Scedosporiosis in a Combined Kidney and Liver Transplant Recipient: A Case Report of Possible Transmission from a Near-Drowning Donor.

Scedosporium spp. are saprobic fungi that cause serious infections in immunocompromised hosts and in near-drowning victims. Solid organ transplant recipients are at increased risk of scedosporiosis as they require aggressive immunosuppression to prevent allograft rejection. We present a case of disseminated Scedosporium apiospermum infection occurring in the recipient of a combined kidney and liver transplantation whose organs were donated by a near-drowning victim and review the literature of scedosporiosis in solid organ transplantation.

1. Introduction

Scedosporium is a saprobic fungus that naturally occurs in soil, manure, sewage, and water bodies polluted by environmental contaminants. Cases of infections with Scedosporium spp. are reported worldwide and can range in severity from colonization or local infection to disseminated disease [1-5]. S. apiospermum most commonly infects the lungs as inhalation is often the suspected mode of organism acquisition [6].

The genus Scedosporium includes, but is not limited to, three species that cause life-threatening infections in humans: Scedosporium apiospermum, Scedosporium prolificans (recently renamed Lomentospora prolificans), and Scedosporium aurantiacum [7]. Scedosporium spp. appear as branching septate hyphae when isolated on standard culture media.

Scedosporium spp. have been implicated in near-drowning accidents [8-10]. Indeed Scedosporium spp. are the most common cause of fungal pneumonia, infection of the central nervous system, and disseminated disease following near-drowning events. There are few cases of donor to recipient transmission of infection of Scedosporium spp. and even fewer reports of near-drowning donor transmission of diseases [11, 12]. We report the clinical course and management of disseminated S. apiospermum infection in a combined kidney and liver transplantation case receiving organs from a brain-dead donor who suffered a near-drowning accident; we further review the literature on scedosporiosis in solid organ transplant recipients.

2. Case Presentation: Donor

A 41-year-old male fell into a freshwater lake. Emergency responders pulled him from the lake and return of spontaneous circulation was achieved after twenty minutes of resuscitation. Subsequent chest radiographs showed development and worsening of bilateral opacities suspicious for pneumonia. Brain death was declared three days after hospital admission.

3. Case Presentation: Recipient

A 66-year-old male actively listed for a kidney and liver transplant presented to the surgical intensive care unit with sepsis and an oxacillin-sensitive Staphylococcus aureus bacteremia. He was treated with appropriate antibiotic therapy. He then developed acute tubular necrosis requiring continuous venovenous hemofiltration (CVVH). The patient had a chest X-ray showing mild pulmonary congestion and bronchoscopy was not performed as the patient did not show signs of pneumonia. After two weeks within his admission, the patient was treated for Escherichia coli bacteremia with piperacillin-tazobactam. Repeat blood cultures were negative after two days of therapy.

While the patient was hospitalized, a donor became available. The donor kidney and liver were grossly normal. The patient underwent a combined kidney and liver transplant for chronic kidney failure with associated liver cirrhosis caused by the hepatitis C virus and alcoholism. The explanted liver was cirrhotic without any malignancy. At the time of transplantation, the patient's Model for End Stage Liver Disease (MELD) score was 40, having been decompensated in the surgical intensive care unit for the previous month. A summary of the patient's immunosuppression and antifungal management after transplant is provided in Figure 1.

Figure 1

Antifungal agents and immunosuppression management.

The patient was given methylprednisolone 500 mg and mycophenolate mofetil 1,000 mg intraoperatively as induction immunosuppression. Maintenance immunosuppression protocols were followed after transplant. CVVH was performed intraoperatively and was discontinued on postoperative day (POD) 1 when renal graft function improved. The patient's hospital stay was complicated by a contained urine leak from the ureteroureterostomy which was managed nonoperatively with drains and ureteral stents. On POD 8, the patient was transferred out of the intensive care unit and on POD 14, to the inpatient rehab care unit as graft function continued to improve. The hepatic transaminases fluctuated and, on POD 25, he was transferred back to the surgical intensive care unit with peritonitis. As infection was suspected, immunosuppression was restricted to the use of corticosteroids tapered down to prednisone 5 mg daily. The patient was taken back to the operating room on POD 28 for a peritoneal washout. Cultures obtained during the procedure are presented in Tables 1 and 2. Of most concern was the S. apiospermum isolated from the perihepatic, perinephric, and biloma fluid. Endoscopic Retrograde Cholangiopancreatography (ERCP) was performed the following day, which did not reveal any extravasation. Discovery of S. apiospermum prompted contact with the Centers for Disease Control and Prevention (CDC), the Disease Transmission Advisory Committee (DTAC) of the United Network for Organ Sharing (UNOS), and the transplant centers treating recipients of allografts from the same donor. Other recipients had no evidence of infection.

