Journal of Infection (I992) 25, 201-204
CASE REPORT Fatal d i s s e m i n a t e d Scedosporium inflatum i n f e c t i o n in a neutropenic immunocompromised patient Sherif S. Farag,*~ Frank C. Firkin,* John H. Andrew,$ C. Soon Lee~ and David H. Ellis][
* Departments of Medicine, t Microbiology and $ Anatomical Pathology, St Vincent's Hospital, Fitzroy, Victoria 3065 and []Department of Microbiology, Adelaide Children's Hospital, North Adelaide, South Australia 5006, Australia Accepted for publication 19 December I99I Summary Disseminated infection with the fungus Scedosporium inflatum in a neutropenic patient with non-Hodgkins lymphoma presented with the triad of muscle tenderness, papular skin lesions and fever, and progressed rapidly to a fatal outcome. This represents the first reported instance of fatal widely disseminated infection with this organism, and demonstrates that the triad of presenting clinical features, formerly reported to be pathognomic of systemic candidiasis, can no longer be regarded as specific for infection with a particular species of yeast or fungus.
Introduction Disseminated fungal infections are a major cause of death in i m m u n o c o m p r o mised patients, especially those with prolonged granulocytopenia, 1-3 and occur in between approximately IO % and 30 % patients with acute leukaemia and l y m p h o m a ) '3'~ Candida species are the most frequently identified causative agents, accounting for 7o-80 % systemic fungal infections 2,3'5 and the clinical triad of fever, skin lesions, and diffuse, severe muscle tenderness has been reported to be a specific feature of disseminated candidiasis under these circumstances. This report describes the triad of fever, skin lesions and severe muscle tenderness as the presenting feature of disseminated infection with Scedosporium inflatum in a neutropenic l y m p h o m a patient. It is the first report, to our knowledge, of a widely disseminated and fatal infection with this organism in the h u m a n , and demonstrates that these presenting clinical features cannot be regarded as specific for infection by a particular species of yeast or fungus.
Case report A 7z-year-old woman with follicular small cleaved cell l y m p h o m a was admitted for m a n a g e m e n t of neutropenic sepsis. L y m p h o m a had been diagnosed z years earlier, when she had presented with generalised ~[ Address correspondence to: Dr S. S. Farag, Department of Clinical Haematology, St Vincent's Hospital, Fitzroy, Victoria 3o65, Australia. oi63-4453/92/o5o2oi + o 4 $o8.oo/o 8
© x99I The British Society for the Study of Infection JIN 25
202
S.S. FARAG E T A L .
lymphadenopathy. Initial therapy had been with cycles of cyclophosphamide, vincristine and prednisolone (CVP), and was followed by unremitting neutropenia (o'5-r'2 x Iog/1). A year before the present admission she was treated with a 5-day course of high-dose Iv gammaglobulin (Intragam C S L , Melbourne, Australia) for a presumptive diagnosis of i m m u n e neutropenia. T h e r e was no response. T h r e e m o n t h s before admission she developed increasing lymphadenopathy, fever and night sweats. She was then treated with chlorambucil and prednisolone, but this was followed by more severe neutropenia. D u r i n g the m o n t h preceding her final admission she had an episode of fever which resolved on treatment with ticarcillin and gentamicin. N o causative organism was identified. Bone-marrow biopsy revealed extensive infiltration with lymphoma. T w o courses of mitoxantrone (r6 mg), etoposide (too mg) and prednisolone (IOO m g for 5 days) were administered, but she was then admitted with fever and neutropenia. At presentation she had been ill for r week with fever, fatigue, vomiting and mild diffuse muscular pains which had failed to improve following treatment with oral amoxycillin and potassium clavulanate. Her temperature on admission was 37"2 °C. She had no rash except for some petechiae over the legs. T h e r e was enlargement of the axillary lymph nodes to 2 cm in diameter. T h e H b was 6"4 g/dl, W C C 0"5 x IO9/1, and platelet count 27 x tog/1. T h e chest X-ray was normal. Cultures of blood and urine were taken and treatment with ticarcillin and gentamicin was started. D u r i n g the next 3 days her temperature varied between 37"5 and 38 °C and she had increasing pain and tenderness in the limb muscles; on day 7 this became severe and involved also the