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Clinical and morphologic findings in disseminated Scedosporium apiospermum infections in immunocompromised patients.

Scedosporium apiospermum (teleomorph state, Pseudallescheria apiospermum) is a ubiquitous, saprophytic, filamentous mold. It is found in the environment, including in soil, sewage, polluted water, and compost (1, 2). It cannot be transmitted from person to person (3). Immunocompetent patients can acquire subcutaneous infections (mycetoma), but disseminated infection is possible in patients with severely immunocompromised states, such as hematopoietic or solid organ transplant recipients. Scedosporium spp. account for approximately 25% of non-Aspergillus mold infections in transplant patients (1). Histologically, this organism is indistinguishable from Aspergillus, Fusarium, and many other molds, with septate hyphae branching at 45-degree angles. Therefore, identification requires culture from the infected organ (2). It is a highly resistant organism, with a notable innate resistance to amphotericin B and variable susceptibility to other antifungals (2). In this paper, we present the clinical and autopsy findings of two patients with fatal disseminated S. apiospermum infection.

CASE REPORTS

Case 1

A 72-year-old man with a history of myelodysplastic syndrome and transformation to acute myelogenous leukemia received a bone marrow transplant from a human leukocyte antigen--matched unrelated donor. Sixty-one days after his bone marrow transplant, the patient was noted to have decreased mental status. A head computed tomography (CT) scan with contrast revealed the development a 2.6 cm ring-enhancing lesion within the posterior aspect of the right frontal lobe that had mild surrounding vasogenic edema and local mass effect-findings that are typical for a pyogenic abscess (Figure 1a). The patient was also noted to have multiple black raised skin lesions, which were biopsied and cultured to yield the diagnosis of fungal infection by S. apiospermum. This was concordant with positive blood cultures done at the same time. The patient was treated with voriconazole and micafungin, and immunosuppressive drug doses were reduced. Despite intervention, the patient continued to decline and had radiologic evidence of progression of disease (Figure 1b, 1c). Eventually the patient instituted a do-not-resuscitate order and was placed on end-of-life care. He died 73 days post-bone marrow transplant.

Relevant autopsy findings included multiple necrotic abscesses within the myocardium and multiple areas of softening and red-brown discoloration within the brain parenchyma (Figure 2a). Microscopic examination showed a dense fungal infiltrate. The fungus displayed 45-degree angle, dichotomous branching and septate hyaline hyphae (Figure 3a). Microscopically, there were hyphae in sections of the brain abscesses as well as in the leptomeninges, liver, and lung. Postmortem blood cultures were positive for S. apiospermum.

Case 2

A 62-year-old man with a history of atrial fibrillation and idiopathic pulmonary fibrosis presented to the hospital for a consecutive double-lung transplant. On postoperative day 27, the patient became increasingly lethargic and unresponsive. He developed acute respiratory distress, involuntary myoclonic movements, anasarca, marked oliguria, and persistent atrial fibrillation. On postoperative day 28, the laboratory reported mold growing in pleural fluid. Intravenous amphotericin B was started. A magnetic resonance imaging (MRI) study without contrast was performed, which showed numerous supratentorial mass lesions, the largest measuring 2.5 cm in greatest dimension, with minimal surrounding vasogenic edema and mild local mass effect. There were scattered areas of susceptibility artifact, which suggested a microhemorrhagic component (Figure 4a, 4b). Cultures from a tracheal aspirate and the surgical incision site grew mold, but blood cultures remained negative.

[FIGURE 1 OMITTED]

Five days after the first MRI without contrast, a second was performed, which showed progressive interval growth of the previously identified lesions and the development of additional lesions (Figure 4c, 4d). It was determined that these lesions were most likely opportunistic or fungal in origin. The patient's family consented to the withdrawal of care, and he died under comfort measures. The mold from pleural, tracheal aspirate, and incision site cultures was identified postmortem as S. apiospermum.

Relevant autopsy findings included dull pleural lung surfaces with thick fibrinous exudate that was microscopically found to contain large branching septate hyphae. Fungal abscesses with prominent angioinvasion were seen in the kidneys, outer portion of the aortic wall, thyroid gland (Figure 3b), brain, and heart (Figure 2b). Postmortem lung cultures grew S. apiospermum and Cladosporium spp.

[FIGURE 2 OMITTED]

DISCUSSION

These two patients portray the clinical and autopsy manifestations of disseminated S. apiospermum infection (Table 1). Both had early signs of rapidly changing mental status with corresponding changes in brain imaging studies. Myocardial abscesses were found at autopsy in both cases, which might have allowed for rapid dissemination to multiple organs. Myocardial wall abscesses by S. apiospermum are uncommon, and only a few have been reported (4).

