© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd Transplant Infectious Disease, ISSN 1398-2273
Epidemiology, clinical manifestations, and outcomes of Scedosporium infections among solid organ transplant recipients L.S. Johnson, R.K. Shields, C.J. Clancy. Epidemiology, clinical manifestations, and outcomes of Scedosporium infections among solid organ transplant recipients. Transpl Infect Dis 2014: 16: 578–587. All rights reserved Abstract: Background. Few studies of Scedosporium infections following solid organ transplantation have been performed in the era of induction immunosuppression and widespread antifungal prophylaxis. Methods. We performed a single-center, retrospective study of transplant recipients from 2000 through 2010 who had a positive Scedosporium culture. Results. Among 27 patients, 67% (n = 18) and 33% (n = 9) were infected with Scedosporium apiospermum and Scedosporium prolificans, respectively. A total of 67% received induction immunosuppression and 74% received prior antifungal therapy. Isolates were broadly resistant to antifungals. Of these patients, 59% (n = 16) were colonized by Scedosporium, and 41% (n = 11) had disease (scedosporiosis). No significant clinical differences were seen between species. Colonization occurred exclusively in the lungs of lung transplant recipients (LTR). Scedosporiosis followed lung transplantation in 55%, and other organ transplants (multivisceral [18%]; and heart, liver, small intestine [9% each]) in 45%. Scedosporiosis was preceded by colonization in 36%. Diseases included pneumonia (64%), mediastinitis (18%), and fungemia/ disseminated infections (18%). The 6-month outcomes were death in 55%, progression in 18%, stability in 9%, and resolution in 18%. Patients who died had earlier onset scedosporiosis post transplant (median: 80.5 vs. 1388 days; P = 0.04), and were more likely to have mediastinitis or disseminated infections than pneumonia (100% vs. 29%; P = 0.06). The 3 patients who developed scedosporiosis >1 year post transplant survived. All patients who survived were treated with a voriconazole-containing regimen. Conclusions. LTR were most susceptible to Scedosporium colonization and scedosporiosis, particularly within the lungs. Death was common with scedosporiosis in the first year after all types of organ transplants, consistent with profound immunosuppression and antifungal resistance, but not encountered thereafter.
Scedosporium species are fungi with a predilection for infecting immunosuppressed patients, including solid organ transplant recipients (SOTR) (1). Like many medically relevant fungi, Scedosporium species are ubiquitous soil organisms, especially in polluted areas (2). The most common species, Scedosporium apiosper-
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L.S. Johnson1, R.K. Shields1,2, C.J. Clancy2 1
Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA, 2Infectious Diseases, Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
Key words: Scedosporium; transplantation; colonization; S. apiospermum; S. prolificans; scedosporiosis Correspondence to: Cornelius J Clancy, MD, Infectious Diseases, Department of Medicine, University of Pittsburgh, Scaife Hall 867, 3550 Terrace Street, Pittsburgh, PA 15261, USA Tel: 412 383 5193 Fax: 412 648 8455 E-mail: [email protected]
Received 5 September 2013, revised 2 January 2014, accepted for publication 1 March 2014 DOI: 10.1111/tid.12244 Transpl Infect Dis 2014: 16: 578–587
mum, was initially thought to be an anamorph of Pseudallescheria boydii, but following a series of reclassifications it was defined as a distinct species in 2008 (3–5). Scedosporium prolificans (formerly Scedosporium inflatum), which shares many common features with S. apiospermum, first appeared in the literature in the
Johnson et al: Scedosporium in transplantation
