1 JCM 02615-10 Revised 1 Fatal mycotic aneurysms due to Scedosporium/Pseudallescheria ...

23 Pages·2011·1.32 MB·English

JCM Accepts, published online ahead of print on 23 March 2011
J. Clin. Microbiol. doi:10.1128/JCM.02615-10
Copyright © 2011, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.
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1 JCM 02615-10 Revised
2 Fatal mycotic aneurysms due to Scedosporium/Pseudallescheria infection: case reports and
3 literature review
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5 Adrian Ong1, Christopher C Blyth2, Rosamma Bency3, Mauro Vicaretti4, Azian Harun5, Wieland
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6 Meyer5, Meena Shingde6, Nicky Gilroy1, Jeremy Chapman3, Sharon C-A Chen1,5 * o
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8 1Centre for Infectious Diseases and Microbiology, Westmead Hospital, Westmead, New South ed

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9 Wales, 2School of Paediatrics and Child Health, University of Western Australia, Perth, o
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10 3Department of Renal Medicine, Westmead Hospital, Westmead, New South Wales, t
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11 4Department of Surgery, Westmead Hospital, Westmead, New South Wales, 5Molecular /jc
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12 Mycology Research Laboratory, Centre for infectious Diseases and Microbiology, Westmead .a
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13 Millennium Institute, Sydney Medical School - Westmead Hospital, Westmead, 6Department of .o
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14 Anatomical Pathology, Westmead Hospital, Westmead, New South Wales, Australia. /
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16 *Correspondence to: il 6
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17 SHARON CHEN, 0
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18 Centre for Infectious Diseases and Microbiology, b
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19 3rd Level, ICPMR Building, Westmead, NSW 2145, AUSTRALIA, u
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20 Phone: [phone], Fax: [phone],
21 Email: [email protected]
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23 Running title: Scedosporium mycotic aneurysms
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24 ABSTRACT
25 Angio-invasive complications of Scedosporium infections are rare. We report two cases of
26 mycotic aneurysm, following apparent localized infection, due to Scedosporium
27 apiospermum/Pseudallescheria boydii. The thoraco-abdominal aorta was affected in one patient,
28 and cerebral vessels, in the other. Despite voriconazole therapy and surgical resection, the
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29 patients died. Previously-reported cases are reviewed. o
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30 CASE REPORTS
31 Patient A
32 A 55-year-old male living-related kidney transplant recipient with diabetes mellitus presented in
33 2009 with a left index finger lesion following a trivial gardening injury. Immunosuppressive
34 treatment included mycophenolate mofetil 500 mg thrice daily, tacrolimus 3 mg twice daily and
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35 prednisolone 10 mg daily, with a course of therapy with methylprednisolone (1 g daily for three o
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36 days) in the preceding six months. Culture of material from the lesion grew Scedosporium lo
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37 apiospermum/Pseudallescheria boydii. The in vitro MIC of voriconazole was 1 µg/ml (5). X rays ed

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38 of the hand showed no evidence of osteomyelitis and there were no abnormalities on chest X ray o
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39 and cerebral computer tomography (CT) scanning. He received three months of oral t
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40 voriconazole (200 mg twice daily after a loading dose of 6 mg/kg twice daily), with unchanged /jc
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41 immunosuppression, with apparent complete clinical response. .a
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42 Nine months later, the patient developed progressive, severe flank and lower back pain. .o
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43 He was afebrile and his blood pressure was 190/100 mmHg. There was bilateral soft tissue /
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44 tenderness of the mid lumbar region but no vertebral or abdominal tenderness. A CT scan of the A
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45 abdomen revealed non-specific thickening of the aortic wall at the level of the 3rd and 4th lumbar il 6
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46 vertebra (LV3-LV4). Magnetic resonance imaging (MRI) of the thoraco-lumbar-sacral vertebra 0
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47 showed destruction of LV4 without evidence of discitis between LV3 and LV4. A b
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48 paravertebral abscess was observed extending from the 10th thoracic vertebra (TV) to the LV4 u
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49 level (Figure 1a), in addition to an inflammatory aortitis with aneurysm formation of the aorta
50 from the level of the TV9 to LV4 (Figure 1b).
51 Empiric therapy with vancomycin, rifampicin and ciprofloxacin was commenced.
52 Cultures of blood were negative for bacteria and fungi. Drainage of the paravertebral abscess
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53 yielded 20 mL of purulent material; no organisms were seen on Gram, or Ziehl-Nielsen staining.
54 S. apiospermum/P. boydii was cultured after 14 days of incubation. A single, 1 x 2 cm
55 subcutaneous nodule then appeared over the right wrist. Histopathological examination
56 (Gromori-Grocott and periodic acid-Schiff [PAS] staining) of the excised lesion revealed
57 granulomatous inflammation and septate hyaline fungal hyphae; S. apiospermum/P. boydii was
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58 recovered on culture. Treatment with voriconazole was re-initiated (6 mg/kg twice daily and then o
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59 4 mg/kg twice daily) in association with reduction in intensity of the immunosuppressive lo
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60 regimen. Voriconazole serum levels were checked regularly (trough levels were between 2-3 ed

