Medical Mycology Case Reports 2 (2013) 75–78
Contents lists available at ScienceDirect
Medical Mycology Case Reports journal homepage: www.elsevier.com/locate/mmcr
Scedosporium apiospermum brain abscesses in an immunocompetent man with silicosis Heather L. Wilson a,n, Karina J. Kennedy a,b a b
Canberra Hospital and Health Services, P.O. Box 11 Woden, ACT 2606, Australia Australian National University Medical School, Canberra ACT 0200, Australia
a r t i c l e i n f o
abstract
Article history: Received 30 December 2012 Received in revised form 14 February 2013 Accepted 20 February 2013
We report a case of Scedosporium apiosporum brain abscesses in an immunocompetent 69-year-old man with a history of silicosis. Delayed diagnosis and institution of antifungal therapy was associated with neurological impairment, with subsequent complications resulting in death, highlighting the need for early diagnostic aspiration of brain abscesses non-responsive to antibiotics. We propose that, in the absence of identifiable immunosuppression, silicosis may have been a contributing factor to the development of central nervous system infection. & 2013 International Society for Human and Animal Mycology. Published by Elsevier B.V. All rights reserved.
Keywords: Scedosporium Silicosis Brain abscess Immunocompetent
1. Introduction Scedosporium apiospermum has emerged as an infrequent, but significant, invasive fungal pathogen in immunocompromised patients [1]. It causes a wide spectrum of clinical disease, however S. apiospermum appears to involve the central nervous system (CNS) disproportionately compared to other filamentous fungi [2], with brain abscess being the main clinical presentation [3]. Like other forms of invasive scedosporiosis, medical immunosuppression is a major predisposing factor for CNS infection. In the absence of immunosuppression, CNS infection is usually associated with near-drowning or trauma. S. apiospermum CNS infection has a poor prognosis, with an overall mortality rate of 74% reported based on case reports [3]. Antifungal therapy combined with surgery is generally considered important for successful treatment of invasive S. apiospermum infection [4]. Voriconazole has the most potent in vitro activity against S. apiospermum [5], and would be considered the primary agent of choice. The role of combination antifungal therapy is yet to be defined. We report the unusual case of S. apiospermum brain abscesses resulting in death, in a 69-year-old immunocompetent man with silicosis in the absence of any history of near-drowning or trauma. The case highlights the need for early microbiological diagnosis of brain abscesses where there is no response to empirical
n
Corresponding author. Tel.: þ61 2 6244 2105; fax: þ 61 2 6244 4646. E-mail address: [email protected] (H.L. Wilson).
antibiotics. It also raises the question of the possible role of silicosis in the development of invasive disease.
2. Case A 69-year old man was admitted to a regional hospital (day 0) with a 2 week history of increasingly severe headache, associated with fevers, lethargy, nausea and vomiting. He was an ex-smoker, with a history of chronic obstructive pulmonary disease (COPD) and silicosis, but remained physically active. He was managed with tiotropium (18 mg daily) and fluticasone/salmeterol (125/ 25 mg 2 puffs twice daily). He had taken short course oral corticosteroids on occasions, but none within the 6 months prior to presentation. He was also prescribed esomeprazole (20 mg twice daily) for gastroesophageal reflux, and irbesartan/hydrochlorothiazide (300/12.5 mg daily) for hypertension. For the first 48 h he was treated with ceftriaxone (1 g daily) and prednisolone (50 mg daily) for suspected lower respiratory tract infection. This therapy was ceased when on further review of the chest x-ray it was considered that there was no pulmonary consolidation and changes were due to the underlying chronic lung disease. On day 4 of admission he was again febrile and complaining of worsening headache. Neurological examination was normal. A lumbar puncture was performed and he was transferred to a tertiary referral hospital for further investigation and management. The cerebrospinal fluid (CSF) analysis showed 9 106/L erythrocytes and 3177 106/L white cells with 70% monocytic cells.
