormycosis, 1 examination of the palatal biopsy specimen from this patient showed no neutrophil response even though she was not neutropenic on admission. N e u t r o p h i l chemotaxis induced by m e m b e r s of the Mucorales order is mediated b y products of the alternative c o m p l e m e n t pathway, s C o m p l e m e n t levels in this patient were normal (C3 = i- 3 g / l ; normal range = o'7-1" 7 g/l). Therefore, the observed lack of infiltration may have been the result of a functional defect in neutrophils caused by the diabetes or steroid treatment. It is also possible that the concurrent C. albicans infection resulted in further reduction of neutrophil function. Candida spp. culture supernatants contain an inhibitory peptide which binds to the surface o f n e u t r o p h i l s and inhibits both the respiratory burst and chemotaxis. 9
D. S. H Y A T T E T A L .
70
In addition, the candidial polysaccharide m a n n a n has been shown to have a deleterious effect on h u m a n phagocytic cell function. 1° Once invasive m u c o r m y c o t i c infections become established t r e a t m e n t is difficult and mortality is high. W h e r e possible, reducing i m m u n o s u p p r e s s i o n and improving diabetic control m a y help; however, the mainstay of therapy remains aggressive surgery in combination with antifungal drugs. 1 In a review of p o s t - B M T p u l m o n a r y fungal infections the two patients who survived (of 27 reported) had both extensive surgery and drug treatment. 11 Similarly, in a review of head and neck infections with Aspergillus the authors concluded that both radical surgery and systemic amphotericin B therapy were required for cure. 12 It was possible that p r o m p t head and neck surgery in our patient, while the lesion was still localised, could have assisted in a cure. By the time p u l m o n a r y infiltrates were found, thoracic surgery had been precluded by her general condition and the extent of her rhinocerebral involvement. Early diagnosis before the patient is too unwell for aggressive therapy is therefore crucial. T h e frequency with which Mucorales are isolated as culture plate contaminants means that the significance of their isolation is difficult to evaluate. Biopsy is therefore essential and should be performed as soon as mucormycosis is suspected so that treatment can be started as soon as possible. F o u r previous cases of mucormycosis following B M T have appeared in the literature; one cutaneous with rapid dissemination 13 and three pulmonary. 11 T h e s e patients received amphotericin B alone and all died. A recent report has shown in vitro evidence for synergy between amphotericin B and rifampicin and demonstrated the success of this combination therapy in a keto-acidotic patient with R h i z o p u s infection. 14 T h e problems of infection in the early p o s t - B M T period are now well recognised, j5 T h e i r anticipation allows prophylaxis, early diagnosis and p r o m p t treatment, which in our patient would have been d e b r i d e m e n t as well as amphotericin B. References i. Lehrer RI, Howard DH, Sypher PS et al. Mucormycosis. Ann Intern Med I98o; 93: 93-1o8. 2. Sheldon WH, Bauer H. The development of the acute inflammatory response to experimental cutaneous mucormycosis in normal and diabetic rabbits. J Exp Med I959; IIO: 845--852.
3- Abe F, Inaba H, Katch T, Hdeki M. Effects of iron and desferrioxamine on Rhizopus infections. Mycopathologia I99O; IIO: 87-91. 4. Baker RD. Mucormycosis - a new disease? J A M A I957; 163 : 8o5-808. 5. Bauer H, Flanagan JF, Sheldon WH. Experimental cerebral mucormycosis in rabbits with alloxan diabetes. Yale J Biol Med I955; z8: 29-36. 6. Bagdade JD, Root RI, Bulger RI. Impaired leucocyte function of patients with poorly controlled diabetes. Diabetes 1974; 23: 9-15. 7. Clemmensen O, Andersen V, Ebbe-Hansen Net al. Sequential studies of lymphocytes, neutrophils and serum proteins during prednisone treatment. Acta Med Scand z976; x99: 105--111. 8. Marx RS, Forsyth KR, Hentz SK. Mucorales species activation of a serum leukotactic factor. Infect Immun I982; 38: 1217-I222. 9. Diamond RD, Oppenheim F, Nakagawa Vet al. Properties of a product of Candida albicans hyphae and pseudohyphae that inhibits contact between the fungi and human neutrophils in vitro. J lmmunol I98O; IZS: 2804.