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61 mg/L after reaching steady-state). o
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62 Serial MRI imaging of the spine demonstrated progressive enlargement of the aneurysm t
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63 extending from TV10 to LV4. Urgent surgical resection and bypass of the aneurysm was /jc
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64 performed. An 8.8 cm diameter thoraco-abdominal aortic aneurysm extending from the distal .a
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65 thoracic aorta to inferior to the native renal arteries (Type V Crawford aneurysm) (31) with a .o
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66 sealed rupture at the distal thoracic aorta was identified. The aneurismal aorta was excised and /
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67 revascularisation of the thoracic and abdominal aorta, celiac and superior mesenteric arteries was A
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68 performed using rifampicin-soaked gelatine-sealed Dacron grafts. Histopathological examination il 6
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69 showed intimal fibrosis, fragmentation of elastic lamina and multifocal granulomatous 0
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70 inflammation containing giant cells. Aggregates of PAS-positive fungal elements with branching b
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71 septate hyphae and yeast-like structures were seen at the centre of the granuloma (Figure 2). S. u
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72 apiospermum/P. boydii was grown from the diseased aorta. Unfortunately, the patient died four
73 months after surgery after suddenly developing intractable abdominal pain. Investigations
74 revealed an occluded superior mesenteric artery graft and gut ischemia. No post mortem was
75 performed.
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76 Species identification of all four S. apiospermum/P. boydii isolates (finger, paravertebral
77 abscess, cutaneous wrist lesion and aortic wall) was performed by standard morphological
78 methods (7) and confirmed by DNA sequencing of the internal transcribed spacer (ITS1/2)
79 region of the fungal rRNA gene cluster (8, 11). All isolates were identified as S. apiospermum
80 with 100% sequence similarity to the type strain of S. apiospermum sensu stricto (strain CBS
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81 117407; GenBank accession number AJ 888416) (10, 12). Repeat susceptibility testing (5) o
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82 revealed that the voriconazole MICs of all isolates were 1 µg/ml. lo
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83 ed

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84 Patient B o
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85 A 48-year-old Aboriginal male with diabetes mellitus presented with severe headache, t
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86 photophobia, left-sided visual loss and dysphasia four weeks after partial left mastoidectomy for /jc
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87 a cholesteatoma. Physical examination revealed impaired vision (visual acuity 6/60) of the left .a
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88 eye and palsies affecting the III, IV, VI, VII and VIII cranial nerves. MRI of the face and sinuses .o
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89 demonstrated marked erosion of left petrous temporal bone with surrounding soft tissue /
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90 enhancement on T2-weighted images. There was disease extension to the bony margins of the A
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91 infratemporal fossa, pterygopalatine fossa, apex of the left orbit and encroaching on the left il 6
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92 cavernous sinus, consistent with extensive skull base osteomyelitis. There were no intracerebral 0
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93 lesions. b
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94 Empiric intravenous ticarcillin/clavulanate, flucloxacillin and metronidazole were u
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95 commenced and left functional endoscopic sinus surgery (FESS) performed. Marked necrosis,
96 and invasion of bone and soft tissue with numerous septate fungal hyphae were seen on
97 histopathological examination and a fungus, identified as S. apiospermum/P. boydii by
98 standard morphological methods (7), was cultured from bone. As for Patient A, ITS
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99 sequence analysis of the isolate yielded a sequence with 100% sequence similarity to the
100 type strain of S. apiospermum sensu stricto (see above) (10, 12). Voriconazole (loading dose 6
101 mg/kg daily followed by 200 mg twice daily thereafter) was commenced. Serum voriconazole
102 levels were not measured as therapeutic drug monitoring facilities were not available at that time.
103 The patient received 12 weeks of ticarcillin/clavulanate and voriconazole. Although the headache
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104 resolved, the patient’s cranial nerve deficits persisted. Two weeks post cessation of therapy, the o
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105 patient had a recurrence of severe headache. A gallium-67 citrate scan revealed persistent erosion lo
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106 of the left petrous temporal bone with new erosions extending into the right petrous temporal. He ed