2211-7539/$ - see front matter & 2013 International Society for Human and Animal Mycology. Published by Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.mmcr.2013.02.006
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H.L. Wilson, K.J. Kennedy / Medical Mycology Case Reports 2 (2013) 75–78
The protein was elevated at 691 mg/L (RR: 150–450 mg/L) and glucose 2.5 mmol/L. Routine blood tests revealed a slightly elevated white cell count (14.0 109/L, RR: 4.0–11.0 109/L) and C-reactive protein (21 mg/L, RR: o5 mg/L). A non-contrast CT brain was initially reported as normal, but the report revised to note a subtle left corpus callosum abnormality. There was no radiological evidence of sinus disease. On further questioning it was revealed that he had travelled to Papua New Guinea in the 1970s and had an aunt who died of tuberculosis in the 1940s. No other significant exposures were identified. He was treated with ceftriaxone (2 g twice daily) and benzylpenicillin (2.4 g four hourly). The differential at that stage was broad, including early brain abscess, partially treated bacterial meningitis, tuberculous meningitis, viral meningitis and cryptococcal meningitis. The CSF showed no microbial growth after 7 days, was cryptococcal latex antigen (IMMY) and pneumococcal antigen (Binax) negative and HSV1/2, Enterovirus and VaricellaZoster PCR negative. On day 9 of admission a MRI scan showed a left paracallosal abscess and ventriculitis (Fig. 1A), at which stage he developed dysarthria. Antibiotics were broadened to benzylpenicillin (2.4 g four hourly), cefepime (2 g twice daily) and metronidazole (500 mg twice daily). The neurosurgical team was consulted, however declined surgical intervention. On day 12 of admission his neurological function deteriorated with drowsiness and right-sided limb weakness. A CT brain demonstrated increasing oedema surrounding the pericallosal abscess associated with some effacement of the left lateral ventricle. A new small right periventricular lesion was also noted. Dexamethasone 4 mg three times daily was added in light of the new mass effect, but provided only transient improvement in symptoms and signs. Standard four-drug tuberculosis therapy was also added. At day 16 a CT chest showed subsegmental right lower lobe consolidation on a background of emphysematous changes. With no neurological improvement, cotrimoxazole 320/ 1600 mg twice daily was added to the antimicrobial regimen to provide extended Nocardia sp. cover. The neurosurgical team again declined intervention. A repeat MRI brain obtained on day 20 of admission demonstrated clear disease progression compared to the previous study, with more defined and larger ring-enhancing abscesses in the left posterior frontal/parietal lobe and right frontal lobe, and new abscesses and regions of cerebritis (Fig. 1B). Infection with a resistant organism or a fungus was considered as a possible reason for disease progression. Vancomycin was added to cover methicillin resistant Staphylococcus aureus, and the following day stereotactic abscess drainage was performed. Purulent material was drained from the left posterior frontal/parietal lobe lesion and a tissue biopsy was obtained. Histological examination demonstrated necrotic cortical tissue with invasive, septate and branching hyphae (Fig. 2). On day 21 of admission, the patient was commenced on amphotericin B lipid complex (5 mg/kg daily) and intravenous voriconazole (6 mg/kg twice daily, for two doses loading, followed by 4 mg/kg twice daily). All other antibiotics were ceased. After 2 days incubation a light growth of a filamentous fungus was present on blood, chocolate and sabouraud agars. Macroscopic and microscopic morphological criteria identified the fungus as a Scedosporium sp. (likely S. apiospermum). Intravenous voriconazole was continued as a single agent. On day 24 of admission, he deteriorated clinically with recurrence of fevers, decreased level of consciousness and new productive cough, requiring intensive care unit admission. A right middle lobe hospital-acquired pneumonia was diagnosed and treated with piperacillin–tazobactam (4.0/0.5 g thrice daily) and intubation and ventilation. Repeat CT scan revealed a further
Fig. 1. MRI brain. (A) Lobulated, hyperintense enhancing lesion on the left of the corpus callosum, day 9 of admission. (B) Better defined, ring enhancing abscess in the left posterior frontal parietal lobe, day 20 of admission.
increase in the size and number of cerebral abscesses, with an increase in the extent of the associated oedema. By this stage he had developed dense right hemiplegia. Caspofungin was commenced with a 70 mg loading dose followed by 50 mg daily. Transoesophageal echocardiogram did not demonstrate any evidence of infective endocarditis. The organism was confirmed as S. apiospermum by panfungal PCR of the internal transcribed spacer 1 region of the ribosomal
H.L. Wilson, K.J. Kennedy / Medical Mycology Case Reports 2 (2013) 75–78
Fig. 2. Periodic acid Schiff stain of abscess showing septate, branching hyphae (original magnification 20).
DNA gene cluster, followed by DNA sequence analysis for species identification [6]. This was performed at a reference laboratory. S. apiospermum was also cultured from a sputum specimen collected on day 26 of admission. The isolate appeared sensitive to voriconazole (MIC 0.06 mg/ml). The MIC for caspofungin was 0.12 mg/ml and for amphotericin B was 2 mg/ml. The patient recovered from pneumonia and was transferred back to the general ward on day 34 of admission. Therapeutic voriconzole levels were not achieved until day 33 of therapy, with the dose being increased to 500 mg twice daily. In total, he received 9 weeks of intravenous voriconazole and 8 weeks of caspofungin. There was progressive improvement in oedema and abscess size on neuroimaging, however he made no neurological recovery, and suffered recurrent episodes of aspiration pneumonia. He died after almost 3 months in hospital and 24 h after withdrawal of all antimicrobials.