Table 1

Culture results.

Date	Culture site	Source	Result
POD 28	Abdominal fluid	Surgical specimen	C. tropicalis
			E. faecalis
			E. coli
			M. morganii
POD 28	Biloma fluid	Surgical specimen	E. faecium
			E. faecalis
			S. apiospermum
			C. tropicalis
POD 28	Perihepatic fluid	Surgical specimen	S. apiospermum
			E. faecium
			C. tropicalis
POD 28	Perinephric hematoma tissue	Surgical specimen	S. apiospermum
POD 32	Abdominal clot	Surgical specimen	S. apiospermum
POD 32	Intestinal serosal tissue	Surgical specimen	S. apiospermum
			E. faecium
POD 50	LUQ abdominal fluid	Surgical specimen	C. glabrata
			C. tropicalis
POD 50	Cerebrospinal fluid	Lumbar puncture	Negative

Table 2

Susceptibility testing of fungal isolates.

Isolate	Resistant (MIC)	Intermediate (MIC)	Susceptible (MIC)
Scedosporium apiospermum	5-Fluorocytosine (>64),amphotericin B (>16),caspofungin (>8),micafungin (>8),terbinafine (>2)	None	Voriconazole (1)
Candida tropicalis	None	None	Caspofungin (≤0.25),fluconazole (≤1),voriconazole (≤0.12)
Candida glabrata	None	None	Caspofungin (2),fluconazole (≤1),voriconazole (≤0.12)

On POD 28, due to worsening hemodynamics and peritonitis, another laparotomy and another washout were performed to evacuate an infected hematoma. The entire peritoneal surface was lined with mold. On POD 32, a mold suggestive of Scedosporium spp. grew from surgical cultures. Expert opinion for the management of our patient's suspected S. apiospermum infection was to use voriconazole targeting a trough of 2–4 mcg/mL, which we started on POD 32. Additionally, terbinafine was started for suspected synergy with voriconazole. A sample of the S. apiospermum was sent out for synergy studies which were expected to take a week or more to be conclusive. On POD 41 S. apiospermum was identified. Laboratory results suggested terbinafine was not synergistic with voriconazole. Additionally, terbinafine is distributed rapidly to skin and bone and as such is not distributed well into visceral tissue and accumulation of terbinafine may cause hepatotoxicity. In response, terbinafine was discontinued and granulocyte macrophage colony-stimulating factor (GM-CSF) initiated on POD 42. The patient developed neurologic deficits with decreased vision to the right side and blurred vision bilaterally on POD 46. Magnetic resonance imaging (MRI) of the brain, shown in Figure 2, revealed multiple ring-enhancing lesions in the supratentorial compartment consistent with hematogenous central nervous system (CNS) scedosporiosis. We continued treatment with antifungal therapy. He developed septic shock and expired on POD 55.

Figure 2

MRI of the brain. Multiple ring-enhancing lesions with associated diffusion restriction and T2/FLAIR hyperintensity are present throughout the supratentorial white matter.

4. Discussion

Differential diagnoses for opportunistic pathogens causing pneumonia related to near-drowning events include several key pathogenic bacteria and fungi. Gram negative bacteria are most often the causative agents in near-drowning cases [13]. Aeromonas spp. have been described most often in near-drowning pneumonia cases. Aeromonas spp. naturally thrive in fresh and brackish waters and have been isolated in humans in wound and gastrointestinal infections after exposure to contaminated water. Other potential bacterial pathogens include Pseudomonas aeruginosa, Legionella spp., Klebsiella spp., and other Enterobacteriaceae [13]. Scedosporium spp. are the most common cause of invasive fungal infection, including pneumonia, CNS disease, and dissemination following near-drowning.

We identified 60 published cases of scedosporiosis after solid organ transplantation between the year 2000 and the present. Few were cases of scedosporiosis after solitary liver transplantation (5/60); most were reported following solitary lung (18/60) or kidney (18/60) transplantation. Table 3 [2, 12, 14–42] provides a summary of the comprehensive literature review performed. S. apiospermum was isolated in the majority of cases, though S. prolificans and S. aurantiacum were also isolated. In four cases, both S. apiospermum and S. prolificans were identified in the same patient. In patients who had infections with a single isolate of Scedosporium spp., the observed mortality rates of S. apiospermum, S. prolificans, and S. aurantiacum were 54.5% (24/44), 70% (7/10), and 100% (3/3), respectively (excluding four cases with combined infections). Observed mortality of all Scedosporium spp. infections was 59% (36/61) including our patient case.

Table 3

Review of solid organ transplant-associated Scedosporium infection.