1980s (6). Both organisms cause diverse diseases (scedosporiosis) that carry mortality rates as high as 80%, particularly with disseminated infections (7, 8). The clinical features of scedosporiosis are similar to those of the more recognized Aspergillus species, and the genera are indistinguishable by routine histopathology of infected tissue (1, 3, 8). Scedosporium species are notable for their resistance to polyene antifungals and variable susceptibility to newer azole agents that are generally effective against Aspergillus (3, 8). Despite the importance of Scedosporium infections, studies among transplant recipients are limited, and much of our understanding comes from case reports and epidemiologic series (8–17). In a series of 7 SOTR with scedosporiosis due to S. apiospermum at our center from 1986 to 1996, the mortality rate was 86% (8). Scedosporiosis was encountered in patients after liver, lung, heart, heart-lung, and kidney transplantation. Disseminated disease, pneumonia, and sinusitis occurred in 43% (3/7), 43% (3/7), and 14% (1/7) of patients, respectively. In a multicenter, retrospective case series and review of the literature through 2003, which included 57 SOTR, the majority of scedosporiosis occurred after kidney (35%), heart (28%), and liver (18%) transplantation (18); 83% of transplant recipients were infected with S. apiospermum, and 55% had disseminated infections. The overall mortality rate was 54%, with worse outcomes among patients with disseminated infections. Patients reported in earlier studies did not receive induction immunosuppression, and mold-active antifungal prophylaxis was employed in a minority. More recently, data from 17 transplant centers between 2004 and 2007 indicated that lung transplant recipients (LTR) were at greatest risk for scedosporiosis, but detailed clinical information was not provided (15). Respiratory tract colonization by Scedosporium has been reported to progress to disseminated disease (16, 17). However, the relationship between colonization and the subsequent development of scedosporiosis following solid organ transplantation is unclear. Our objective in this study was to evaluate the epidemiology, clinical manifestations, and outcomes of Scedosporium colonization and scedosporiosis among SOTR at our center since 2000. During this period, induction immunosuppression and mold-active antifungal prophylaxis were widely employed.
We searched the University of Pittsburgh Medical Center medical record database for positive culture results for Scedosporium species from patients, who had undergone solid organ transplantation from January 1, 2000 to December 31, 2010. The search included the organism’s previous identifiers, such as Pseudallescheria boydii. Clinical characteristics were reviewed and abstracted from patients’ electronic medical records. Patients were classified as colonized or suffering from scedosporiosis based on clinical course, radiographic findings, histopathology, and, in unclear cases, the consensus classifications of the authors. Patients were defined as having possible, probable, or proven scedosporiosis, in keeping with criteria adapted from the Mycoses Study Group and European Organization for Research and Treatment of Cancer (19). We classified 6-month treatment outcomes for scedosporiosis into the categories of complete resolution, partial resolution, stable, progression of disease, and death. None of the patients identified in this review were included in earlier studies of scedosporiosis that included University of Pittsburgh Medical Center transplant recipients (8, 18). Statistical analyses were performed using the PASW Statistics 18 software program (SPSS Inc, Chicago, Illinois, USA). Comparisons between 2 groups were performed by Wilcoxon rank sum test for continuous variables, and chi-square or Fisher’s exact tests for categorical variables. Significance was defined as P-value ≤0.05 (2-tailed).
Results A total of 27 SOTR had positive Scedosporium cultures, including 17 women and 10 men. The median age was 52 years (range 20–69). Patient demographics are presented in Table 1; 85% (22/27) of patients were LTR; 59% (16/27) of patients were colonized, and the remaining 41% (11/17) had scedopsoriosis. Patients were infected with S. apiospermum in 67% (18/27) and with S. prolificans in 33% (9/27). Among isolates tested, both species were broadly resistant to antifungal agents (Table 2).
Patients colonized by Scedosporium
Materials and methods The University of Pittsburgh Institutional Review Board approved this retrospective study (#PRO09050022).