tongue, jaw and extra-ocular muscles. She was no longer able to stand or walk because of pain and weakness, and parenteral narcotic analgesia was required. An erythematous papular rash with lesions of between i and I'5 cm in diameter developed on the trunk and limbs. N o organisms were grown from repeated blood cultures and IV vancomycin was started. Plasma creatine kinase, aldolase and lactate dehydrogenase levels were normal. D u r i n g the next 3 days there was persistent fever and increasing muscle pain and weakness. New skin lesions developed and became haemorrhagic. T h e r e were no sensory abnormalities, all reflexes were present and nerve conduction studies were normal. On day Io further blood cultures were taken and a lumbar puncture was performed under platelet transfusion cover. T h e C S F was clear, and microscopy revealed no WBCs and 3 R B C s x lO6/1. No organisms were seen on Gram-stained specimens, and cryptococcal antigen was not detected. Intravenous amphotericin B and flucytosine were administered, but during the next e days the patient's condition deteriorated and she died on day r 3. P o s t - m o r t e m examination revealed disseminated fungal deposits consisting of hyphal elements in liver, spleen, thyroid, m y o c a r d i u m and skeletal muscle (Plate I). F u n g u s was first detected by the D e p a r t m e n t of Microbiology at St Vincent's Hospital z days after death in cultures of blood and C S F obtained 5 days previously. T h e organism was referred to the D e p a r t m e n t of Microbiology, Adelaide Children's Hospital, where it was identified as
Scedosporium inflatum.
Journal of Infection
Plate I
Plate z. Skeletal muscle showing necrosis of muscle fibres and invasion by filamentous fungal elements. Haematoxylin and eosin ( x 400).
S. S. FARAGET AL.
(Facing p. 202)
Journal of Infection
Plate 2
Plate 2. Conidia and characteristic inflated annellides of Scedosporium inflatum (indicated by arrows). Phase contrast with lactophenol cotton blue stain ( × 7o0).
Disseminated Scedosporium inflatum infection
203
Discussion
Our observations demonstrate two previously u n r e p o r t e d findings in patients with haematological neoplasia and disseminated fungal infection. T h e y indicate that fatal disseminated infection with S. inflatum can occur in this setting, and can present with the triad of fever, rash, and myalgia. T h e syndrome of fever, papular skin rash and severe muscle tenderness has been reported to be a distinctive presentation of disseminated candidiasis. 6'7 T h e s e observations were in patients rendered neutropenic during treatment of acute leukaemia, and Candida tropicalis was the responsible organism. All patients died despite treatment with amphotericin B, and in one case (6), the triad of signs appeared while the patient was receiving amphotericin. Jarowski et al. 7 considered the syndrome sufficiently specific to warrant the presumptive diagnosis of disseminated candidiasis and to justify the empirical use of antifungal therapy. T h e case we report had almost identical features; profound and prolonged neutropenia, fever, a diffuse erythematous papular skin rash involving the trunk and extremities, and such severe muscle pain and tenderness that she refused to move legs, arms or eyes. Indeed the similarity to the reported cases p r o m p t e d a presumptive diagnosis of disseminated candidiasis ante mortem. However, failure to culture Candida species from repeated specimens of blood, urine and C S F , and the isolation of S. inflatum from blood and C S F casts serious doubt on a specific linkage of the syndrome to candidiasis. We suggest that further observations will indicate the triad to be a relatively non-specific feature of disseminated fungal infection. Scedosporium inflatum is a newly recognised pathogen of the dematiaceous h y p h o m y c e t o u s genus Scedosporium saccardo, first described by Malloch and Salkin. 