Patients may acquire S. apiospermum via inhalation of fungal conidia, traumatic inoculation of the skin, or colonization of the upper respiratory tract. It is unclear which of these caused the infection in the patient in Case 1, as both lung and skin lesions were present. The skin lesions provided the opportunity for morphologic characterization in the first patient, and correlation with the blood culture allowed for diagnosis of disseminated, invasive S. apiospermum infection. In Case 2, possible sources of infection include inhalation, inoculation of the surgical wound site, or tracheal colonization. Tracheal colonization has been described in patients with cystic fibrosis (3). Colonization is a less likely source, as this patient did not have cystic fibrosis or a history of this infection. In our opinion, inhalation or inoculation of the patient's surgical wound is the most likely source of infection. Surgical intervention was not performed on either patient.

[FIGURE 3 OMITTED]

[FIGURE 4 OMITTED]

Prognosis following disseminated infection is dismal. In both of the patients in this series, myocardial wall invasion presumably led to dissemination throughout several organs, including the brain. S. apiospermum is known to be relatively neurotropic, usually due to hematogenous spread from a primary focus (2, 5). Due to morphologic and clinical similarity to the widely prevalent Aspergillus and frequently negative blood cultures, S. apiospermum infections are often identified late in the course of disease.

Infection by S. apiospermum is exquisitely difficult to treat. Empiric therapy for a suspected disseminated fungal infection may include an echinocandin, an azole, and/or amphotericin B (6). S. apiospermum is innately resistant to amphotericin B, and the current treatment of choice is voriconazole in combination with an echinocandin (7-9). In vitro studies have shown a synergistic effect of these two antifungals (10). When feasible, this treatment should be combined with surgical debridement (11, 12). The use of voriconazole in cases that involve central nervous system (CNS) infection is particularly important, as it has increased CNS penetration compared to amphotericin B, echinocandins, itraconazole, or posaconazole (8). Due to wide variation in antifungal resistance, susceptibility testing can be useful (11). However, this testing is not available in many laboratories, and the rapid disease course makes it unlikely that sent-out laboratory results will be of value. Moreover, there are no Clinical and Laboratory Science Institute-approved breakpoints for in vitro susceptibility testing for this organism (13).

After the cause of infection was known to be S. apiospermum, the first patient was treated with the recommended combination of voriconazole and micafungin, but he did not improve. The lack of response might have been due to the already advanced course at the time of diagnosis. The second patient was treated with amphotericin B monotherapy, as the organism was not identified until after the patient's death. He was also given inhaled prophylactic amphotericin after his transplant. It has been suggested that antifungal prophylaxis may select for Scedosporium spp., as these fungi are generally resistant to the commonly used prophylactic antifungals (1).

Acknowledgment

The authors would like to thank Thomas P. Lohmann, MD, for his critical review of this paper.

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(4.) Riddell J 4th, Chenoweth CE, Kauffman CA. Disseminated Scedosporium apiospermum infection in a previously healthy woman with HELLP syndrome. Mycoses 2004; 47(9-10): 442-446.

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(13.) Clinical and Laboratory Standards Institute. Reference Method for Broth Dilution Antifungal Susceptibility Testing of Filamentous Fungi: Approved Standard (2nd ed., CLSI document M38-A2). Wayne, PA: Clinical and Laboratory Standards Institute, 2008.

Molly M. Campa-Thompson, MD, James A. West, MD, Joseph M. Guileyardo, MD, Cedric W. Spak, MD, MPH, Louis M. Sloan, MD, and Stacy G. Beal, MD

From the Departments of Pathology (Campa-Thompson, Guileyardo, Beal), Radiology (West), and Internal Medicine, Division of Infectious Diseases (Spak, Sloan), Baylor University Medical Center at Dallas; and med fusion Laboratory (Campa-Thompson, Beal), Lewisville, Texas.

Corresponding author: Stacy G. Beal, MD, Department of Pathology, Baylor University Medical Center at Dallas, 3500 Gaston Avenue, Dallas, TX 75246 (e-mail: stacygbeal@gmail.com).
Table 1. Clinical and autopsy manifestations of disseminated
Scedosporium apiospermum infection in the two patients

Variable                     Patient 1               Patient 2

Age (years) at death      72                     62
Organ transplanted        Bone marrow            Bilateral lungs
Underlying disease        Acute myeloid          Idiopathic pulmonary
                            leukemia,              fibrosis, atrial
                            cytomegalovirus        fibrillation
Diagnosis of S.           63                     28
  apiospermum
  (days posttransplant)
Initially identified      Skin, blood            Pleural fluid
  source of organism
Organs involved by S.     Brain, dermis,         Brain, dermis (skin
  apiospermum               heart, lung,           incision), kidneys,
                            liver, blood           thyroid gland,
                                                   heart, lung
Interval (days)           73                     34
  transplant to death
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Author:Campa-Thompson, Molly M.; West, James A.; Guileyardo, Joseph M.; Spak, Cedric W.; Sloan, Louis M.; B
Publication:Baylor University Medical Center Proceedings
Article Type:Clinical report
Date:Jul 1, 2014
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