Sixteen patients were colonized by Scedosporium (excluding those who went on to develop scedosporiosis); 69% (11/16) of colonized patients were women and 31% (5/16) were men. The median age was
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Demographics of patients with (+) Scedosporium cultures Total population: N (%); N = 27
Characteristic
Colonization: N (%); N = 16
Disease: N (%); N = 11
Age at first (+) Scedosporium culture 60 Gender
Race/Ethnicity
Underlying disease Lung transplant COPD1
Other solid organ transplants
Type of transplant Lung
22 (81)
16 (100)
6 (55)
Multivisceral
2 (7)
0
2 (18)
Heart
1 (4)
0
1 (9)
Small intestine
1 (4)
0
1 (9)
Liver
1 (4)
0
1 (9)
1
Including isolated emphysema. One patient also suffered liver cirrhosis. 3 Includes 1 (4%) instance each of hepatitis C, idiopathic dilated cardiomyopathy, and congenital periportal fibrosis. 4 Includes 1 (9%) instance each of hepatitis C, idiopathic dilated cardiomyopathy, and congenital periportal fibrosis. COPD, chronic obstructive pulmonary disease. 2
Table 1
55 years (range 20–69). All colonized patients were LTR who were colonized in the respiratory tract only. Overall, 73% (16/22) of LTR were colonized in the absence of disease. The colonizing isolates were S. apiospermum in 75% (12/16) and S. prolificans in 25% (4/12). Of the colonized patients, 81% (13/16) were treated with antifungal agents. All patients who received antifungals received an azole; 38% (5/13) received
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combination therapy with 2 or more antifungal agents. At 6 months after the first positive culture, 75% (12/16) of patients cleared their colonization (i.e., subsequent cultures did not grow Scedosporium), and 25% (4/12) were still infected (i.e., no documentation of clearance). The 19% (3/16) of colonized patients who were not treated with antifungals had colonization that was diagnosed >1 year after lung transplantation; each patient cleared their colonization.
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Antifungal resistance among Scedosporium isolates Species and antifungal agent, criterion for resistance
% resistant (no. resistant/ no. tested)
Scedosporium apiospermum Amphotericin B, MIC ≥1 lg/mL
100 (6/6)
Posaconazole, MIC ≥0.5 lg/mL
100 (4/4)
Terbinafine, MIC ≥1 lg/mL
86 (6/7)
Voriconazole, MIC ≥1 lg/mL
80 (4/5)
Scedosporium prolificans Amphotericin B, MIC ≥1 lg/mL
67 (2/3)
Posaconazole, MIC ≥0.5 lg/mL
86 (6/7)
Terbinafine, MIC ≥1 lg/mL Voriconazole, MIC ≥1 lg/mL
100 (3/3) 86 (6/7)
MIC, minimum inhibitory concentration.
Table 2
Patients with scedosporiosis Disease due to Scedosporium species developed in 11 patients. Table 3 compares the clinical characteristics of patients who were colonized with those who developed scedosporiosis. Clinical data on the cases of scedosporiosis are presented in Table 4. Of the patients with scedosporiosis, 55% (6/11) were women and 45% (5/11) were men. The median age was 48 years (range 23–65). LTRs were 55% (6/11), and 18% (2/11) were multivisceral transplant recipients. The rate of scedosporiosis among LTR was 0.6% (6/944). The remaining patients were heart, liver, or small intestine transplant recipients (9% each; 1/11). Overall, 27% (6/22) of LTR and 100% (5/5) of other transplant recipients, who were infected with Scedosporium, developed scedosporiosis (P = 0.006). Scedosporiosis was caused by S. apiospermum in 55% (6/11) and by S. prolificans in 45% (5/11) of patients. Of patients with scedosporiosis, 36% (4/11) were previously colonized by the same species (3 LTR and 1 liver transplant recipient); 3 of these patients were colonized before transplantation (2 LTR and 1 liver transplant recipient). All 4 colonized patients developed disease despite receiving preemptive therapy with voriconazole, alone or in combination with another agent. Of LTR, 33% (2/6) had diseases that were considered likely to stem from seeding at the time of surgery, based on the recovery of Scedosporium from recipients’ explanted lungs at the time of transplant, and from an intra-thoracic site of infection within 90 days of trans-
plant. The median time to scedosporiosis post transplantation, among the patients colonized before transplantation, was 15 days (range 4–90 days). Among the patients who were not colonized pretransplant, the median time to scedosporiosis post transplantation was 217 days (range 6–45,914 days; P = 0.11). The diseases caused by Scedosporium were pneumonia (64%; 7/11), mediastinitis (18%; 2/11), and fungemia/disseminated infections (18%; 2/11). Both patients with disseminated infections were multivisceral transplant recipients infected with S. prolificans. Respiratory symptoms, such as cough, dyspnea, or respiratory failure, were the initial presenting symptoms in 73% (8/11) of patients. Other initial presentations were diabetic ketoacidosis, heart failure, and gastrointestinal distress (9% each; 1/11). None of the patients had a sepsis-like syndrome, which has been reported in previous studies of stem cell transplant recipients (3, 4). Concurrent positive cultures for other pathogens were found in 82% (9/11) of patients. Six-month outcomes were death, progression of disease, stable disease, and complete resolution in 55% (6/11), 18% (2/11), 9% (1/11), and 18% (2/11) of patients, respectively. The median time to death among patients who died was 45.5 days (range 25–88 days) following the diagnosis of scedosporiosis. Patients who died had earlier disease onset post transplantation (median 80.5 days [range 0–327] vs. 1388 days [range 4–4591]; P = 0.04). All 3 patients who developed scedosporiosis >1 year post transplant were alive 6 months after their diagnosis. Patients with pneumonia were more likely to be alive at 6 months than patients with mediastinitis or disseminated infections (71% (5/7) vs. 0% (0/4), P = 0.06). Both patients who resolved their infections at 6 months were infected with S. apiospermum. Antifungal therapy consisted of regimens that included voriconazole (91%, 10/11), amphotericin B (64%, 7/11), caspofungin (55%, 6/11), terbinafine (55%, 6), and posaconazole (9%, 1/11). All patients who were alive at 6 months received voriconazole. Four patients received adjuvant surgical treatment; all died.