8 It has been isolated from the soil of potted plants, and is most likely a soil saprophyte. T h e clinical spectrum of S. inflatum infection has been reported recently) Virtually all infections have been localised, and have involved musculoskeletal tissue (often following penetrating trauma or surgery), or have caused skin ulcers, and in one case a self-limited respiratory illness. One previous fatal case of disseminated S. inflatum infection, which also occurred in our hospital in I986, has been reported by Wilson et al. 9 T h i s was in an i m m u n o c o m p r o m i s e d renal transplant patient who developed peritonitis following a r u p t u r e d sigmoid diverticulum. Scedosporium inflatum was isolated before death from peritoneal fluid, an infected abdominal w o u n d and a pleural effusion. T h e isolation of the organism from the culture of blood and C S F has not been previously reported. T h e present report is the first d o c u m e n t e d case of widely disseminated infection with S. inflatum giving rise to extensive tissue invasion. T h e identification of this fungus from the better-known Scedosporium apiospermum was by the recognition of annellides with distinctive swollen bases (Plate a), and by its failure to grow on cycloheximide-containing media. 1° Annellides occur singly or in clusters along the vegetative hyphae, and produce aggregates of unicellular, smooth-walled, hyaline to pale-brown, ovoid conidia. Cultures of S. inflatum are typically olive-grey to black in colour. Scedosporium apiospermum has been reported to cause both focal and disseminated 8-2
204
S. S. FARAG E T A L .
i n f e c t i o n s . 11 T h e clinical i m p l i c a t i o n s o f d i s s e m i n a t e d i n f e c t i o n w i t h S. inflatum are o m i n o u s in v i e w o f t h e r e s i s t a n c e o f this o r g a n i s m to a m p h o t e r i c i n a n d o t h e r a n t i f u n g a l agents. 9'1° W e c o n c l u d e t h a t t h e clinical s p e c t r u m o f i n f e c t i o n w i t h S. inflatum can b e e x p a n d e d to i n c l u d e d i s s e m i n a t e d i n f e c t i o n in g r a n u l o c y t o p e n i c p a t i e n t s , a n d t h a t s u c h i n f e c t i o n can p r e s e n t w i t h t h e t r i a d o f f e v e r , r a s h a n d m y a l g i a s , p r e v i o u s l y t h o u g h t to b e specific f o r d i s s e m i n a t e d candidiasis. References
I. Levine AS, Graw RG, Young RC. Management of infections in patients with leukemia and lymphoma: current concepts and experimental approaches. Semin Hematol I972; 9: I4I-I7r. 2. Bodey GP. Infections in cancer patients. Cancer Treat Rev x975; 2: 89-I28. 3. Bodey GP. Fungal infections complicating acute leukemia, ff Chronic Dis I966; I9: 667-687. 4. Meunier F. Candidiasis. Eur ff Clin Microbiol Infect Dis I989; 8: 438-447. 5. Young RC, Bennett JE, Geelhoed G, Levine AS. Fungemia with compromised host resistance: a study of 70 cases. Ann Intern Med I974; 80: 6o5-612. 6. Arena FP, Perlin M, Brahman H, Weiser B, Armstrong D. Fever, rash and myalgias of disseminated candidiasis during antifimgal therapy. Arch Intern Med I98I ; I41 : I233. 7. Jarowski CI, Fialk MA, Murray HW et al. Fever, rash and muscle tenderness : a distinctive clinical presentation of disseminated candidiasis. Arch Intern Med r978; I38: 544-546. 8. Malloch D, Salkin IF. A new species of Scedosporium associated with osteomyelitis in humans. Mycotaxon I984; 2x: 247-255. 9. Wilson CM, O'Rourke EJ, McGinnis MR, Salkin IF. Scedosporium inflatum: clinical spectrum of a newly recognized pathogen. J Infect Dis I99O; ,6I : Io2-Io7. to. Salkin IF, McGinnis MR, Dykstra MJ, Rinaldi MG. Scedosporium inflatum, an emerging pathogen. J Clin Microbiol r988; 26: 498-503. II. Travis LB, Roberts GD, Wilson WR. Clinical significance of Pseudallescheria boydii: a review of io years experience. Mayo Clin Proc I985; 6o: 531-537-
CASE REPORT Fatal d i s s e m i n a t e d Scedosporium inflatum i n f e c t i o n in a neutropenic immunocompromised patient Sherif S. Farag,*~ Frank C. Firkin,* John H. Andrew,$ C. Soon Lee~ and David H. Ellis][
* Departments of Medicine, t Microbiology and $ Anatomical Pathology, St Vincent's Hospital, Fitzroy, Victoria 3065 and []Department of Microbiology, Adelaide Children's Hospital, North Adelaide, South Australia 5006, Australia Accepted for publication 19 December I99I Summary Disseminated infection with the fungus Scedosporium inflatum in a neutropenic patient with non-Hodgkins lymphoma presented with the triad of muscle tenderness, papular skin lesions and fever, and progressed rapidly to a fatal outcome. This represents the first reported instance of fatal widely disseminated infection with this organism, and demonstrates that the triad of presenting clinical features, formerly reported to be pathognomic of systemic candidiasis, can no longer be regarded as specific for infection with a particular species of yeast or fungus.