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107 developed a subarachnoid haemorrhage into the basal cisterns and lateral ventricles. Magnetic o
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108 resonance angiography revealed a right superior cerebellar artery (SCA) aneurysm with t
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109 areas of ectasia of the posterior cerebral arteries highly suggestive for aneurysmal /jc
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110 formation. Surgical clipping of the SCA aneurysm was complicated by extensive cerebellar .a
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111 infarction and the patient died. Confirmation of mycological involvement was not possible .o
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112 (post mortem was not performed), however the aneurysm was very likely directly caused o/
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113 by Scedosporium infection. A
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114 DISCUSSION
115 This report describes two cases of fatal mycotic aneurysm implicating the fungus, S.
116 apiospermum. The causative role of this emergent pathogen was confirmed in patient A,
117 and highly likely resulted in aneurysmal formation in patient B. Despite antifungal therapy
118 and surgical resection, both patients died. Notable features of the cases presented herein include
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119 the insidious nature of bone involvement, with subsequent delayed presentation of aneurysmal o
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120 dilation and aggressive extent of vascular invasion due to this pathogen. lo
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121 Infections caused by Scedosporium/Pseudallescheria species are increasingly ed

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122 encountered in both immunocompromized and immune competent individuals (6, 17, 20, 33). o
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123 Mycotic aneurysms due to Scedosporium, however. are rare with only 10 biopsy-proven cases t
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124 reported in the English literature (see table 1) (2, 3, 14, 16, 19, 20, 26, 28, 32, 37). These reports /jc
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125 were identified through a MEDLINE search for the terms “Pseudallescheria boydii, .a
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126 “Scedosporium apiospermum” and “Scedosporium prolificans”, cross referenced to terms .o
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127 including “mycotic aneurysm”, “infectious aneurysm”, “fungal” and “aneurysm”. Case o/
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128 series describing infectious aneurysms or intracranial or aortic aneurysms were also A
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129 scrutinised. With one exception, all patients with Scedosporium aneurysms were adults. Five il 6
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130 (42%) had underlying malignancy and/or were organ transplant recipients; four of seven 0
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131 immunocompetent hosts had near-drowning accidents and one suffered major trauma (Table 1). b
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132 Both patients in the present report had diabetes mellitus; of interest, diabetes was an independent u
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133 predictor of invasive disease in one population-based survey of scedosporiosis (17),
134 Intracranial fungal aneurysms are most commonly caused by Aspergillus spp. (21,
135 34) whilst aortic aneurysms, in association with vertebral osteomyelitis, have been typically
136 ascribed to Salmonella spp. and other gram-negative bacteria, and mycobacteria, with
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137 fungi (primarily Aspergillus spp.) comprising only 2.1% of cases in one series (25).
138 Nonetheless, given the angioinvasive nature of Scedosporium/Pseudallescheria fungi (6, 17),
139 careful investigation of any patient with invasive scedosporiosis with unexplained clinical
140 symptoms that may be referable to a vascular cause is warranted. The majority of
141 Scedosporium aneurysms (10/12 cases; Table 1) have been reported to be caused by S.
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142 apiospermum/P. boydii. Access to DNA sequencing further enabled us to identify the causative o
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143 pathogen as S. apiospermum sensu stricto. Recent genetic analyses have revealed P. boydii to be lo
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144 now separated from S. apiospermum as a distinct species and identified new species of ed