Discussion Scedosporiosis was associated with poor outcomes among SOTR at our center. The 6-month mortality rate was 55%, which is consistent with an earlier case series and review of the literature of scedosporiosis following organ transplantation (18). At the same time, our
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Clinical characteristics of patients with (+) Scedosporium cultures Total (N = 27): N (%)
Clinical characteristic
Colonization (N = 16): N (%)
Disease (N = 11) N (%)
Induction immunosuppression None Alemtuzumab
8 (30)
6 (38)
2 (18)
15 (56)
10 (63)
5 (45)
Anti-thymocyte globulin
3 (11)
0
3 (27)
Unknown
1 (4)
0
1 (9)
Maintenance immunosuppression Tacrolimus, mycophenolate mofetil, prednisone Others Documented previous rejection
22 (81)
15 (94)
7 (64)
4 (19)
1 (6)
4 (36)
9 (33)
5 (31)
4 (36)
CMV infection
14 (52)
8 (50)
6 (55)
Concurrent (+) cultures for other fungi1
15 (56)
5 (31)
10 (91)
Concurrent (+) cultures for other pathogens1
12 (44)
4 (25)
9 (82)
Prior antifungals
20 (74)
11 (69)
Median time in days to first (+) Scedosporium culture post transplant (range)
373 ( 2683 to 4584)
643 (6 to 2933)
9 (82) 34 ( 2683 to 4584)
1
From the same date as a (+) Scedosporium culture. CMV, cytomegalovirus.
Table 3
findings highlight several new insights into both disease and colonization by Scedosporium. First, 86% of positive cultures for Scedosporium species occurred in LTR, including 55% and 100% of scedosporiosis and colonization in the absence of disease, respectively. In the previous study of transplant recipients, only 14% of patients had undergone lung transplantation, and colonization was not assessed (18). The susceptibility of LTR is in keeping with a recent epidemiologic survey of fungal infections following transplantation (15). Second, the respiratory tract was the predominant site of Scedosporium infection: pneumonia accounted for 64% of scedosporiosis, and colonization was diagnosed exclusively in the respiratory tract. Disseminated disease occurred in at least 50% of transplant patients in earlier studies (8, 18), but in only 18% of our patients. Third, early-onset scedosporiosis following transplantation was associated with increased mortality in our patients, which is not noted elsewhere. Patients who died had scedosporiosis diagnosed at median 80.5 days, and those who survived had Scedosporium diagnosed at median 1388 days post transplant; 75% of patients with scedosporiosis within the first year of transplantation died, compared with none of the patients with later-onset disease. Finally, early-onset scedosporiosis often occurred after colonization by Scedosporium.