Rhinocerebral mucormycosis
7I
lO. Domer JE. Candida cell wall mannan: a polysaccharide with diverse immunological properties. Crit Rev Microbiol I989; I 7 : 3 3 - 5 1 . I I. Allan BT, Patton D, Ramsey N K C , Day DL. Pulmonary fungal infections after bone marrow transplantation. Paediatr Radiol I988 ; I8: I I8-I22. Ia. Schubert MM, Peterson DE, Meyers JD et al. Head and neck aspergillosis in patients undergoing bone marrow transplantation. Cancer 1986; 57: lO92-1o96. 13. Muskowski PL, Brown AE, Dinsmore R et al. Mucormycosis following bone marrow transplantation. J Am Acad Dermatol I983 ; 9 : I I I - I 15. 14. Christenson JC, Shalit I, Welch D F et al. Synergistic action of amphotericin B and rifampicin against Rhizopus species. Antimicrob Agents Chemother 198o; 3I: I775-1778. 15. Rogers TR. Infective complications of bone marrow transplantation. Curr Opinion Infect Dis 1988; I: 616-6~ 4.
CASE REPORT Rhinocerebral
mucormycosis following bone marrow transplantation
D. S. Hyatt,* Y. M. Young,~: K. A. Haynes,* J. M. T a y l o r , t D. M. M c C a r t h y ~ a n d T. R. Rogers*
* Department of Medical Microbiology, Charing Cross and Westminster Medical School, I7 Horseferry Road, London S W I and t Department of Haematology, Charing Cross Hospital, Fulham Palace Road, London W6 8RF, U.K. Accepted for publication 27 June I99I Summary
Rhizopus oryzae was the causative organism in a fatal case of rhinocerebral and then pulmonary mucormycosis in a patient cured of her underlying leukaemia by bone marrow transplantation. We discuss the risk factors involved and the need for maintaining a high index of suspicion of fungal infection in the late post-transplant period.
Introduction Members of the order Mucorales (class Zygomycetes) are ubiquitous moulds which have been documented as opportunistic pathogens of man. T h e most common aetiological agent is Rhizopus oryzae. Invasive infection with these fungi is most commonly associated with uncontrolled diabetes mellitus (particularly if there is ketoacidosis), though infection in neutropenic cancer patients has been reported? We discuss here a patient who presented with the classical signs and symptoms of rhinocerebral and then pulmonary mucormycosis 6 months after an allogeneic bone marrow graft for chronic granulocytic leukaemia. This is the first time that this presentation of mucormycosis has been reported following bone marrow transplantation (BMT).
Case report A 39-year-old woman was admitted to Westminster Hospital in November I988 with an 8 days' history of headache, transient loss of sight, facial pain and numbness for which she had been treated with aspirin. Chronic granulocytic leukaemia had been diagnosed in February I988 and she had undergone B M T from her HLA-compatible sister in May of the same year. T h e initial transplant period was complicated by cutaneous graft-vs.host disease (GVHD) which was controlled with steroids. She was discharged home, well, on prednisolone (I5 mg daily), glibenclamide for steroid induced Present address: Department of Public Health Medicine, St Georges' Hospital, Blackshaw Road,
London SWw oRE, U.K. oi63-4453/92/oioo67+05 $03.00/0
© I992 The British Society for the Study of Infection 3-2
68
D. S. H Y A T T
ET AL.
diabetes (5 mg daily), cyclosporin A (I3O mg daily) and cotrimoxazole for prophylaxis of Pneumocystis carinii pneumonia (two tablets twice weekly). Physical examination on admission revealed she was afebrile, had facial swelling more on the left side than the right and decreased sensation in the distribution of the left trigeminal nerve. Other cranial nerves were intact. She had a black necrotic lesion on the left side of the palate (Plate I). Swabs of this area were taken on days I and 2 after admission and it was biopsied on the sixth day. T h e chest was clinically and radiologically clear. A peripheral total WBC was normal and the patient was not neutropenic. Her blood glucose level was raised at 22 mmol/6, though she was not keto-acidotic. Sliding-scale insulin treatment was started. During the next 48 h the necrotic lesion spread to cover most of the hard palate, and intravenous metronidazole, erythromycin and amphotericin B (I m g / k g / d a y ) were started. T h e patient was also given oral itraconazole (200 mg daily). On day 3 she became pyrexial (39 °C) and developed a nonproductive cough. Slight shadowing on the chest radiograph was noted which progressed to a 'whiteout' of both lung fields by day IO. Antibiotic therapy was changed to include sequentially ceftazidime, imipenem and netilmicin, with no clinical response. T h e palatal necrosis and facial pain also progressed over the same time and involvement of the gums was noted. By day 7 it became impossible for her to eat and parenteral nutrition was started. T h e patient died from respiratory failure I5 days after admission.