Introduction Disseminated fungal infections are a major cause of death in i m m u n o c o m p r o mised patients, especially those with prolonged granulocytopenia, 1-3 and occur in between approximately IO % and 30 % patients with acute leukaemia and l y m p h o m a ) '3'~ Candida species are the most frequently identified causative agents, accounting for 7o-80 % systemic fungal infections 2,3'5 and the clinical triad of fever, skin lesions, and diffuse, severe muscle tenderness has been reported to be a specific feature of disseminated candidiasis under these circumstances. This report describes the triad of fever, skin lesions and severe muscle tenderness as the presenting feature of disseminated infection with Scedosporium inflatum in a neutropenic l y m p h o m a patient. It is the first report, to our knowledge, of a widely disseminated and fatal infection with this organism in the h u m a n , and demonstrates that these presenting clinical features cannot be regarded as specific for infection by a particular species of yeast or fungus.
Case report A 7z-year-old woman with follicular small cleaved cell l y m p h o m a was admitted for m a n a g e m e n t of neutropenic sepsis. L y m p h o m a had been diagnosed z years earlier, when she had presented with generalised ~[ Address correspondence to: Dr S. S. Farag, Department of Clinical Haematology, St Vincent's Hospital, Fitzroy, Victoria 3o65, Australia. oi63-4453/92/o5o2oi + o 4 $o8.oo/o 8
© x99I The British Society for the Study of Infection JIN 25
202
S.S. FARAG E T A L .
lymphadenopathy. Initial therapy had been with cycles of cyclophosphamide, vincristine and prednisolone (CVP), and was followed by unremitting neutropenia (o'5-r'2 x Iog/1). A year before the present admission she was treated with a 5-day course of high-dose Iv gammaglobulin (Intragam C S L , Melbourne, Australia) for a presumptive diagnosis of i m m u n e neutropenia. T h e r e was no response. T h r e e m o n t h s before admission she developed increasing lymphadenopathy, fever and night sweats. She was then treated with chlorambucil and prednisolone, but this was followed by more severe neutropenia. D u r i n g the m o n t h preceding her final admission she had an episode of fever which resolved on treatment with ticarcillin and gentamicin. N o causative organism was identified. Bone-marrow biopsy revealed extensive infiltration with lymphoma. T w o courses of mitoxantrone (r6 mg), etoposide (too mg) and prednisolone (IOO m g for 5 days) were administered, but she was then admitted with fever and neutropenia. At presentation she had been ill for r week with fever, fatigue, vomiting and mild diffuse muscular pains which had failed to improve following treatment with oral amoxycillin and potassium clavulanate. Her temperature on admission was 37"2 °C. She had no rash except for some petechiae over the legs. T h e r e was enlargement of the axillary lymph nodes to 2 cm in diameter. T h e H b was 6"4 g/dl, W C C 0"5 x IO9/1, and platelet count 27 x tog/1. T h e chest X-ray was normal. Cultures of blood and urine were taken and treatment with ticarcillin and gentamicin was started. D u r i n g the next 3 days her temperature varied between 37"5 and 38 °C and she had increasing pain and tenderness in the limb muscles; on day 7 this became severe and involved also the tongue, jaw and extra-ocular muscles. She was no longer able to stand or walk because of pain and weakness, and parenteral narcotic analgesia was required. An erythematous papular rash with lesions of between i and I'5 cm in diameter developed on the trunk and limbs. N o organisms were grown from repeated blood cultures and IV vancomycin was started. Plasma creatine