Ref #	Year	Recipient information		Recipient organ(s)	Species of Scedosporium	Treatment approach	Outcome
		Age (years)	Gender
[14]	2000	67	Male	Heart	apiospermum	Voriconazole	Deceased
[15]	2001	42	Female	Heart/lung	apiospermum	Fluconazole, itraconazole	Deceased
		22	Female	Heart/lung	prolificans + apiospermum	Fluconazole, itraconazole	Deceased
		42	Male	Heart/lung	prolificans + apiospermum	Fluconazole, itraconazole	Alive
		49	Male	Lung	prolificans + apiospermum	Fluconazole, itraconazole	Deceased
		39	Male	Lung	prolificans + apiospermum	Fluconazole, itraconazole	Alive
		52	Female	Lung	apiospermum	Fluconazole, itraconazole	Alive
		38	Female	Heart/lung	apiospermum	Fluconazole, itraconazole	Deceased
[16]	2002	58	Female	Liver	apiospermum	Itraconazole, miconazole	Alive
		37	Male	Lung	apiospermum	Itraconazole	Deceased
		30	Male	Lung	apiospermum	Amphotericin B, miconazole	Deceased
		37	Female	Heart/lung	apiospermum	Miconazole	Deceased
		39	Male	Liver	apiospermum	5-Flucytosine, amphotericin B	Deceased
		67	Male	Heart	apiospermum	Itraconazole, voriconazole	Deceased
		36	Male	Kidney	apiospermum	Itraconazole, miconazole	Deceased
[17]	2002	49	Male	Kidney	apiospermum	Voriconazole	Deceased
[18]	2002	62	Female	Kidney	apiospermum	None	Deceased
		58	Male	Kidney	apiospermum	Itraconazole, voriconazole	Alive
[19]	2002	64	Female	Lung	apiospermum	Amphotericin B, itraconazole	Deceased
[20]	2002	71	Male	Heart	apiospermum	Itraconazole	Alive
[21]	2003	24	Male	Lung	apiospermum	Voriconazole	Alive
		59	Male	Kidney	apiospermum	Voriconazole	Alive
[22]	2004	50	Male	Kidney	apiospermum	Voriconazole	Alive
[23]	2004	58	Male	Kidney	apiospermum	Amphotericin B, fluconazole, itraconazole, miconazole	Alive
[24]	2004	56	Female	Lung	prolificans	Voriconazole	Deceased
[25]	2005	55	Male	Small bowel	prolificans	Amphotericin B	Deceased
		40	Male	Kidney/pancreas	prolificans	Voriconazole	Alive
		67	Male	Kidney	apiospermum	Amphotericin B	Alive
		51	Female	Small bowel	prolificans	Amphotericin B, Voriconazole, caspofungin	Deceased
		67	Male	Heart	apiospermum	Voriconazole	Deceased
		17	Male	Liver	prolificans	Voriconazole	Deceased
		64	Male	Liver	apiospermum	None	Deceased
		45	Male	Heart	apiospermum	Itraconazole	Deceased
		56	Male	Liver	apiospermum	Voriconazole	Deceased
		44	Female	Heart	prolificans	Amphotericin B	Deceased
		68	Male	Kidney	prolificans	Voriconazole	Alive
		52	Male	Small bowel	apiospermum	Amphotericin B, Voriconazole, caspofungin	Alive
		62	Male	Kidney/pancreas	apiospermum	Voriconazole	Alive
[26]	2005	26	Female	Lung	apiospermum	Miconazole, voriconazole	Deceased
[27]	2006	58	Male	Kidney	apiospermum	Miconazole, voriconazole	Alive
[28]	2006	57	Male	Lung	apiospermum	Terbinafine, voriconazole	Alive
		63	Male	Lung	apiospermum	Liposomal amphotericin B, terbinafine, voriconazole	Alive
[29]	2007	59	Female	Kidney	apiospermum	Voriconazole	Alive
[30]	2007	43	Male	Lung	apiospermum	Caspofungin, itraconazole, liposomal amphotericin B	Deceased
[31]	2008	70	Male	Kidney	prolificans	Terbinafine, voriconazole	Alive
[32]	2009	65	Female	Kidney	apiospermum	Voriconazole	Alive
[33]	2010	37	Female	Lung	apiospermum	Caspofungin, terbinafine, voriconazole	Deceased
[34]	2011	16	Female	Lung	apiospermum	Voriconazole	Alive
[35]	2012	35	Male	Lung/liver	apiospermum	Caspofungin, voriconazole	Deceased
[36]	2012	37	Female	Lung	apiospermum	Aerosolized amphotericin B, caspofungin, itraconazole, voriconazole	Deceased
[37]	2013	17	Female	Lung	apiospermum	Caspofungin, posaconazole, voriconazole	Alive
[38]	2013	70	Female	Lung	prolificans	Caspofungin, terbinafine, voriconazole	Deceased
[39]	2014	50	Female	Kidney	apiospermum	Voriconazole	Alive
[40]	2014	35	Male	Kidney	prolificans	Itraconazole, liposomal amphotericin B, micafungin, voriconazole	Deceased
[41]	2015	70	Male	Heart	apiospermum	Posaconazole, terbinafine	Deceased
[12]	2015	19	Male	Heart	aurantiacum	Amphotericin B prophylaxis	Deceased
		56	Male	Kidney	aurantiacum	Itraconazole, liposomal amphotericin B	Deceased
		57	Female	Kidney	aurantiacum	Caspofungin, voriconazole	Deceased
[2]	2015	40	Male	Kidney	apiospermum	Voriconazole	Deceased
[42]	2015	18	Female	Lung	apiospermum	Terbinafine, voriconazole	Alive