3. Discussion S. apiospermum is a saprophyte with world-wide distribution, found in soil, polluted water and sewage, cattle and poultry manure, and coastal waters. It was recognised as a leading cause of lower limb mycetoma during the first half of the 20th century, however, by the 1970s there were several cases of it causing pulmonary disease [7]. In the 1990s S. apiospermum emerged as an infrequent, but significant, invasive fungal pathogen in immunocompromised patients [1]. The respiratory tract is thought to be the major portal of entry for invasive disease, either by the inhalation of conidia or aspiration of polluted water, with haematogenous spread to other organs. However, dissemination may also occur from other primary sites of infection, or from direct inoculation, for example penetrating injury or surgery [7]. The immune response against Scedosporium relies heavily on functioning neutrophils and monocytes, explaining the higher risk of infection in neutropenic patients [8]. S. apiospermum causes a wide spectrum of clinical disease from colonisation, to localised infections such as mycetoma, and finally disseminated disease, typically in the immunocompromised. Infection may involve almost any site including cutaneous and subcutaneous tissues, lung, brain, eye, sinuses, bone and joint [7]. However, S. apiospermum appears to involve the CNS disproportionately compared to other filamentous fungi. Some studies estimate that up to 50% of invasive scedosporiosis cases involve the CNS [2], with
77
brain abscess being the main clinical presentation, either alone, or in conjunction with meningitis or ventriculitis [3]. Like other forms of invasive scedosporiosis, medical immunosuppression – including immunosuppressive therapy, transplantation, haematological malignancy and diabetes – is a major predisposing factor for Scedosporium CNS infection. A literature review from 1948 to 2007, however found that 44/99 (44%) of reported cases involving the CNS occurred in ‘‘previously healthy’’ individuals. Of these patients, 24/44 (55%) had a history of near drowning, 10/44 (23%) were post-traumatic/iatrogenic cases and 4/44 (10%) had a history of alcohol abuse [3]. Our case is highly unusual as there is no history of immunosuppression, near drowning or trauma. The most likely predisposing factor for our patient is chronic lung disease (silicosis and COPD). We are aware of two cases of disseminated S. apiospermum associated with chronic lung disease: a 60-year-old-woman with extensive pulmonary infection and disseminated Pseudallescheria boydii on a background of severe bullous emphysema [9] and a 58year-old woman with idiopathic pulmonary fibrosis and S. apiospermum brain abscess [10]. The second case, however was immunosuppressed as a result of systemic corticosteroid therapy and chronic liver disease. More often, chronic lung diseases such as COPD and cystic fibrosis are associated with S. apiospermum airways colonisation, rather than invasive disease [11]. The respiratory tract appeared to be the source for infection in this case, with S. apiospermum being identified from sputum on day 26, although it is likely that it was merely colonising as initial chest x-rays demonstrated no consolidation. We are not aware of any published reports of disseminated Scedosporium sp. infection in association with silicosis, however it is conceivable that silicosis was a contributing factor to CNS involvement in this case. Silicosis is a risk factor for active tuberculosis [12], and has been shown to be associated with an increased risk of death due to any mycosis (predominantly Aspergillosis, Cryptococcosis and other endemic mycoses) [13]. Silica impairs alveolar macrophage function [13,14], which appears to be important in the early recognition of and immune response to inhaled fungal conidia [15], helping to prevent parenchymal invasion. It is therefore plausible that our case was colonised as a result of his COPD, and was prone to dissemination due to macrophage impairment from silicosis. S. apiospermum CNS infection has a poor prognosis, with an overall mortality rate of 74% based on case reports [3]. While the predictors of outcome of scedosporiosis are largely unknown, patients with immunosuppression and disseminated and deep infection, including CNS infection, have a poorer response to therapy [16]. There is not a general consensus for the treatment of invasive scedosporiosis. Current antifungal agents have modest activity, with suboptimal clinical responses. However, there is increasing evidence to support the use of voriconazole as primary antifungal therapy. Voriconazole has good blood brain barrier penetration. Of the available triazoles, voriconazole has the most potent in vitro activity against S. apiospermum, with MIC values from 0.03 to 1 mg/ml [5]. Posaconazole has good in vitro activity (MIC 0.5–2 mg/ml), however, clinical data is lacking [5,17]. Other antifungals have demonstrated less promising results. Amphotericin B has weak in vitro activity against S. apiospermum with an MIC of 1–16 mg/ml [5], and when used as monotherapy for CNS infection had a mortality rate of 87.5% in 16 reported cases [3]. There is limited clinical experience with echinocandins which have highly variable activity against Scedosporium sp. (MIC 0.2–16 mg/ml for caspofungin and anidulofungin) [17]. A retrospective study of voriconazole therapy involving 107 patients with scedosporiosis, both S. apiospermum and Scedosporium prolificans, was conducted using the voriconazole global clinical trials
