Scedosporium apiospermum: An Emerging Fatal Cause of Fungal Abscess and Ventriculitis after Near-drowning.

Herein, we describe a fatal case of central nervous system (CNS) pseudallescheriasis following near-drowning. A 13-year-old boy, who had been successfully resuscitated after near-drowning, presented with a transient episode of mental confusion during a hospital stay after recovering from severe aspiration pneumonia and respiratory failure. A magnetic resonance imaging (MRI) scan of the brain showed a small brain abscess in the left basal ganglia and ventriculitis in the left lateral ventricle. The brain abscess and ventriculitis did not respond to 4 weeks of antibiotic treatment and appeared even worse on a follow-up MRI. A diagnosis of CNS pseudallescheriasis was only possible with invasive stereotactic biopsy and aspiration of the abscess that showed the presence of hyphae and Scedosporium apiospermum. CNS pseudallescheriasis did not respond to multiple combinations of antifungal agents, including amphotericin B, isoconazole, itraconazole, and voriconazole. Two ventricular drainages and insertion of Ommaya reservoirs with intraventricular injection of voriconazole were insufficient to halt the infection. The patient passed away from sudden septic shock 2 months after identification of the brain abscess and ventriculitis. The patient's diagnosis was delayed because multiple examinations of the cerebrospinal fluid did not show positive cultures and could only be obtained from the aspirates of stereotactic biopsy. Physicians should be aware of CNS pseudallescheriasis associated with near-drowning because of the difficulty of diagnosis and the high mortality rate (70%) owing to poor responses to currently available antifungal agents.

Introduction

Drowning is one of the three leading causes of accidental death in young, otherwise healthy individuals.[1] Near-drowning, defined as a submersion episode severe enough to warrant hospital admission, is estimated to occur 2–20 times more frequently than drowning. Infection is one of the complications of near-drowning that may result in premature death or permanent disability. Fungal infection caused by the presence of generally harmless saprophytes in victims of near-drowning is increasingly being reported to cause serious or lethal infections, even in immunocompetent individuals.[2] Scedosporium apiospermum and its teleomorph (sexual form) Pseudallescheria boydii are increasingly recognized as causes of localized and disseminated mycotic infections in near-drowning victims.[3456] These fungi are ubiquitous and are present in soil, manure, sewage, polluted water and decaying vegetation.[456]

Over the last two decades, at least 21 cases of S. apiospermum/P. boydii infection associated with near-drowning in polluted waters have been reported; two of those cases involved survivors of the tsunami in Southeast Asia in December 2004.[7] Currently, P. boydii/S. apiospermum is recognized as the fungus most commonly implicated in invasive disease after near-drowning. Scedosporiosis after near-drowning was reported to be associated with high mortality (70%), even in immunocompetent hosts and showed a slow progression (mean survival time, 87 days).[38] Dissemination to the central nervous system (CNS) resulting in multiple brain abscesses was also high (91%) and the diagnosis is typically delayed (mean time to diagnosis 28 days).[3] We report a fatal case of S. apiospermum which presented as a brain abscess and ventriculitis in a boy following a near-drowning accident. This study was approved by the Institutional Review Board of our institute (KC16ZISE0596).

Case Report

A 13-year-old boy was referred to the Department of Neurosurgery for stereotactic biopsy for a brain abscess which did not respond to over 4 weeks of treatment with antifungal agents. Seventy-five days before consultation, he had experienced an accidental near-drowning event in a river and had been revived from for cardiac arrest. Severe aspiration pneumonia associated acute respiratory failure and acute renal failure subsequently developed, and he was treated with ventilator support, extracorporeal membrane oxygenation, and continuous renal replacement therapy in an intensive care unit (ICU) for 1 month. During the stay in the ICU, multiple bacteria were cultured from his sputum, including Acinetobacter baumannii, Elizabethkingia meningoseptica, and methicillin-resistant Staphylococcus aureus. Several antibiotics were prescribed according to the culture results, and he was weaned from the ventilator with improvement of pneumonia.

He was then transferred to the general ward specializing in vancomycin-resistant enterococci and was managed for poor oral intake, nausea, and general weakness. Forty days after admission, a transient episode of mental confusion with disorientation developed and a magnetic resonance imaging (MRI) scan of the brain was performed. The brain MRI scan showed an approximately 8 mm diameter contrast-enhancing lesion in the left frontal white matter [Figure 1]. Examination of the cerebrospinal fluid (CSF) showed red blood cell (RBC), 0 cells/μl; white blood cell (WBC), 1600 cells/μl (neutrophils, 58%, lymphocytes, 12%, eosinophils, 1%, monocytes, 28%, and basophils, 1%); protein, 141.3 mg/dl; and glucose, 36 mg/dl. The CSF culture was negative for bacteria and fungi. Under a diagnosis of brain abscess and ventriculitis, antibiotics (vancomycin, cefotaxime, metronidazole, Cotrim® [trimethoprim and sulfamethoxazole], and amphotericin B) with broad-spectrum coverage including action against anaerobes were prescribed. The patient's mental confusion improved immediately, and intravenous antibiotics were maintained for 4 weeks.