kinase, aldolase and lactate dehydrogenase levels were normal. D u r i n g the next 3 days there was persistent fever and increasing muscle pain and weakness. New skin lesions developed and became haemorrhagic. T h e r e were no sensory abnormalities, all reflexes were present and nerve conduction studies were normal. On day Io further blood cultures were taken and a lumbar puncture was performed under platelet transfusion cover. T h e C S F was clear, and microscopy revealed no WBCs and 3 R B C s x lO6/1. No organisms were seen on Gram-stained specimens, and cryptococcal antigen was not detected. Intravenous amphotericin B and flucytosine were administered, but during the next e days the patient's condition deteriorated and she died on day r 3. P o s t - m o r t e m examination revealed disseminated fungal deposits consisting of hyphal elements in liver, spleen, thyroid, m y o c a r d i u m and skeletal muscle (Plate I). F u n g u s was first detected by the D e p a r t m e n t of Microbiology at St Vincent's Hospital z days after death in cultures of blood and C S F obtained 5 days previously. T h e organism was referred to the D e p a r t m e n t of Microbiology, Adelaide Children's Hospital, where it was identified as
Scedosporium inflatum.
Journal of Infection
Plate I
Plate z. Skeletal muscle showing necrosis of muscle fibres and invasion by filamentous fungal elements. Haematoxylin and eosin ( x 400).
S. S. FARAGET AL.
(Facing p. 202)
Journal of Infection
Plate 2
Plate 2. Conidia and characteristic inflated annellides of Scedosporium inflatum (indicated by arrows). Phase contrast with lactophenol cotton blue stain ( × 7o0).
Disseminated Scedosporium inflatum infection
203
Discussion
Our observations demonstrate two previously u n r e p o r t e d findings in patients with haematological neoplasia and disseminated fungal infection. T h e y indicate that fatal disseminated infection with S. inflatum can occur in this setting, and can present with the triad of fever, rash, and myalgia. T h e syndrome of fever, papular skin rash and severe muscle tenderness has been reported to be a distinctive presentation of disseminated candidiasis. 6'7 T h e s e observations were in patients rendered neutropenic during treatment of acute leukaemia, and Candida tropicalis was the responsible organism. All patients died despite treatment with amphotericin B, and in one case (6), the triad of signs appeared while the patient was receiving amphotericin. Jarowski et al. 7 considered the syndrome sufficiently specific to warrant the presumptive diagnosis of disseminated candidiasis and to justify the empirical use of antifungal therapy. T h e case we report had almost identical features; profound and prolonged neutropenia, fever, a diffuse erythematous papular skin rash involving the trunk and extremities, and such severe muscle pain and tenderness that she refused to move legs, arms or eyes. Indeed the similarity to the reported cases p r o m p t e d a presumptive diagnosis of disseminated candidiasis ante mortem. However, failure to culture Candida species from repeated specimens of blood, urine and C S F , and the isolation of S. inflatum from blood and C S F casts serious doubt on a specific linkage of the syndrome to candidiasis. We suggest that further observations will indicate the triad to be a relatively non-specific feature of disseminated fungal infection. Scedosporium inflatum is a newly recognised pathogen of the dematiaceous h y p h o m y c e t o u s genus Scedosporium saccardo, first described by Malloch and Salkin. 