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database [16]. It reported an overall response rate of 57% in voriconazole treated patients, with a better response rate of 64% in patients with S. apiospermum infection versus S. prolificans. A poorer overall response of 43% was noted in those with CNS infection, however, all successfully treated cases of CNS infection involved S. apiospermum. These results are far more promising than those seen in older case reports [3]. However, it is important to note that an overall response rate includes patients that had a complete or a partial response to therapy. In addition, the duration of voriconazole treatment in successful cases was long and the median survival time in successful cases was only 252 days [16]. Due to the high mortality associated with invasive scedosporiosis and the modest activity of currently available antifungals, combination antifungal therapy has been described in a number of case reports, usually involving S. prolificans. Synergy and favourable outcomes have been reported in patients with invasive infections treated with voriconazole and terbinafine [18], and with voriconazole or amphotericin B combined with an echinocandin [19,20]. However, there are no clinical studies outside of case reports to support the use of combination anti-fungal therapy in the setting of invasive scedosporiosis. Combination therapy with voriconazole and caspofungin was used in this case when the patient’s condition deteriorated post-operative, although it is likely this was multi-factorial rather than primary drug failure. However, it should be noted that there were difficulties in achieving therapeutic voriconazole levels, possibly related to the residual effects of empirical tuberculosis treatment with rifampicin. Antifungal therapy combined with surgery is generally considered important for successful treatment of invasive S. apiospermum infection [4]. A significant difference in the mortality of patients with S. apiospermum CNS infection has been documented in those treated with antifungals alone (74%) and those treated with antifungals in addition to surgical debridement (31%) [3]. In summary, S. apiospermum is an important opportunistic pathogen causing invasive mycosis with high mortality. It has a neurotropic tendency, and can cause severe diseases in both immunocompromised and immunocompetent patients. The major risk factors in immunocompetent patients are aspiration of polluted water and direct implantation. Appropriate treatment of the patient in this case was delayed as empirical antifungal treatment was not considered in the setting of relative immunocompetence, and microbiological diagnosis was not undertaken until after the progression of neurological impairment. Early microbial diagnosis of CNS abscesses is therefore essential in order to identify unusual pathogens. There is increasing evidence to support the use of voriconazole as primary antifungal therapy, however, the prognosis of S. apiospermum invasive disease remains poor. Despite radiological improvement on the combination of voriconazole and caspofungin, the patient in this case died of complications of neurological impairment. Silicosis may have been an unrecognised risk for invasive scedosporiosis in this case.
Conflict of interest There are none. References [1] Husain S, Alexander BD, Munoz P, Avery RK, Houston S, Pruett T, et al. Opportunistic mycelial fungal infections in organ transplant recipients: emerging importance of non-Aspergillus mycelial fungi. Clinical Infectious Diseases 2003;37:221–9. [2] Bouza E, Munoz P. Invasive infections caused by Blastoschizomyces capitatus and Scedosporium spp. Clinical Microbiology and Infection 2004;10:76–85. [3] Kantarcioglu AS, Guarro J, de Hoog GS. Central nervous system infections by members of the Pseudallescheria boydii species complex in healthy and immunocompromised hosts: epidemiology, clinical characteristics and outcome. Mycoses 2008;51:275–90. [4] Nesky MA, McDougal EC, Peacock JE. Pseudallescheria boydii brain abscess successfully treated with voriconazole and surgical drainage: case report and literature review of central nervous system Pseudallescheriasis. Clinical Infectious Diseases 2000;31:673–7. [5] Mycology Online. /http://www.mycology.adelaide.edu.au/S. [6] Lau A, Chen S, Sorrell T, Carter D, Malik P, Halliday C. Development and clinical application of a panfungal PCR assay to detect and identify fungal DNA in tissue specimens. Journal of Clinical Microbiology 2007;45:380–5. [7] O0 Bryan TA. Pseudallescheriasis in the 21st century. Expert Review of Antiinfective Therapy 2005;3(5):765–73. [8] Roilides E, Simitsopoulou M, Katragkou A, Walsh TJ. Host immune response against Scedosporium species. Medical Mycology 2009;47:433–40 