mycoses
Diagnosis,Therapy and Prophylaxis of Fungal Diseases
Review article
Fusarium brain abscess: case report and literature review Raquel Ramos Garcia,1 Zaw Min,1 Supriya Narasimhan2 and Nitin Bhanot1 1 Division of Infectious Disease, Allegheny General Hospital, Allegheny Health Network, Pittsburgh, PA, USA and 2Division of Infectious Disease, Santa Clara Valley Medical Center, San Jose, CA, USA
Summary
Severely immunocompromised patients such as those with haematological malignancies and haematopoietic stem cell transplant recipients are at an increased risk of acquiring invasive mould infections. Fusarium, a ubiquitous fungus, can cause potentially fatal infections in such hosts. It usually manifests as skin lesions, fevers and sino-pulmonary infections. Brain abscesses have been reported, but are relatively uncommon. We report a case of a 50-year-old patient with acute lymphocytic leukaemia and failed autologous peripheral stem cell transplant that presented with new onset seizures and was found to have Fusarium solani brain abscess. Nasal route was the presumed mode of entry of the fungus into the cerebrum. Treatment comprised surgical excision of the lesion, and antimycotic therapy with liposomal amphotericin B and voriconazole. Despite aggressive therapy, patient succumbed to the disease. We have provided an overview of infections secondary to Fusarium, along with a review of the central nervous system involvement by this pathogenic mould.
Key words: Fusarium, abscess, stem cell transplant.
Introduction The advent of potent immunosuppressants and evolving transplant medicine has shifted the paradigm of opportunistic infections to include previously considered innocuous environmental moulds.1 Fusarium is one amongst them, implicated as the second most common mould after Aspergillus in hosts with haematological malignancies, transplant recipients and those with prolonged neutropenia.1 The role of Fusarium as a human pathogen dates back to 1964 when it was isolated from skin lesions of burn patients.2 In 1973, one of the first reports of disseminated fusariosis in a paediatric patient with acute leukaemia was Correspondence: N. Bhanot, MD, MPH, Division of Infectious Disease, Allegheny General Hospital, Allegheny Health Network, 320 East North Avenue, East Wing, Suite 407, Pittsburgh, PA 15212, USA. Tel.: +4123593683. Fax: +4123593373. E-mail: [email protected] Submitted for publication 11 August 2014 Revised 21 October 2014 Accepted for publication 22 October 2014
doi:10.1111/myc.12271
published.3 Over the years, the pathogenic role of Fusarium in certain high-risk patient population has been clearly established.1
Case A 50-year-old lady presented to our hospital with confusion and altered mental status of acute onset. Her medical history was significant for diabetes mellitus and acute lymphocytic leukaemia with failed autologous peripheral stem cell transplantation about 6 months prior to admission. She had received fludarabine, busulfan and total body irradiation as the conditioning regimen at the time of the transplant, and was on ponatinib 30 mg daily and dexamethasone 10 mg every other day at the time of admission. The absolute neutrophil count (ANC) was in the range of 50–350 cells mm 3 for approximately 3 months prior to hospitalisation. Soon after admission, she had an episode of generalised tonic-clonic seizure. On physical examination, she was confused, but afebrile and normotensive without neck stiffness. Motor tone was normal and there was no focal weakness.
© 2014 Blackwell Verlag GmbH Mycoses, 2015, 58, 22–26
Fusarium brain abscess
Figure 2 Histopathology slide demonstrating presence of hyphal
elements on Gomori’s methenamine silver stain.
Figure 1 Magnetic resonance imaging brain with postcontrast
T1-weighted image showed a round ring-enhancing lesion measuring 1 cm in diameter at the right temporo-parietal lobe junction.
Deep tendon reflexes were symmetrical and flexor plantar reflexes were present. A necrotic ulcer on the nasal septum was noted. The remainder of physical examination was unremarkable. Laboratory studies were significant for pancytopenia with profound neutropenia (ANC of 73 cells mm 3). Blood cultures were negative. Serum Aspergillus galactomannan antigen assay was negative, while the 1-3-beta-D-glucan level was 69 pg ml 1, which was in the indeterminate range. A magnetic resonance imaging of the brain with intravenous gadolinium was performed that showed a solitary rounded ring-enhancing lesion (1 cm in diameter) with significant surrounding vasogenic oedema at the right temporo-parietal lobe junction (Fig. 1). Empiric intravenous vancomycin, cefepime, metronidazole and amphotericin B lipid complex were initiated, awaiting diagnostic confirmation. Excisional biopsy of the cerebral lesion and punch biopsy of the necrotic nasal ulcer were performed. Specimens were sent to pathology and microbiology. Histopathological analysis of the tissue revealed hyphae, branching at narrow angles on Gomori’s methenamine silver stain (GMS) stain (Fig. 2). Fluffy, yellowish white colonies grew on dextrose potato agar.