Kim et al. reported three fatal and two nonfatal cases of scedosporiosis following solid organ transplantation from the same donor who was victim to a near-drowning accident [12]. Additionally, they reviewed national Korean data on transplants and found that, among 2600 deceased-donor transplants over thirteen years, 27 (1%) of donors were victims of drowning. We accessed data from the United States Organ Procurement and Transplantation Network and found a similar rate: in 2015, 102/7586 (approximately 1.3%) of solid organ donors died of near-drowning events [43]. While this is a low percentage of all donors, the significance of our case is enhanced by the 58.3% mortality rate of infections involving Scedosporium spp. after solid organ transplantation.

At our center, liver transplant recipients are given antifungal prophylaxis based on their risk level. We stratify higher risk patients as those with MELD scores greater than 35, renal failure, requiring hemodialysis or CVVH prior to transplantation, recurrent spontaneous bacterial peritonitis, or preoperative prealbumin less than 10. High risk liver transplant recipients receive micafungin intravenously unless resistant Candida glabrata, Aspergillus spp., or Cryptococcus spp. are suspected; in such cases, amphotericin B lipid complex or voriconazole would be used. Our patient was classified as high risk and given micafungin prophylaxis.

All cases of suspected donor-derived infections should be reported to the DTAC. Communications with the CDC, DTAC, and the centers treating the recipients of the other organs provided by this donor revealed the recipient of the heart was receiving voriconazole prophylaxis, while the recipients of the other kidney and the pancreas were not. To the best of our knowledge, no other recipient of this donor's organs is infected with Scedosporium spp. The other centers were advised by the CDC to commence voriconazole prophylaxis for an undetermined duration. Expert opinion for the management of our patient's scedosporiosis was voriconazole targeting a trough of 2–4 mcg/mL. Additionally, immunosuppression was to be limited or discontinued to improve infection clearance.

S. apiospermum is inherently resistant to amphotericin B, including the lipid formulations. Of the newer triazole antifungals, data on the in vitro activity of voriconazole is most robust, showing activity against S. apiospermum with MICs of 0.12 to 0.5 mcg/mL in clinical isolates [30]. Because of poor activity with single agents, various antifungal combinations have been examined for efficacy against S. apiospermum. Strong synergy was found in vitro between voriconazole and terbinafine against clinical isolates of Scedosporium spp. [30]. Combination of micafungin and voriconazole has demonstrated a synergistic effect against several fungi in vitro including Scedosporium spp. The synergistic mechanism may include reorganization of the cell wall allowing increased exposure of beta-glucan to the immune system [44].

In addition to antifungal agents, GM-CSF has been studied with some success [44, 45]. While antifungal therapy remains crucial to recovery, the treatment of scedosporiosis infections depends on the function of the host's innate immune system, in particular, polymorphonuclear cells (PMNs). The mechanism of GM-CSF increases the antifungal action of PMNs in vitro [45].

Despite good allograft function, our patient did not survive disseminated infection with S. apiospermum after combined kidney and liver transplantation. The exact mode of transmission and acquisition of S. apiospermum in this patient remains uncertain. We suspect donor to recipient transmission as the donor was the victim of a near-drowning event and had chest radiographs suspicious for pneumonia; however, we cannot rule out recipient colonization or nosocomial infection after the transplant.

Infections caused by Scedosporium spp. following solid organ transplant, while not common, are often fatal for recipients. There are no standards of practice for prophylaxis for patients at risk for developing scedosporiosis, such as recipients of organs from nearly drowned donors. Considering our case and the scedosporiosis mortality rate over 50% and the low rate of nearly drowned donors, we recommend screening for Scedosporium spp. when donated organs originate from a near-drowning victim.