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145 Scedosporium that would previously have been assigned as “S. apiospermum” (8, 10, 11). None o
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146 of the isolates recovered from patients described previously (Table 1) were speciated using t
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147 molecular methods. Species identification of Scedosporium/Pseudallescheria is important /jc
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148 because of differences in virulence and antifungal susceptibility (11, 13). .a
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149 A key feature of Patient A’s illness was the development of a large abdominal aorta .o
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150 aneurysm; two similar cases have been previously described but with less extensive involvement /
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151 of the aorta (Table 1) (28, 3). In our patient, the aneurysm most likely developed as a result of A
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152 direct invasion of the arterial wall from anterior spread of vertebral osteomyelitis. Alternatively, il 6
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153 infection may have originated from the aorta and then spread to the vertebra via the 0
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154 bloodstream; however, the absence of discitis (on MRI) mitigates against this hypothesis. b
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155 Both purported routes of infection are consistent with the findings of one review of u
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156 vertebral osteomyelitis co-existent with aortic pathology. In the event of bony origin,
157 anterior extension to involve the aorta was identified to be the more typical (25).
158 Scedosporium aneurysms may also develop at unusual sites including the hepatic artery (Table 1)
159 (19).
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160 We noted that intracranial aneurysms caused by Scedosporium/Pseudallescheria have
161 had a tendency to affect blood vessels at the base of the brain - seven of eight patients developed
162 aneurysms in the posterior cerebral circulation including Patient B (Table 1) (21). We postulate
163 that the apparent increased frequency of posterior circulation aneurysms may be related to direct
164 anatomical spread from infected mastoid air cells, malignant otitis externa or invasive soft tissue
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165 and skull base osteomyelitis (as in Patient B). Whilst spread from cerebral, or meningeal, o
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166 infection is also possible (1, 15, 23), intracranial aneurysms complicating central nervous system lo
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167 scedosporiosis appears to be uncommon. There was no clinical evidence antemortem of ed

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168 endocarditis although occult infection was not definitively excluded. o
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169 This report further underscores the mostly, fatal outcomes (90% mortality) of this rare t
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170 manifestation of scedosporiosis. This is consistent with the 80% mortality for fungal aneurysms /jc
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171 of the internal carotid artery (all caused by fungi other than Scedosporium) (18). The sole .a
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172 survivor in the cases we reviewed was an immunosuppressed patient infected with S. prolificans .o
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173 (Table 1). This patient was treated by surgical resection of the affected hepatic artery together /
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174 with combined voriconazole and terbinafine therapy (19). Mortality rates of 79-100% have been A
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175 reported for disseminated infection caused by both S. prolificans and S. apiospermum (4, 24). il 6
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176 A multidisciplinary approach with surgical resection of affected tissue and antifungal 0
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177 therapy is fundamental in managing patients with scedosporiosis (6, 20). A retrospective review b
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178 of infected aortic aneurysms (only two cases were due to fungi) found that for those who had u
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179 surgical treatment, the 1-year survival (90%), free of graft-related complications, was
180 comparable to that reported for patients who had repair of non-infected aneurysms (27).
181 However, early surgical outcomes were associated with significant morbidity including ischemic
182 colitis (27); indeed, Patient A died following occlusion of the mesenteric artery graft. In another
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183 study of patients with vertebral osteomyelitis and infected aortic aneurysms, the best outcomes
184 occurred in those who underwent surgical resection together with extra anatomic bypass (25).
185 The management of intracranial fungal aneurysms is also problematic. While there is general
186 agreement that ruptured aneurysms should be immediately secured via either surgical means (as
187 attempted in Patient B) or endovascular aneurysm repair (EVAR) (22), unruptured infectious
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188 (predominantly bacterial) aneurysms have been treated medically with antimicrobials and o
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189 followed by serial angiography (9, 30). lo
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190 The decision to use voriconazole therapy was based on the in vitro susceptibility testing ed

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191 results and currently available clinical information for the treatment of invasive scedosporiosis. o
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192 Voriconazole is the preferred therapy for S. apiospermum/P.boydii infections (6, 35) although no t
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193 recommendations regarding the optimal antifungal therapy or of its duration have been /jc
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194 established. Prolonged therapy is typically required. The complications of osteomyelitis and .a
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195 aneurysm formation in patient A did not manifest until nine months post cessation of the initial .o
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196 course of antifungal therapy. Hence, careful follow up of all high risk patients for delayed /
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197 complications even with apparent clinical response is critical. Although clinical benefit of A
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198 antifungal combination therapy has been reported for S. prolificans infections (6), a similar il 6
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199 benefit has not been established for those due to S. apiospermum/P. boydii. 0
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200 In summary, despite their rarity, mycotic aneurysms due to Scedosporium spp. are often b
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201 fatal and may be delayed in their presentation. Clinicians should be vigilant for unusual u
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202 manifestations of disease caused by this important pathogen. Early detection and prolonged
203 antifungal therapy combined with surgical resection of the affected tissue are the cornerstones of
204 management.