special issue. [9] Kurshid A, Barnett VT, Sekosan M, Ginzbury AS, Onal E. Disseminated Pseudallescheria boydii infection in a nonimmunocompromised host. Chest 1999;116(2):572–4. [10] Caggiano G, Cantisani P, Rolli M, Gianfreda CD, Pizzolante M, Montagna MT. The importance of a proper aetiological diagnosis in the management of patients with invasive mycoses: a case report of a brain abscess by Scedosporium apiospermum. Mycopathologia 2011;172:317–22. [11] Heath CH, Slavin MA, Sorrell TC, Handke R, Harun A, Phillips M, et al. Population-based surveillance for scedosporiosis in Australia: epidemiology, disease manifestations and emergence of Scedosporium aurantiacum infection. Clinical Microbiology and Infection 2009;15:680–97. [12] Rees D, Murray J. Silica, silicosis and tuberculosis. International Journal of Tuberculosis and Lung Disease 2007;11:474–84. [13] Iossifova Y, Bailey R, Wood J, Kreiss K. Concurrent silicosis and pulmonary mycosis at death. Emerging Infectious Disease 2010;16:318–20. [14] Pernis B. Silica and the immune system. Acta BioMedica 2005;2:38–44 Suppl. [15] Segel BH. Role of macrophages in host defense against aspergillosis and strategies for immune augmentation. Oncologist 2007;12(2):7–13. [16] Troke P, Aguirrebengoa K, Arteaga C, Ellis D, Heath CH, Lutsar I, et al. Treatment of scedosporiosis with voriconazole: clinical experience with 107 patients. Antimicrobial Agents and Chemotherapy 2008;52(5):1743–50. [17] Wiederhold NP, Lewis RE. Antifungal activity against Scedosporium species and novel assays to assess antifungal pharmacodynamics against filamentous fungi. Medical Mycology 2009;47:422–32. [18] Gosbell IB, Toumasatos V, Yong J, Kuo RS, Ellis DH, Perrie RC. Cure of orthopaedic infection with Scedosporium prolificans, using voriconazole plus terbinafine, without the need for radical surgery. Mycoses 2003;46(5–6) 233–6. [19] Yustes C, Guarro J. In vitro synergistic interaction between amphotericin B and micafungin against Scedosporium spp. Antimicrobial Agents and Chemotherapy 2005;49:3498–500. [20] Heyn K, Tredup A, Salvenmoser S, Muller FM. Effect of voriconazole combined with micafungin against Candida, Aspergillus, and Scedosporium spp. and Fusarium solani. Antimicrobial Agents and Chemotherapy 2005;49(12): 5157–9.
Contents lists available at ScienceDirect
Medical Mycology Case Reports journal homepage: www.elsevier.com/locate/mmcr
Scedosporium apiospermum brain abscesses in an immunocompetent man with silicosis Heather L. Wilson a,n, Karina J. Kennedy a,b a b
Canberra Hospital and Health Services, P.O. Box 11 Woden, ACT 2606, Australia Australian National University Medical School, Canberra ACT 0200, Australia
a r t i c l e i n f o
abstract
Article history: Received 30 December 2012 Received in revised form 14 February 2013 Accepted 20 February 2013
We report a case of Scedosporium apiosporum brain abscesses in an immunocompetent 69-year-old man with a history of silicosis. Delayed diagnosis and institution of antifungal therapy was associated with neurological impairment, with subsequent complications resulting in death, highlighting the need for early diagnostic aspiration of brain abscesses non-responsive to antibiotics. We propose that, in the absence of identifiable immunosuppression, silicosis may have been a contributing factor to the development of central nervous system infection. & 2013 International Society for Human and Animal Mycology. Published by Elsevier B.V. All rights reserved.
Keywords: Scedosporium Silicosis Brain abscess Immunocompetent
1. Introduction Scedosporium apiospermum has emerged as an infrequent, but significant, invasive fungal pathogen in immunocompromised patients [1]. It causes a wide spectrum of clinical disease, however S. apiospermum appears to involve the central nervous system (CNS) disproportionately compared to other filamentous fungi [2], with brain abscess being the main clinical presentation [3]. Like other forms of invasive scedosporiosis, medical immunosuppression is a major predisposing factor for CNS infection. In the absence of immunosuppression, CNS infection is usually associated with near-drowning or trauma. S. apiospermum CNS infection has a poor prognosis, with an overall mortality rate of 74% reported based on case reports [3]. Antifungal therapy combined with surgery is generally considered important for successful treatment of invasive S. apiospermum infection [4]. Voriconazole has the most potent in vitro activity against S. apiospermum [5], and would be considered the primary agent of choice. The role of combination antifungal therapy is yet to be defined. We report the unusual case of S. apiospermum brain abscesses resulting in death, in a 69-year-old immunocompetent man with silicosis in the absence of any history of near-drowning or trauma. The case highlights the need for early microbiological diagnosis of brain abscesses where there is no response to empirical
n
Corresponding author. Tel.: þ61 2 6244 2105; fax: þ 61 2 6244 4646. E-mail address: [email protected] (H.L. Wilson).
antibiotics. It also raises the question of the possible role of silicosis in the development of invasive disease.