Figure 1

Magnetic resonance imaging findings in central nervous system pseudallescheriasis. T2-weighted axial (a) and enhanced T1-weighted coronal (b) images showing a small, round enhancing mass with surrounding edema in the left frontal white matter

However, surrounding edema became enlarged, and enhancement of the left lateral ventricle indicating ventriculitis was present on the follow-up MRI taken after 4 weeks of antibiotic treatment [Figure 2]. The antibiotic regimen was changed to a combination of voriconazole, meropenem, and Cotrim®. The CSF culture did not reveal any growth of bacteria or fungi, despite of CSF pleocytosis. Considering antibiotic resistance and the possibility of a fungal abscess, a stereotactic biopsy was performed. During aspiration of the abscess, a greenish-yellow pus was observed and multiple hyphae were found on H- and E-stained sections [Figure 2c]. The analysis of CSF at the time of biopsy revealed RBC, 0 cells/μl; WBC, 16,500 cells/μ (neutrophils, 65%, lymphocytes, 15%, and macrophages, 20%); protein, 141.3 mg/dl, and glucose, 36 mg/dl.

Figure 2

Magnetic resonance imaging findings after 4 weeks of antibiotic treatment. T2-weighted axial (a) and enhanced T1-weighted coronal (b) images showing an aggravation of brain edema with enhancement of the left lateral ventricle. (c) A photograph showing the appearance of multiple hyphae (arrows) in the aspirates (silver stain, ×40)

S. apiospermum was found in a culture of the aspirate. The intravenous antibiotics were changed to voriconazole, isoconazole, and amphotericin B and maintained as such. After 3 weeks of treatment with multiple antifungal agents and maintenance of an alert mentality without neurologic impairment, more diffuse contrast enhancement and dilation of the left lateral ventricle and aggravation of the edema around the abscess were observed on a follow-up MRI. Extraventricular drainage of the left lateral ventricle was performed, and CSF drainage (150–200 ml/day) was maintained along with continued treatment with multiple antifungal agents, including voriconazole.

After 2 weeks of left frontal external ventricular drain (EVD), an intraventricular injection of voriconazole (5 mg) was performed through an Ommaya valve in the left lateral ventricle. However, the patient became quite drowsy on the day following intraventricular injection of voriconazole, and an emergent MRI revealed a marked dilation with acute hydrocephalus, along with septations within the left lateral ventricle [Figure 3]. Following mannitol treatment, he became alert and reported experiencing a minimal headache. A repeated EVD associated with endoscopic septostomy was performed with an occipital burr-hole trephination the next day. After EVD, the patient was alert and no signs or symptoms of increased intracranial pressure were observed. His vital signs were stable. On the day following the occipital EVD, sudden hypotension with respiratory distress consistent with acute septic shock developed and the patient was transferred to the ICU. Despite maximal vasopressor and ventilator treatment, the patient expired after 12 h.

Figure 3

Further aggravation of brain edema (a) and further enhancement of the lateral ventricle with septated hydrocephalus in T1-weighted axial (b) and coronal (c) images

Discussion

Central nervous system pseudallescheriasis after near-drowning

The members of the P. boydii species complex are commonly found in soil, sewage, mud, and the polluted waters of streams and ponds with still water.[910] P. boydii is, after Aspergillus, one of the most prevalent molds that give rise to human disease. These fungi show a particular tropism for the CNS.[10] P. boydii are known to consist of a complex that includes several phylogenetic species[11] and S. apiospermum, traditionally considered the anamorph (asexual state of P. boydii), and S. apiospermum are two different species.[12]

According to a comprehensive review,[8] only 99 cases of CNS pseudallescheriasis had been reported until 2008, and 25 of them were associated with near-drowning.[8] It was found that CNS pseudallescheriasis affected both previously healthy, immunocompetent patients (44%) and immunosuppressed patients (56%).[8] Fifty-five percent of immunocompetent patients had a prior history of aspiration of polluted water in association with near-drowning; they included tsunami survivors[7] or those involved in motor vehicle accidents.[813] Medically induced immunosuppression in transplant recipients is a major risk in immunocompromised patients.[8] The main clinical spectrums of CNS involvement are brain abscess (69%), coinfection of brain and/or spinal cord meninges (10%), and meningitis (9%).[38] Cerebral abscess with concomitant ventriculitis, as in the clinical findings in the present case, was reported in four previous cases (4%).[8]