© 2014 Blackwell Verlag GmbH Mycoses, 2015, 58, 22–26
Figure 3 Narrow angle branching septated hyphae and presence
of banana-shaped macroconidia on culture growth (stained with lactophenol cotton blue preparation).
Lactophenol stain preparation on the culture colonies revealed septated hyphae and canoe-shaped clusters of macroconidia, highly suggestive of Fusarium spp (Fig. 3). The species was confirmed as F. solani based on DNA sequencing (Labcorp, Burlington, NC, USA). Antimycotic susceptibilities by microbroth dilution technique [voriconazole minimum inhibitory concentration (MIC): 0.25 mcg ml 1, amphotericin MIC: 0.25 mcg ml 1] were obtained (Focus Diagnostics, Cypress, CA, USA). Intravenous voriconazole (6 mg kg 1 every 12 h for two doses, followed by 4 mg kg 1 every 12 h) was added to the amphotericin B lipid complex therapy 5 mg kg 1 every 24 h, as soon as the pathological slides were viewed. Granulocyte-colony stimulating
23
R. R. Garcia et al.
factor (G-CSF) was administered given the persistent and profound neutropenia. Once the susceptibility results were obtained, voriconazole monotherapy was continued. Voriconazole level, obtained a week from the time of initiation of the drug by high-performance liquid chromatography, was 5.0 mcg ml 1. She tolerated the antifungal agent well, but unfortunately, leukaemia failed to respond to multiple modalities of therapy. The ANC remained 10 days) and profound neutropenia (ANC < 100 cells mm 3) is the major risk factor for invasive disseminated fusariosis, which usually manifests as persistent fever, not responding to antibiotic therapy.4,5 The most common clinical presentation in disseminated Fusarium disease is multiple painful cutaneous erythematous papules or nodules with central necrosis from angioinvasion, giving rise to target-like appearance.4,5 Central nervous system (CNS) manifestations in disseminated Fusarium infection include meningo-encephalitis and brain abscesses, but these are relatively rare compared to the other clinical manifestations.1,6 The diagnosis of Fusarium infection requires tissue cultures for accurate identification.1 Fusarium species appear as septated hyaline hyphae with acute angle branching on GMS stain.1 The appearance of bananaor canoe-shaped macroconidia on lactophenol stain (Fig. 3) is a pathognomonic feature of Fusarium species.5 The presence of angioinvasion by Fusarium fungal elements on histology provides definite evidence of invasive disease.6 Blood cultures should be obtained and are reportedly positive in up to 60% of the patients with disseminated fusariosis, in contrast to aspergillosis and most other invasive mould infections where they are rarely positive.1 1-3-beta-D-glucan and Aspergillus galactomannan antigen assays have been utilised to aid in diagnosis of invasive fusariosis.7,8 However, because of variable sensitivities and lack of specificity, the interpretation of test results needs to be made with caution.7,8
24
The treatment of invasive fusariosis is challenging for a few reasons. Fusarium spp are one of the most drug-resistant fungi.1 Additionally, antifungal susceptibilities tend to vary amongst different species of Fusarium.1,6 F. solani tends to be more resistant to antifungal agents compared to the other species.1 Moreover, since there are no controlled studies, the optimal therapy is not well established.4,6 Initial recommended therapy by experts includes a combined lipid formulation of amphotericin B and voriconazole regimen in disseminated disease to provide the broadest spectrum of activity while awaiting susceptibilities.6 There have been use of combination antifungal therapy, but no definite conclusions can be made from the limited information available.5 Surgical resection of infected tissues is important for source control and although this is known to favourably impact clinical outcomes, it may not be feasible in patients with altered