2. Case A 69-year old man was admitted to a regional hospital (day 0) with a 2 week history of increasingly severe headache, associated with fevers, lethargy, nausea and vomiting. He was an ex-smoker, with a history of chronic obstructive pulmonary disease (COPD) and silicosis, but remained physically active. He was managed with tiotropium (18 mg daily) and fluticasone/salmeterol (125/ 25 mg 2 puffs twice daily). He had taken short course oral corticosteroids on occasions, but none within the 6 months prior to presentation. He was also prescribed esomeprazole (20 mg twice daily) for gastroesophageal reflux, and irbesartan/hydrochlorothiazide (300/12.5 mg daily) for hypertension. For the first 48 h he was treated with ceftriaxone (1 g daily) and prednisolone (50 mg daily) for suspected lower respiratory tract infection. This therapy was ceased when on further review of the chest x-ray it was considered that there was no pulmonary consolidation and changes were due to the underlying chronic lung disease. On day 4 of admission he was again febrile and complaining of worsening headache. Neurological examination was normal. A lumbar puncture was performed and he was transferred to a tertiary referral hospital for further investigation and management. The cerebrospinal fluid (CSF) analysis showed 9 106/L erythrocytes and 3177 106/L white cells with 70% monocytic cells.
2211-7539/$ - see front matter & 2013 International Society for Human and Animal Mycology. Published by Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.mmcr.2013.02.006
76
H.L. Wilson, K.J. Kennedy / Medical Mycology Case Reports 2 (2013) 75–78
The protein was elevated at 691 mg/L (RR: 150–450 mg/L) and glucose 2.5 mmol/L. Routine blood tests revealed a slightly elevated white cell count (14.0 109/L, RR: 4.0–11.0 109/L) and C-reactive protein (21 mg/L, RR: o5 mg/L). A non-contrast CT brain was initially reported as normal, but the report revised to note a subtle left corpus callosum abnormality. There was no radiological evidence of sinus disease. On further questioning it was revealed that he had travelled to Papua New Guinea in the 1970s and had an aunt who died of tuberculosis in the 1940s. No other significant exposures were identified. He was treated with ceftriaxone (2 g twice daily) and benzylpenicillin (2.4 g four hourly). The differential at that stage was broad, including early brain abscess, partially treated bacterial meningitis, tuberculous meningitis, viral meningitis and cryptococcal meningitis. The CSF showed no microbial growth after 7 days, was cryptococcal latex antigen (IMMY) and pneumococcal antigen (Binax) negative and HSV1/2, Enterovirus and VaricellaZoster PCR negative. On day 9 of admission a MRI scan showed a left paracallosal abscess and ventriculitis (Fig. 1A), at which stage he developed dysarthria. Antibiotics were broadened to benzylpenicillin (2.4 g four hourly), cefepime (2 g twice daily) and metronidazole (500 mg twice daily). The neurosurgical team was consulted, however declined surgical intervention. On day 12 of admission his neurological function deteriorated with drowsiness and right-sided limb weakness. A CT brain demonstrated increasing oedema surrounding the pericallosal abscess associated with some effacement of the left lateral ventricle. A new small right periventricular lesion was also noted. Dexamethasone 4 mg three times daily was added in light of the new mass effect, but provided only transient improvement in symptoms and signs. Standard four-drug tuberculosis therapy was also added. At day 16 a CT chest showed subsegmental right lower lobe consolidation on a background of emphysematous changes. With no neurological improvement, cotrimoxazole 320/ 1600 mg twice daily was added to the antimicrobial regimen to provide extended Nocardia sp. cover. The neurosurgical team again declined intervention. A repeat MRI brain obtained on day 20 of admission demonstrated clear disease progression compared to the previous study, with more defined and larger ring-enhancing abscesses in the left posterior frontal/parietal lobe and right frontal lobe, and new abscesses and regions of cerebritis (Fig. 1B). Infection with a resistant organism or a fungus was considered as a possible reason for disease progression. Vancomycin was added to cover methicillin resistant Staphylococcus aureus, and the following day stereotactic abscess drainage was performed. Purulent material was drained from the left posterior frontal/parietal lobe lesion and a tissue biopsy was obtained. Histological examination demonstrated necrotic cortical tissue with invasive, septate and branching hyphae (Fig. 2). On day 21 of admission, the patient was commenced on amphotericin B lipid complex (5 mg/kg daily) and intravenous voriconazole (6 mg/kg twice daily, for two doses loading, followed by 4 mg/kg twice daily). All other antibiotics were ceased. After 2 days incubation a light growth of a filamentous fungus was present on blood, chocolate and sabouraud agars. Macroscopic and microscopic morphological criteria identified the fungus as a Scedosporium sp. (likely S. apiospermum). Intravenous voriconazole was continued as a single agent. On day 24 of admission, he deteriorated clinically with recurrence of fevers, decreased level of consciousness and new productive cough, requiring intensive care unit admission. A right middle lobe hospital-acquired pneumonia was diagnosed and treated with piperacillin–tazobactam (4.0/0.5 g thrice daily) and intubation and ventilation. Repeat CT scan revealed a further
Fig. 1. MRI brain. (A) Lobulated, hyperintense enhancing lesion on the left of the corpus callosum, day 9 of admission. (B) Better defined, ring enhancing abscess in the left posterior frontal parietal lobe, day 20 of admission.