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In many regards, our new findings should not be surprising. It is widely recognized that LTR are at particular risk for respiratory tract infections by environmental molds. This susceptibility is a result of the continuous exposure of the transplanted organ to the external environment, the frequent need for prolonged mechanical ventilation (20), impaired mucociliary clearance (21), and profound immune suppression (22). Moreover, patients awaiting lung transplantation are commonly colonized with fungi as a result of their underlying diseases. Scedosporium colonization of the respiratory tract, for example, is well recognized among patients with chronic obstructive pulmonary disease and cystic fibrosis (11, 16, 17), which were the most common indications for transplantation in our series. Fungal colonization among LTR, in turn, is a risk factor for subsequent invasive pulmonary infections. Increased mortality with early-onset scedosporiosis is not unexpected during the period of most intense immunosuppression. In each of these aspects, our findings with Scedosporium colonization and disease are similar to the experience with Aspergillus species, and are consistent with pathogenesis that generally stems from inhalation of airborne conidia by highly susceptible hosts. Scedosporium infections among other SOTR differed from lung transplantation in several ways. Whereas the recovery of Scedosporium from the respiratory tract
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41/F
3
4
24/F
59/F
2
6
26/M
1
26/F
65/M
Pt
5
Age years/ gender
Lung
Lung
Lung
Lung
Lung
Lung
Transplant type
Shortness of breath, chest pain, fever
Diabetic ketoacidosis
Failure to wean from ventilator
Hypoxia
Dyspnea; productive cough
Respiratory distress, tachycardia, atrial flutter
Initial clinical manifestations
73
90
15
1388
4591
2841
Time to disease (days)
Clinical information on patients with scedosporiosis
Pneumonia (proven)
Mediastinitis/ sternal osteo (proven)
Pneumonia, wound infection (proven1)
Pneumonia (probable)
Pneumonia (probable)
Pneumonia (probable)
Disease type
S. apiospermum
S. prolificans
S. apiospermum
S. prolificans
S. prolificans
S. apiospermum
Scedosporium species
(+)
Pseudomonas aeruginosa (BAL); Pseudomonas mirabilis (sputum)
None
Rhizopus, K. pneumonia (BAL)
Klebsiella pneumoniae (BAL)
Mycobacterium fortuitum (BAL)
Stenotrophomonas maltophilia (BAL, wash)
Concurrent cultures
Death
Death
Surgery2 + posaconazole, terbinafine, voriconazole
Progression of disease
Progression of disease
Stable
Complete resolution
6-month outcome
Surgery + terbinafine, voriconazole
Amphotericin, caspofungin, fluconazole, terbinafine, voriconazole
Amphotericin, terbinafine, voriconazole
Terbinafine, voriconazole
Voriconazole
Treatment
Surgical biopsies revealed Scedosporium. Autopsy report attributed cause of death to Enterococcus faecium pneumonia, pulmonary and myocardial infarction. The patient was colonized prior to disease
Surgical biopsies revealed Scedosporium. Death due to mycotic pseudoaneurysm. The patient was colonized at time of transplant, and disease was likely to stem from surgical seeding
Scedosporium and Rhizopus both grew from respiratory culture. Tissue pathology was consistent with Scedosporium. The patient was colonized at time of transplant, and disease was likely to stem from surgical seeding
The patient died 9 months after diagnosis due to unknown causes
The patient was also treated for M. fortuitum pneumonia. Scedosporium was cultured from multiple respiratory samples
Discharged home
Comments
Johnson et al: Scedosporium in transplantation
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584
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23/F
48/M
10
11
Liver
Heart
Small intestine
Multivisceral
Multivisceral
Transplant type
Worsening of baseline bronchiectasis
Heart failure
Non-productive cough, fever, chills
Respiratory difficulty, stridor
Abdominal discomfort
Initial clinical manifestations
4
Pneumonia (probable)
Mediastinitis (proven)
Pneumonia (probable)
3273
0
Disseminated (proven)
Disseminated (proven)
Disease type
107
34
Time to disease (days)
S. apiospermum
S. apiospermum
S. apiospermum
S. prolificans
S. prolificans
Scedosporium species
(+)
P. aeruginosa (BAL)
None
Citrobacter freundii (sputum)
Staphylococcus aureus, E. faecium, Klebsiella oxytoca, P. aeruginosa (various autopsy sites)
Enterococcus cloacae, E. faecium (autopsy abscess)
Concurrent cultures
Death
Surgery2 + amphotericin, caspofungin
Table 4
2
Complete resolution
Death
Surgery + caspofungin, terbinafine, voriconazole
Caspofungin, voriconazole
Death
Death
6-month outcome
Amphotericin, caspofungin, voriconazole
Amphotericin, caspofungin, voriconazole
Treatment
Probable infection with Scedosporium; proven invasive fungal infection. Mediastinal exploration. 3 Time from second transplant; 837 days from first. M, male; F, female; BAL, bronchoalveolar lavage; CNS, central nervous system; MRI, magnetic resonance imaging.