haematological parameters such as thrombocytopenia.1,6 Last, but not the least, one of the most important and crucial determinant of improved survival is the recovery of the host neutrophil count.1,6 Thus, the administration of granulocyte- or granulocyte-macrophage-colony stimulating factors (G-CSF) is suggested as adjunctive immunotherapy to augment the host response to the infection, although its efficacy is yet to be determined.4,5,9 Despite these available therapeutic options, the mortality from disseminated Fusarium infection is dismal and invariably fatal if neutrophil recovery cannot be achieved.5 Central nervous system fusariosis is relatively rare compared to other organ involvement such as skin and sino-pulmonary region.1 When encountered, it is usually attributed to haematogenous dissemination.1 In our patient, the route of infection into the brain was likely through the naso-sinus path since the blood cultures were negative and the septum of the nose had an ulcer that revealed hyphae on the GMS stain. Central nervous system fusariosis may manifest as meningoencephalitis or brain abscesses.6 It tends to be associated with endophthalmitis and chorioretinitis, disproportionately more compared to other CNS fungal infections.6 We reviewed the medical literature for CNS involvement by Fusarium spp and identified 17 cases of CNS fusariosis that had reported salient details about them.2,4,10–19 It is likely that more of such cases have been encountered by clinicians, but are either not reported, or have may have been grouped under disseminated infections in previously published work. We have tabulated cases where pertinent details of CNS fusariosis were reported by authors. Patient characteristics including demographics, underlying
© 2014 Blackwell Verlag GmbH Mycoses, 2015, 58, 22–26
Aplastic anaemia, allogeneic donor-matched BMT Acute lymphocytic leukaemia Malignancy
Acute myelogenous leukaemia, Prostate cancer NA Acute promyelocytic leukaemia Pulmonary sarcoidosis, bilateral lung transplantation Focal segmental glomerulosclerosis Acute lymphocytic leukaemia
17/F
53/M
15/M
6/F
NR
NR
76/M
NR 53/F
55/F
23/M
50/F
10/1983
11/1986
12/1991
© 2014 Blackwell Verlag GmbH Mycoses, 2015, 58, 22–26
13/1996
14/1998
15/2003 Case series (five cases) 16/2003
17/2007 18/2008
19/2009
4/2013
Current case/2014
Yes
NR
NR
NR NR
Yes
NR
NR
NR
NR
Yes
NR
NR
Absolute neutrophil count (
Diagnosis,Therapy and Prophylaxis of Fungal Diseases
Review article
Fusarium brain abscess: case report and literature review Raquel Ramos Garcia,1 Zaw Min,1 Supriya Narasimhan2 and Nitin Bhanot1 1 Division of Infectious Disease, Allegheny General Hospital, Allegheny Health Network, Pittsburgh, PA, USA and 2Division of Infectious Disease, Santa Clara Valley Medical Center, San Jose, CA, USA
Summary
Severely immunocompromised patients such as those with haematological malignancies and haematopoietic stem cell transplant recipients are at an increased risk of acquiring invasive mould infections. Fusarium, a ubiquitous fungus, can cause potentially fatal infections in such hosts. It usually manifests as skin lesions, fevers and sino-pulmonary infections. Brain abscesses have been reported, but are relatively uncommon. We report a case of a 50-year-old patient with acute lymphocytic leukaemia and failed autologous peripheral stem cell transplant that presented with new onset seizures and was found to have Fusarium solani brain abscess. Nasal route was the presumed mode of entry of the fungus into the cerebrum. Treatment comprised surgical excision of the lesion, and antimycotic therapy with liposomal amphotericin B and voriconazole. Despite aggressive therapy, patient succumbed to the disease. We have provided an overview of infections secondary to Fusarium, along with a review of the central nervous system involvement by this pathogenic mould.
Key words: Fusarium, abscess, stem cell transplant.