8 It has been isolated from the soil of potted plants, and is most likely a soil saprophyte. T h e clinical spectrum of S. inflatum infection has been reported recently) Virtually all infections have been localised, and have involved musculoskeletal tissue (often following penetrating trauma or surgery), or have caused skin ulcers, and in one case a self-limited respiratory illness. One previous fatal case of disseminated S. inflatum infection, which also occurred in our hospital in I986, has been reported by Wilson et al. 9 T h i s was in an i m m u n o c o m p r o m i s e d renal transplant patient who developed peritonitis following a r u p t u r e d sigmoid diverticulum. Scedosporium inflatum was isolated before death from peritoneal fluid, an infected abdominal w o u n d and a pleural effusion. T h e isolation of the organism from the culture of blood and C S F has not been previously reported. T h e present report is the first d o c u m e n t e d case of widely disseminated infection with S. inflatum giving rise to extensive tissue invasion. T h e identification of this fungus from the better-known Scedosporium apiospermum was by the recognition of annellides with distinctive swollen bases (Plate a), and by its failure to grow on cycloheximide-containing media. 1° Annellides occur singly or in clusters along the vegetative hyphae, and produce aggregates of unicellular, smooth-walled, hyaline to pale-brown, ovoid conidia. Cultures of S. inflatum are typically olive-grey to black in colour. Scedosporium apiospermum has been reported to cause both focal and disseminated 8-2
204
S. S. FARAG E T A L .
i n f e c t i o n s . 11 T h e clinical i m p l i c a t i o n s o f d i s s e m i n a t e d i n f e c t i o n w i t h S. inflatum are o m i n o u s in v i e w o f t h e r e s i s t a n c e o f this o r g a n i s m to a m p h o t e r i c i n a n d o t h e r a n t i f u n g a l agents. 9'1° W e c o n c l u d e t h a t t h e clinical s p e c t r u m o f i n f e c t i o n w i t h S. inflatum can b e e x p a n d e d to i n c l u d e d i s s e m i n a t e d i n f e c t i o n in g r a n u l o c y t o p e n i c p a t i e n t s , a n d t h a t s u c h i n f e c t i o n can p r e s e n t w i t h t h e t r i a d o f f e v e r , r a s h a n d m y a l g i a s , p r e v i o u s l y t h o u g h t to b e specific f o r d i s s e m i n a t e d candidiasis. References
I. Levine AS, Graw RG, Young RC. Management of infections in patients with leukemia and lymphoma: current concepts and experimental approaches. Semin Hematol I972; 9: I4I-I7r. 2. Bodey GP. Infections in cancer patients. Cancer Treat Rev x975; 2: 89-I28. 3. Bodey GP. Fungal infections complicating acute leukemia, ff Chronic Dis I966; I9: 667-687. 4. Meunier F. Candidiasis. Eur ff Clin Microbiol Infect Dis I989; 8: 438-447. 5. Young RC, Bennett JE, Geelhoed G, Levine AS. Fungemia with compromised host resistance: a study of 70 cases. Ann Intern Med I974; 80: 6o5-612. 6. Arena FP, Perlin M, Brahman H, Weiser B, Armstrong D. Fever, rash and myalgias of disseminated candidiasis during antifimgal therapy. Arch Intern Med I98I ; I41 : I233. 7. Jarowski CI, Fialk MA, Murray HW et al. Fever, rash and muscle tenderness : a distinctive clinical presentation of disseminated candidiasis. Arch Intern Med r978; I38: 544-546. 8. Malloch D, Salkin IF. A new species of Scedosporium associated with osteomyelitis in humans. Mycotaxon I984; 2x: 247-255. 9. Wilson CM, O'Rourke EJ, McGinnis MR, Salkin IF. Scedosporium inflatum: clinical spectrum of a newly recognized pathogen. J Infect Dis I99O; ,6I : Io2-Io7. to. Salkin IF, McGinnis MR, Dykstra MJ, Rinaldi MG. Scedosporium inflatum, an emerging pathogen. J Clin Microbiol r988; 26: 498-503. II. Travis LB, Roberts GD, Wilson WR. Clinical significance of Pseudallescheria boydii: a review of io years experience. Mayo Clin Proc I985; 6o: 531-537-