1
52/M
9
7
51/F
54/M
Pt
8
Age years/ gender
Table 4 Continued
The patient was colonized prior to transplant. Discharged home
Surgical biopsy revealed Scedosporium infection mixed with Candida parapsilosis. Death due to failure of transplanted heart
Scedosporium grew from BAL and sputum cultures. The patient suffered CNS symptoms and MRI revealed brain lesions consistent with abscesses. Death due to cardiac arrest and anoxic brain injury
Autopsy-proven scedosporiosis of the pericardium, eyes, dermis, heart, kidneys, and pancreas
Autopsy-proven scedosporiosis of the heart, pericardium, pleura, kidneys, and brain
Comments
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Johnson et al: Scedosporium in transplantation
represented colonization rather than disease in 72% of LTR, positive cultures in other patients were always associated with scedosporiosis or colonization that led to scedosporiosis. Among LTR, 83% with scedosporiosis had pneumonia, while non-LTR had diseases ranging from pneumonia to mediastinitis to fungemia and disseminated infections. Both patients with fungemia underwent multivisceral transplantation and died from widely disseminated scedosporiosis that did not involve the lung parenchyma. Indeed, a strong trend was seen toward improved survival among patients with pneumonia, compared to those with mediastinitis or fungemia, an observation that is consistent with previous studies describing better outcomes in transplant recipients with localized rather than disseminated infections (18). The high mortality rates with scedosporiosis, particularly among patients with early-onset and more extensive disease, underscore the inadequacy of current treatment regimens. The size of our study precludes us from drawing definitive conclusions about treatment. In general, previous studies have shown that voriconazole is active against S. apiospermum in vitro, but S. prolificans is less responsive (23, 24). Our voriconazole resistance data are potentially biased by the fact that isolates were only tested if requested by clinicians. Nevertheless, the high levels of resistance to voriconazole and other agents among tested isolates may stem from the widespread prior receipt of antifungal therapy. In comparison, only 18% of transplant recipients received prior antifungals in the earlier review (18). Voriconazole appeared to have some role in treatment, as all of our surviving patients received a voriconazole-containing regimen. This finding is tempered by the facts that resolution of disease was achieved in only 18% of patients, choices of antifungal regimens may have been biased by the severity of patients’ illnesses, and voriconazole was often employed in combination with other agents. Several clinical studies, including the previous review of transplant recipients, showed improved outcomes among patients treated with voriconazole (18, 25, 26). Of course, noncurative antifungal therapy may still be beneficial by arresting disease progression and facilitating surgical resections or other interventions. Indeed, previous studies reported lower mortality from scedosporiosis among transplant recipients who underwent surgical interventions (12, 18, 27–29). In our experience, however, all patients who underwent surgery died, which may reflect the use of surgery in more extensive infections. In fact, the benefits of surgery for scedosporiosis are most striking for well-localized lesions, particularly in the central nervous system (18, 28, 29).