Introduction The advent of potent immunosuppressants and evolving transplant medicine has shifted the paradigm of opportunistic infections to include previously considered innocuous environmental moulds.1 Fusarium is one amongst them, implicated as the second most common mould after Aspergillus in hosts with haematological malignancies, transplant recipients and those with prolonged neutropenia.1 The role of Fusarium as a human pathogen dates back to 1964 when it was isolated from skin lesions of burn patients.2 In 1973, one of the first reports of disseminated fusariosis in a paediatric patient with acute leukaemia was Correspondence: N. Bhanot, MD, MPH, Division of Infectious Disease, Allegheny General Hospital, Allegheny Health Network, 320 East North Avenue, East Wing, Suite 407, Pittsburgh, PA 15212, USA. Tel.: +4123593683. Fax: +4123593373. E-mail: [email protected] Submitted for publication 11 August 2014 Revised 21 October 2014 Accepted for publication 22 October 2014
doi:10.1111/myc.12271
published.3 Over the years, the pathogenic role of Fusarium in certain high-risk patient population has been clearly established.1
Case A 50-year-old lady presented to our hospital with confusion and altered mental status of acute onset. Her medical history was significant for diabetes mellitus and acute lymphocytic leukaemia with failed autologous peripheral stem cell transplantation about 6 months prior to admission. She had received fludarabine, busulfan and total body irradiation as the conditioning regimen at the time of the transplant, and was on ponatinib 30 mg daily and dexamethasone 10 mg every other day at the time of admission. The absolute neutrophil count (ANC) was in the range of 50–350 cells mm 3 for approximately 3 months prior to hospitalisation. Soon after admission, she had an episode of generalised tonic-clonic seizure. On physical examination, she was confused, but afebrile and normotensive without neck stiffness. Motor tone was normal and there was no focal weakness.
© 2014 Blackwell Verlag GmbH Mycoses, 2015, 58, 22–26
Fusarium brain abscess
Figure 2 Histopathology slide demonstrating presence of hyphal
elements on Gomori’s methenamine silver stain.
Figure 1 Magnetic resonance imaging brain with postcontrast
T1-weighted image showed a round ring-enhancing lesion measuring 1 cm in diameter at the right temporo-parietal lobe junction.
Deep tendon reflexes were symmetrical and flexor plantar reflexes were present. A necrotic ulcer on the nasal septum was noted. The remainder of physical examination was unremarkable. Laboratory studies were significant for pancytopenia with profound neutropenia (ANC of 73 cells mm 3). Blood cultures were negative. Serum Aspergillus galactomannan antigen assay was negative, while the 1-3-beta-D-glucan level was 69 pg ml 1, which was in the indeterminate range. A magnetic resonance imaging of the brain with intravenous gadolinium was performed that showed a solitary rounded ring-enhancing lesion (1 cm in diameter) with significant surrounding vasogenic oedema at the right temporo-parietal lobe junction (Fig. 1). Empiric intravenous vancomycin, cefepime, metronidazole and amphotericin B lipid complex were initiated, awaiting diagnostic confirmation. Excisional biopsy of the cerebral lesion and punch biopsy of the necrotic nasal ulcer were performed. Specimens were sent to pathology and microbiology. Histopathological analysis of the tissue revealed hyphae, branching at narrow angles on Gomori’s methenamine silver stain (GMS) stain (Fig. 2). Fluffy, yellowish white colonies grew on dextrose potato agar.
© 2014 Blackwell Verlag GmbH Mycoses, 2015, 58, 22–26
Figure 3 Narrow angle branching septated hyphae and presence
of banana-shaped macroconidia on culture growth (stained with lactophenol cotton blue preparation).
Lactophenol stain preparation on the culture colonies revealed septated hyphae and canoe-shaped clusters of macroconidia, highly suggestive of Fusarium spp (Fig. 3). The species was confirmed as F. solani based on DNA sequencing (Labcorp, Burlington, NC, USA). Antimycotic susceptibilities by microbroth dilution technique [voriconazole minimum inhibitory concentration (MIC): 0.25 mcg ml 1, amphotericin MIC: 0.25 mcg ml 1] were obtained (Focus Diagnostics, Cypress, CA, USA). Intravenous voriconazole (6 mg kg 1 every 12 h for two doses, followed by 4 mg kg 1 every 12 h) was added to the amphotericin B lipid complex therapy 5 mg kg 1 every 24 h, as soon as the pathological slides were viewed. Granulocyte-colony stimulating