Mycology and microbiology T h e palatal swabs taken on days i and 2 after admission were cultured on Sabouraud's dextrose agar at 30 °C. Candida albicans was isolated from both swabs after 24 h incubation. White cottony colonies were also present on one plate. Lactophenol cotton blue examination of these colonies revealed the broad aseptate hyphae, terminal sporangia and rhizoids (root-like anchors) located directly beneath clumped sporangiophores characteristic of Rhizopus spp. This isolate was sent to the U K Mycological Reference Laboratory, Public Health Laboratory Service, Colindale, London and identified as R. oryzae. This organism has been entered into the U K National Collection of Pathogenic Fungi as R. oryzae N C P F 2712. Histological examination of invasive mucormycotic lesions characteristically shows coagulative and haemorrhagic necrosis, aseptate hyphae, vascular thrombosis and neutrophilic infiltration. 2 Microscopic examination of the hard-palate biopsy specimen from this patient confirmed invasive infection with both R. oryzae and C. albicans, although only limited neutrophil infiltration was seen (Plate 2). Pleural fluid was cultured for bacteria, fungi and viruses; no organisms were isolated. Culture of urine, buffy coat and respiratory secretion specimens for cytomegalovirus and other viruses were negative, as was immunofluorescence for respiratory syncytial virus.
Journal of Infection
Plate I
Plate i. Hard palate showing infarcted area secondary to fungal invasion of blood vessels.
D. S. HYATT ET AL.
(Facing p. 68)
Journal of Infection
Plate 2
q
Place x. Section of palatal biopsy showing broad aseptate hyphae of Rhizopus oryzae and small pSeudofi~pha~ of Candida albicans. Magnification x 400. Stain haematoxylin and eosin.
D. S. HYATT ET AL.
Rhinocerebral mucormycosis
69
Discussion
M u c o r m y c o s i s is almost exclusively a disease of i m m u n o c o m p r o m i s e d hosts. 1 M a n y of the k n o w n risk factors associated with its d e v e l o p m e n t such as administration of corticosteroids and severe neutropenia are present in the p o s t - B M T patient population, in w h o m this infection is likely to b e c o m e increasingly recognised. O u r patient was not neutropenic b u t was also not yet fully i m m u n o c o m p e t e n t , she was only 6 months post-transplant and had mild G V H D ; full i m m u n e reconstitution does not occur for at least 12 months postB M T and is delayed further when G V H D occurs. H e r diabetes mellitus secondary to steroid treatment and concurrent candidial infection m a y also have c o n t r i b u t e d to the development of invasive mucormycosis. A further risk factor for the development of m u c o r m y c o s i s is desferrioxamine therapy for iron overload. Desferrioxamine acts as a siderophore for R. oryzae, a and both its presence and the presence of iron enhance the pathogenicity of this organism by serving as a growth factor. O u r patient was not keto-acidotic and it was therefore unlikely that increased availability of iron (which is associated with this state) was operating as a risk factor. Primary p u l m o n a r y m u c o r m y c o s i s has been reported p o s t - B M T . 1'2 Infection begins with fever and p u l m o n a r y infiltrates, which persist despite antifungal therapy. Dissemination is common. H o w e v e r , rhinocerebral m u c o r m y c o s i s is usually associated with poorly controlled diabetes mellitus. Spores of the fungus are inhaled, begin to germinate and then hyphal invasion of the nasal sinus a n d / o r palate occurs. This is rapidly followed b y spread of the infection to the adjacent paranasal sinuses and possibly to the retro-orbital area and finally to the brain. This accounts for the classical s y m p t o m s seen here of headache, loss of vision and dysfunction of the cranial nerves. Substantial clearing of invasive hyphae has been reported with i m p r o v e d control of diabetes alone, 4 t h o u g h this is rare. Neutrophils seem to play a large role in defence against this infection; neutropenia is a major risk factor, and the presence of neutrophil-rich exudates surrounding hyphae has been associated with the resolution of experimental lesions. 5 Diabetic neutrophils are persistently abnormal; they display impaired chemotaxis and nitroblue tetrazolium reduction, and have disturbances of glycolytic processes. All these factors contribute to their observed reduction in microbicidal efficiency. 6 Similar defects have been demonstrated in neutrophils from patients receiving steroids. 7 In contrast to classical lesions of invasive mucormycosis, 1 examination of the palatal biopsy specimen from this patient showed no neutrophil response even though she was not neutropenic on admission. N e u t r o p h i l chemotaxis induced by m e m b e r s of the Mucorales order is mediated b y products of the alternative c o m p l e m e n t pathway, s C o m p l e m e n t levels in this patient were normal (C3 = i- 3 g / l ; normal range = o'7-1" 7 g/l). Therefore, the observed lack of infiltration may have been the result of a functional defect in neutrophils caused by the diabetes or steroid treatment. It is also possible that the concurrent C. albicans infection resulted in further reduction of neutrophil function. Candida spp. culture supernatants contain an inhibitory peptide which binds to the surface o f n e u t r o p h i l s and inhibits both the respiratory burst and chemotaxis. 9