In considering our outcomes, it is important to note that 63% of patients with scedosporiosis received induction immunosuppression with alemtuzumab or anti-thymocyte globulin. In contrast, none of the transplant recipients in the previous multicenter study received induction therapy (18). It is possible that the intensity of immunosuppression among our patients increased the risk of scedosporiosis and accounted, at least in part, for the high mortality rates in the first several months following transplantation. At the same time, the mortality rate was lower than that reported for SOTR at our center in 1986–1996, prior to use of induction agents (8). As such, these data may attest to improvements in disease recognition and treatment. Based on our experience and other publications, we advocate treatment comprised of prompt surgical resection, where feasible, in conjunction with voriconazole. Combining voriconazole with terbinafine or an echinocandin has been shown to be synergistic in vitro (30), and should be considered in more extensive disease, or for S. prolificans infections. Posaconazole has activity against Scedoporium in vitro (31), but its role as an alternative to voriconazole is unclear. Our poor outcomes, despite antifungal therapy and surgery, illustrate the importance of disease prevention among these high-risk patients. Several approaches to prevention were undertaken in our population. First, voriconazole prophylaxis was routine for 3–6 months after lung transplantation, with additional courses in response to augmented immune suppression for acute cellular rejection and at the discretion of clinicians. Despite concerns that prophylaxis may select for voriconazole-resistant fungi like Scedosporium, only 6 cases of scedosporiosis were encountered among LTR during the study period. It is not possible to determine if the practice contributed to the rate of respiratory tract colonization that was observed or if, in at least some instances, prophylaxis prevented or delayed the onset of scedosporiosis to periods of less intense immune suppression. Second, colonization was treated aggressively with antifungal agents. Of patients who were colonized with Scedosporium at some point after transplantation, 85% (17/20) were treated with voriconazole and/or other agents, with mixed results: 53% (9/17) cleared colonization, 24% (4/17) maintained colonization in the absence of disease, and 24% (4/17) progressed to disease. The 3 patients colonized before transplantation each developed early-onset scedosporiosis despite antifungal therapy. Based on this experience, our current practice among candidates before transplantation is to treat colonization with a voriconazole-containing regimen and document microbiologic clearance.
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Among patients colonized in the first several months after transplantation, approaches are individualized, but we err on the side of preemptive antifungal therapy, as the impact of early-onset scedosporiosis is generally dire. At later time points, we advocate treatment for cases in which disease is suspected clinically. In the absence of signs or symptoms of disease, our experience indicates that antifungal therapy is not absolutely necessary in LTR. In contrast, the recovery of Scedosporium in cultures from non-LTR triggers a low threshold for treatment, as colonization of these patients did not occur in the absence of scedosporiosis. Our series was too small to draw conclusions about the relative virulence of species, but the trend toward more severe disease and worse outcomes with S. prolificans is similar to previous clinical reports (18). These findings are consistent with data from animal studies (32, 33). Of note, the vast majority of our patients with scedosporiosis were also infected with other potential pathogens. Patients fulfilled criteria for proven or probable invasive fungal infections, but the recovery of multiple potential pathogens emphasizes the poor states of health, high levels of immune suppression, and general susceptibility to infections. It is important to acknowledge that our study has shortcomings common to retrospective, single-center studies. Despite these shortcomings, the data are useful because of the limited number of transplant recipients previously reported in the literature. In particular, recent data on scedosporiosis that account for advances in induction immunosuppression and antifungal prophylaxis are lacking. Although some of our findings may be particular to our program, insights such as the susceptibility of LTR and the importance of respiratory tract colonization and disease are likely to be broadly relevant. Further reports on transplant recipients with Scedosporium colonization or scedosporiosis will be valuable for corroborating or expanding upon our findings and offering contrasts to our experience.
Acknowledgements: Thanks: We thank Lloyd Clarke for his help in data collection and retrieval. Funding: This study was funded in part by the National Institutes of Health through Grant Numbers KL2 RR024154 and KL2TR000146 to R.K.S. Author contributions: L.S.J. is primarily responsible for data collection, review and analysis, and writing the manuscript. R.K.S. independently reviewed cases, and assisted with data review and analysis, and in drafting
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and editing the manuscript. C.J.C. is responsible for data collection, review and analysis with L.S.J.; he independently reviewed cases, and was the primary editor of drafts of the manuscript provided by L.S.J. Conflicts: The authors do not have conflicts of interest.