increase in the size and number of cerebral abscesses, with an increase in the extent of the associated oedema. By this stage he had developed dense right hemiplegia. Caspofungin was commenced with a 70 mg loading dose followed by 50 mg daily. Transoesophageal echocardiogram did not demonstrate any evidence of infective endocarditis. The organism was confirmed as S. apiospermum by panfungal PCR of the internal transcribed spacer 1 region of the ribosomal
H.L. Wilson, K.J. Kennedy / Medical Mycology Case Reports 2 (2013) 75–78
Fig. 2. Periodic acid Schiff stain of abscess showing septate, branching hyphae (original magnification 20).
DNA gene cluster, followed by DNA sequence analysis for species identification [6]. This was performed at a reference laboratory. S. apiospermum was also cultured from a sputum specimen collected on day 26 of admission. The isolate appeared sensitive to voriconazole (MIC 0.06 mg/ml). The MIC for caspofungin was 0.12 mg/ml and for amphotericin B was 2 mg/ml. The patient recovered from pneumonia and was transferred back to the general ward on day 34 of admission. Therapeutic voriconzole levels were not achieved until day 33 of therapy, with the dose being increased to 500 mg twice daily. In total, he received 9 weeks of intravenous voriconazole and 8 weeks of caspofungin. There was progressive improvement in oedema and abscess size on neuroimaging, however he made no neurological recovery, and suffered recurrent episodes of aspiration pneumonia. He died after almost 3 months in hospital and 24 h after withdrawal of all antimicrobials.
3. Discussion S. apiospermum is a saprophyte with world-wide distribution, found in soil, polluted water and sewage, cattle and poultry manure, and coastal waters. It was recognised as a leading cause of lower limb mycetoma during the first half of the 20th century, however, by the 1970s there were several cases of it causing pulmonary disease [7]. In the 1990s S. apiospermum emerged as an infrequent, but significant, invasive fungal pathogen in immunocompromised patients [1]. The respiratory tract is thought to be the major portal of entry for invasive disease, either by the inhalation of conidia or aspiration of polluted water, with haematogenous spread to other organs. However, dissemination may also occur from other primary sites of infection, or from direct inoculation, for example penetrating injury or surgery [7]. The immune response against Scedosporium relies heavily on functioning neutrophils and monocytes, explaining the higher risk of infection in neutropenic patients [8]. S. apiospermum causes a wide spectrum of clinical disease from colonisation, to localised infections such as mycetoma, and finally disseminated disease, typically in the immunocompromised. Infection may involve almost any site including cutaneous and subcutaneous tissues, lung, brain, eye, sinuses, bone and joint [7]. However, S. apiospermum appears to involve the CNS disproportionately compared to other filamentous fungi. Some studies estimate that up to 50% of invasive scedosporiosis cases involve the CNS [2], with
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brain abscess being the main clinical presentation, either alone, or in conjunction with meningitis or ventriculitis [3]. Like other forms of invasive scedosporiosis, medical immunosuppression – including immunosuppressive therapy, transplantation, haematological malignancy and diabetes – is a major predisposing factor for Scedosporium CNS infection. A literature review from 1948 to 2007, however found that 44/99 (44%) of reported cases involving the CNS occurred in ‘‘previously healthy’’ individuals. Of these patients, 24/44 (55%) had a history of near drowning, 10/44 (23%) were post-traumatic/iatrogenic cases and 4/44 (10%) had a history of alcohol abuse [3]. Our case is highly unusual as there is no history of immunosuppression, near drowning or trauma. The most likely predisposing factor for our patient is chronic lung disease (silicosis and COPD). We are aware of two cases of disseminated S. apiospermum associated with chronic lung disease: a 60-year-old-woman with extensive pulmonary infection and disseminated Pseudallescheria boydii on a background of severe bullous emphysema [9] and a 58year-old woman with idiopathic pulmonary fibrosis and S. apiospermum brain abscess [10]. The second case, however was immunosuppressed as a result of systemic corticosteroid therapy and chronic liver disease. More often, chronic lung diseases such as COPD and cystic fibrosis are associated with S. apiospermum airways colonisation, rather than invasive disease [11]. The respiratory tract appeared to be the source for infection in this case, with S. apiospermum being identified from sputum on day 26, although it is likely that it was merely colonising as initial chest x-rays demonstrated no consolidation. We are not aware of any published reports of disseminated Scedosporium sp. infection in association with silicosis, however it is conceivable that silicosis was a contributing factor to CNS involvement in this case. Silicosis is a risk factor for active tuberculosis [12], and has been shown to be associated with an increased risk of death due to any mycosis (predominantly Aspergillosis, Cryptococcosis