D. S. H Y A T T E T A L .
70
In addition, the candidial polysaccharide m a n n a n has been shown to have a deleterious effect on h u m a n phagocytic cell function. 1° Once invasive m u c o r m y c o t i c infections become established t r e a t m e n t is difficult and mortality is high. W h e r e possible, reducing i m m u n o s u p p r e s s i o n and improving diabetic control m a y help; however, the mainstay of therapy remains aggressive surgery in combination with antifungal drugs. 1 In a review of p o s t - B M T p u l m o n a r y fungal infections the two patients who survived (of 27 reported) had both extensive surgery and drug treatment. 11 Similarly, in a review of head and neck infections with Aspergillus the authors concluded that both radical surgery and systemic amphotericin B therapy were required for cure. 12 It was possible that p r o m p t head and neck surgery in our patient, while the lesion was still localised, could have assisted in a cure. By the time p u l m o n a r y infiltrates were found, thoracic surgery had been precluded by her general condition and the extent of her rhinocerebral involvement. Early diagnosis before the patient is too unwell for aggressive therapy is therefore crucial. T h e frequency with which Mucorales are isolated as culture plate contaminants means that the significance of their isolation is difficult to evaluate. Biopsy is therefore essential and should be performed as soon as mucormycosis is suspected so that treatment can be started as soon as possible. F o u r previous cases of mucormycosis following B M T have appeared in the literature; one cutaneous with rapid dissemination 13 and three pulmonary. 11 T h e s e patients received amphotericin B alone and all died. A recent report has shown in vitro evidence for synergy between amphotericin B and rifampicin and demonstrated the success of this combination therapy in a keto-acidotic patient with R h i z o p u s infection. 14 T h e problems of infection in the early p o s t - B M T period are now well recognised, j5 T h e i r anticipation allows prophylaxis, early diagnosis and p r o m p t treatment, which in our patient would have been d e b r i d e m e n t as well as amphotericin B. References i. Lehrer RI, Howard DH, Sypher PS et al. Mucormycosis. Ann Intern Med I98o; 93: 93-1o8. 2. Sheldon WH, Bauer H. The development of the acute inflammatory response to experimental cutaneous mucormycosis in normal and diabetic rabbits. J Exp Med I959; IIO: 845--852.
3- Abe F, Inaba H, Katch T, Hdeki M. Effects of iron and desferrioxamine on Rhizopus infections. Mycopathologia I99O; IIO: 87-91. 4. Baker RD. Mucormycosis - a new disease? J A M A I957; 163 : 8o5-808. 5. Bauer H, Flanagan JF, Sheldon WH. Experimental cerebral mucormycosis in rabbits with alloxan diabetes. Yale J Biol Med I955; z8: 29-36. 6. Bagdade JD, Root RI, Bulger RI. Impaired leucocyte function of patients with poorly controlled diabetes. Diabetes 1974; 23: 9-15. 7. Clemmensen O, Andersen V, Ebbe-Hansen Net al. Sequential studies of lymphocytes, neutrophils and serum proteins during prednisone treatment. Acta Med Scand z976; x99: 105--111. 8. Marx RS, Forsyth KR, Hentz SK. Mucorales species activation of a serum leukotactic factor. Infect Immun I982; 38: 1217-I222. 9. Diamond RD, Oppenheim F, Nakagawa Vet al. Properties of a product of Candida albicans hyphae and pseudohyphae that inhibits contact between the fungi and human neutrophils in vitro. J lmmunol I98O; IZS: 2804.
Rhinocerebral mucormycosis
7I
lO. Domer JE. Candida cell wall mannan: a polysaccharide with diverse immunological properties. Crit Rev Microbiol I989; I 7 : 3 3 - 5 1 . I I. Allan BT, Patton D, Ramsey N K C , Day DL. Pulmonary fungal infections after bone marrow transplantation. Paediatr Radiol I988 ; I8: I I8-I22. Ia. Schubert MM, Peterson DE, Meyers JD et al. Head and neck aspergillosis in patients undergoing bone marrow transplantation. Cancer 1986; 57: lO92-1o96. 13. Muskowski PL, Brown AE, Dinsmore R et al. Mucormycosis following bone marrow transplantation. J Am Acad Dermatol I983 ; 9 : I I I - I 15. 14. Christenson JC, Shalit I, Welch D F et al. Synergistic action of amphotericin B and rifampicin against Rhizopus species. Antimicrob Agents Chemother 198o; 3I: I775-1778. 15. Rogers TR. Infective complications of bone marrow transplantation. Curr Opinion Infect Dis 1988; I: 616-6~ 4.