23
R. R. Garcia et al.
factor (G-CSF) was administered given the persistent and profound neutropenia. Once the susceptibility results were obtained, voriconazole monotherapy was continued. Voriconazole level, obtained a week from the time of initiation of the drug by high-performance liquid chromatography, was 5.0 mcg ml 1. She tolerated the antifungal agent well, but unfortunately, leukaemia failed to respond to multiple modalities of therapy. The ANC remained 10 days) and profound neutropenia (ANC < 100 cells mm 3) is the major risk factor for invasive disseminated fusariosis, which usually manifests as persistent fever, not responding to antibiotic therapy.4,5 The most common clinical presentation in disseminated Fusarium disease is multiple painful cutaneous erythematous papules or nodules with central necrosis from angioinvasion, giving rise to target-like appearance.4,5 Central nervous system (CNS) manifestations in disseminated Fusarium infection include meningo-encephalitis and brain abscesses, but these are relatively rare compared to the other clinical manifestations.1,6 The diagnosis of Fusarium infection requires tissue cultures for accurate identification.1 Fusarium species appear as septated hyaline hyphae with acute angle branching on GMS stain.1 The appearance of bananaor canoe-shaped macroconidia on lactophenol stain (Fig. 3) is a pathognomonic feature of Fusarium species.5 The presence of angioinvasion by Fusarium fungal elements on histology provides definite evidence of invasive disease.6 Blood cultures should be obtained and are reportedly positive in up to 60% of the patients with disseminated fusariosis, in contrast to aspergillosis and most other invasive mould infections where they are rarely positive.1 1-3-beta-D-glucan and Aspergillus galactomannan antigen assays have been utilised to aid in diagnosis of invasive fusariosis.7,8 However, because of variable sensitivities and lack of specificity, the interpretation of test results needs to be made with caution.7,8
24
The treatment of invasive fusariosis is challenging for a few reasons. Fusarium spp are one of the most drug-resistant fungi.1 Additionally, antifungal susceptibilities tend to vary amongst different species of Fusarium.1,6 F. solani tends to be more resistant to antifungal agents compared to the other species.1 Moreover, since there are no controlled studies, the optimal therapy is not well established.4,6 Initial recommended therapy by experts includes a combined lipid formulation of amphotericin B and voriconazole regimen in disseminated disease to provide the broadest spectrum of activity while awaiting susceptibilities.6 There have been use of combination antifungal therapy, but no definite conclusions can be made from the limited information available.5 Surgical resection of infected tissues is important for source control and although this is known to favourably impact clinical outcomes, it may not be feasible in patients with altered haematological parameters such as thrombocytopenia.1,6 Last, but not the least, one of the most important and crucial determinant of improved survival is the recovery of the host neutrophil count.1,6 Thus, the administration of granulocyte- or granulocyte-macrophage-colony stimulating factors (G-CSF) is suggested as adjunctive immunotherapy to augment the host response to the infection, although its efficacy is yet to be determined.4,5,9 Despite these available therapeutic options, the mortality from disseminated Fusarium infection is dismal and invariably fatal if neutrophil recovery cannot be achieved.5 Central nervous system fusariosis is relatively rare compared to other organ involvement such as skin and sino-pulmonary region.1 When encountered, it is usually attributed to haematogenous dissemination.1 In our patient, the route of infection into the brain was likely through the naso-sinus path since the blood cultures were negative and the septum of the nose had an ulcer that revealed hyphae on the GMS stain. Central nervous system fusariosis may manifest as meningoencephalitis or brain abscesses.6 It tends to be associated with endophthalmitis and chorioretinitis, disproportionately more compared to other CNS fungal infections.6 We reviewed the medical literature for CNS involvement by Fusarium spp and identified 17 cases of CNS fusariosis that had reported salient details about them.2,4,10–19 It is likely that more of such cases have been encountered by clinicians, but are either not reported, or have may have been grouped under disseminated infections in previously published work. We have tabulated cases where pertinent details of CNS fusariosis were reported by authors. Patient characteristics including demographics, underlying
© 2014 Blackwell Verlag GmbH Mycoses, 2015, 58, 22–26
Aplastic anaemia, allogeneic donor-matched BMT Acute lymphocytic leukaemia Malignancy
Acute myelogenous leukaemia, Prostate cancer NA Acute promyelocytic leukaemia Pulmonary sarcoidosis, bilateral lung transplantation Focal segmental glomerulosclerosis Acute lymphocytic leukaemia
17/F
53/M
15/M
6/F
NR
NR
76/M
NR 53/F
55/F
23/M
50/F
10/1983
11/1986
12/1991
© 2014 Blackwell Verlag GmbH Mycoses, 2015, 58, 22–26
13/1996
14/1998
15/2003 Case series (five cases) 16/2003
17/2007 18/2008
19/2009
4/2013
Current case/2014
Yes
NR
NR
NR NR
Yes
NR
NR
NR
NR
Yes
NR
NR
Absolute neutrophil count (