and other endemic mycoses) [13]. Silica impairs alveolar macrophage function [13,14], which appears to be important in the early recognition of and immune response to inhaled fungal conidia [15], helping to prevent parenchymal invasion. It is therefore plausible that our case was colonised as a result of his COPD, and was prone to dissemination due to macrophage impairment from silicosis. S. apiospermum CNS infection has a poor prognosis, with an overall mortality rate of 74% based on case reports [3]. While the predictors of outcome of scedosporiosis are largely unknown, patients with immunosuppression and disseminated and deep infection, including CNS infection, have a poorer response to therapy [16]. There is not a general consensus for the treatment of invasive scedosporiosis. Current antifungal agents have modest activity, with suboptimal clinical responses. However, there is increasing evidence to support the use of voriconazole as primary antifungal therapy. Voriconazole has good blood brain barrier penetration. Of the available triazoles, voriconazole has the most potent in vitro activity against S. apiospermum, with MIC values from 0.03 to 1 mg/ml [5]. Posaconazole has good in vitro activity (MIC 0.5–2 mg/ml), however, clinical data is lacking [5,17]. Other antifungals have demonstrated less promising results. Amphotericin B has weak in vitro activity against S. apiospermum with an MIC of 1–16 mg/ml [5], and when used as monotherapy for CNS infection had a mortality rate of 87.5% in 16 reported cases [3]. There is limited clinical experience with echinocandins which have highly variable activity against Scedosporium sp. (MIC 0.2–16 mg/ml for caspofungin and anidulofungin) [17]. A retrospective study of voriconazole therapy involving 107 patients with scedosporiosis, both S. apiospermum and Scedosporium prolificans, was conducted using the voriconazole global clinical trials
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database [16]. It reported an overall response rate of 57% in voriconazole treated patients, with a better response rate of 64% in patients with S. apiospermum infection versus S. prolificans. A poorer overall response of 43% was noted in those with CNS infection, however, all successfully treated cases of CNS infection involved S. apiospermum. These results are far more promising than those seen in older case reports [3]. However, it is important to note that an overall response rate includes patients that had a complete or a partial response to therapy. In addition, the duration of voriconazole treatment in successful cases was long and the median survival time in successful cases was only 252 days [16]. Due to the high mortality associated with invasive scedosporiosis and the modest activity of currently available antifungals, combination antifungal therapy has been described in a number of case reports, usually involving S. prolificans. Synergy and favourable outcomes have been reported in patients with invasive infections treated with voriconazole and terbinafine [18], and with voriconazole or amphotericin B combined with an echinocandin [19,20]. However, there are no clinical studies outside of case reports to support the use of combination anti-fungal therapy in the setting of invasive scedosporiosis. Combination therapy with voriconazole and caspofungin was used in this case when the patient’s condition deteriorated post-operative, although it is likely this was multi-factorial rather than primary drug failure. However, it should be noted that there were difficulties in achieving therapeutic voriconazole levels, possibly related to the residual effects of empirical tuberculosis treatment with rifampicin. Antifungal therapy combined with surgery is generally considered important for successful treatment of invasive S. apiospermum infection [4]. A significant difference in the mortality of patients with S. apiospermum CNS infection has been documented in those treated with antifungals alone (74%) and those treated with antifungals in addition to surgical debridement (31%) [3]. In summary, S. apiospermum is an important opportunistic pathogen causing invasive mycosis with high mortality. It has a neurotropic tendency, and can cause severe diseases in both immunocompromised and immunocompetent patients. The major risk factors in immunocompetent patients are aspiration of polluted water and direct implantation. Appropriate treatment of the patient in this case was delayed as empirical antifungal treatment was not considered in the setting of relative immunocompetence, and microbiological diagnosis was not undertaken until after the progression of neurological impairment. Early microbial diagnosis of CNS abscesses is therefore essential in order to identify unusual pathogens. There is increasing evidence to support the use of voriconazole as primary antifungal therapy, however, the prognosis of S. apiospermum invasive disease remains poor. Despite radiological improvement on the combination of voriconazole and caspofungin, the patient in this case died of complications of neurological impairment. Silicosis may have been an unrecognised risk for invasive scedosporiosis in this case.
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