Near-drowning can cause pulmonary and neurological damage, and infection is a potentially life-threatening complication.[2] The incidence of pneumonia has been reported to be as high as 71% among patients with CNS pseudallescheriasis after near-drowning.[8] One interesting finding is that an antemortem diagnosis of P. boydii complex pulmonary infection following a near-drowning episode is quite rare,[814] and the first symptoms exhibited by such patients are usually evident in the brain. Furthermore, sputum and/or other respiratory sample cultures included bacteria belonging to numerous genera but not the P. boydii complex.[8] In line with these previous findings, P. boydii was not found in cultures taken during the patient's stay in the ICU for respiratory failure or while under ventilatory care for 1 month.

The time of onset of CNS pseudallescheriasis is greatly affected by the route of infection and inoculum size.[8] The incubation period in near-drowned patients, who aspirated a sufficient amount of mold, is approximately 1–3 weeks.[815] However, an occurrence of brain abscess secondary to bilateral P. boydii complex endophthalmitis 1 year after surgery in a cadaveric kidney recipient who had been transplanted with a cadaveric kidney of a victim of near-drowning has been reported.[16] Although inhalation of airborne conidia followed by hematogenous spread to the brain is the most common route of CNS pseudallescheriasis,[81718] hematogenous spread after invasive pneumonitis was suspected in the present.

The CSF cultures obtained from lumbar punctures before stereotactic biopsy were negative in the present case, and a diagnosis of brain abscess from pseudallescheriasis was, as usual, delayed (75 days after admission). A relatively high percentage of negative CSF cultures (35%) was reported,[8] and encapsulated abscess formation by the fungus in the brain was suggested as a cause.[8] Even a pachymeningitis case secondary to pansinusitis showed negative culture results.[19] Therefore, a diagnosis is established postmortem in 30% of cases of pseudallescheriasis,[8] and the median time to diagnosis was reported to be 28 days.[3]

Difficulties in early diagnosis

The diagnosis of pseudallescheriasis is typically delayed and difficult.[389] In the present case, clinical manifestations of CNS involvement took 75 days after initial resuscitation to develop, and a definite diagnosis of brain abscess and ventriculitis by P. boydii took an additional 30 days until an invasive, stereotactic biopsy was performed. Although the possibility of a fungal abscess had been kept in mind given poor antibiotics response seen on repeated MRI examinations and antifungal agents were started 4 weeks before stereotactic biopsy, we could not identify the organism causing brain abscess with ventriculitis until the identifying hyphae on the stain and taking a culture of the aspirate through stereotactic biopsy. CSF culture was revealed to not be a very important tool in the diagnosis of pseudallescheriasis.[38] It seems that a history of near-drowning, a latent period, and a preceding pulmonary infection could be clues to a diagnosis of CNS pseudallescheriasis.

Treatment and prognosis of central nervous system pseudallescheriasis

CNS infection caused by P. boydii complex has a poor prognosis. It nearly always proves fatal even when it occurs in previously healthy individuals. The overall mortality of scedosporiosis after near-drowning is approximately 74%[38] while the prognostic factors remain largely unknown. The mortality rates are high regardless of the patient's immune status (immunocompetent or immunocompromised) or the infection type and/or location.[38]

The main reason for the poor prognosis is the resistance of P. boydii to conventional antifungal agents, including amphotericin B, and difficulty in early diagnosis. In the absence of controlled clinical trials on an optimal anti-scedosporial treatment, treatment options are based almost entirely on in vitro and experimental animal studies and published cases reports.[3] In vitro susceptibility studies have shown that S. apiospermum isolates are susceptible to miconazole, voriconazole, and posaconazole, resistant to fluconazole and flucytosine, and appear to have variable susceptibility to ketoconazole, itraconazole, and amphotericin B.[32021] Most successfully treated cases were reported relatively recently, and the beneficial effect of voriconazole was underlined.[14212223] According to a review of cases,[3] it was suggested that voriconazole be used very early in cases of suspected scedosporiosis after near-drowning or even prophylactically in all near-drowned patients.[3]

Conclusions

To date, few cases of CNS pseudallescheriasis have been described. Considering the difficulties in establishing a correct diagnosis, the high mortality rate, and the resistance to antifungal agents, as seen in the present case, pseudallescheriasis should always be suspected in individuals who have suffered near-drowning events.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.