References 1. Shinohara MM, George E. Scedosporium apiospermum: an emerging opportunistic pathogen that must be distinguished from Aspergillus and other hyalohyphomycetes. J Cutan Pathol 2009; 36 (Suppl 1): 39–41. 2. Guarro J, Kantarcioglu AS, Horre R, et al. Scedosporium apiospermum: changing clinical spectrum of a therapy-refractory opportunist. Med Mycol 2006; 44 (4): 295–327. 3. Cortez KJ, Roilides E, Quiroz-Telles F, et al. Infections caused by Scedosporium spp. Clin Microbiol Rev 2008; 21 (1): 157–197. 4. Gilgado F, Cano J, Gene J, Guarro J. Molecular phylogeny of the Pseudallescheria boydii species complex: proposal of two new species. J Clin Microbiol 2005; 43 (10): 4930–4942. 5. Gilgado F, Cano J, Gene J, Sutton DA, Guarro J. Molecular and phenotypic data supporting distinct species statuses for Scedosporium apiospermum and Pseudallescheria boydii and the proposed new species Scedosporium dehoogii. J Clin Microbiol 2008; 46 (2): 766–771. 6. Salkin IF, McGinnis MR, Dykstra MJ, Rinaldi MG. Scedosporium inflatum, an emerging pathogen. J Clin Microbiol 1988; 26 (3): 498–503. 7. Hosseini-Moghaddam SM, Husain S. Fungi and molds following lung transplantation. Semin Respir Crit Care Med 2010; 31 (2): 222–233. 8. Castiglioni B, Sutton DA, Rinaldi MG, Fung J, Kusne S. Pseudallescheria boydii (Anamorph Scedosporium apiospermum). Infection in solid organ transplant recipients in a tertiary medical center and review of the literature. Medicine (Baltimore) 2002; 81 (5): 333–348. 9. Perlroth MG, Miller J. Pseudoallescheria boydii pneumonia and empyema: a rare complication of heart transplantation cured with voriconazole. J Heart Lung Transplant 2004; 23 (5): 647–649. 10. Bibashi E, de Hoog GS, Kostopoulou E, Tsivitanidou M, Sevastidou J, Geleris P. Invasive infection caused by Pseudallescheria boydii in an immunocompetent patient. Hippokratia 2009; 13 (3): 184–186. 11. Morio F, Horeau-Langlard D, Gay-Andrieu F, et al. Disseminated Scedosporium/Pseudallescheria infection after double-lung transplantation in patients with cystic fibrosis. J Clin Microbiol 2010; 48 (5): 1978–1982. 12. Sahi H, Avery RK, Minai OA, et al. Scedosporium apiospermum (Pseudoallescheria boydii) infection in lung transplant recipients. J Heart Lung Transplant 2007; 26 (4): 350–356. 13. Kantarcioglu AS, de Hoog GS, Guarro J. Clinical characteristics and epidemiology of pulmonary pseudallescheriasis. Rev Iberoam Micol 2012; 29 (1): 1–13. 14. Lackner M, Rezusta A, Villuendas MC, Palacian MP, Meis JF, Klaassen CH. Infection and colonisation due to Scedosporium in Northern Spain. An in vitro antifungal susceptibility and molecular epidemiology study of 60 isolates. Mycoses 2011; 54 (Suppl 3): 12–21.
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15. Neofytos D, Fishman JA, Horn D, et al. Epidemiology and outcome of invasive fungal infections in solid organ transplant recipients. Transpl Infect Dis 2010; 12 (3): 220–229. 16. Musk M, Chambers D, Chin W, Murray R, Gabbay E. Successful treatment of disseminated Scedosporium infection in 2 lung transplant recipients: review of the literature and recommendations for management. J Heart Lung Transplant 2006; 25 (10): 1268–1272. 17. Tamm M, Malouf M, Glanville A. Pulmonary Scedosporium infection following lung transplantation. Transpl Infect Dis 2001; 3 (4): 189–194. ~ oz P, Forrest G, et al. Infections due to 18. Husain S, Mun Scedosporium apiospermum and Scedosporium prolificans in transplant recipients: clinical characteristics and impact of antifungal agent therapy on outcome. Clin Infect Dis 2005; 40 (1): 89–99. 19. De Pauw B, Walsh TJ, Donnelly JP, et al.; European Organization for Research and Treatment of Cancer/Invasive Fungal Infections Cooperative Group; National Institute of Allergy and Infectious Diseases Mycoses Study Group (EORTC/MSG) Consensus Group. Revised definitions of invasive fungal disease from the European Organization for Research and Treatment of Cancer/ Invasive Fungal Infections Cooperative Group and the National Institute of Allergy and Infectious Diseases Mycoses Study Group (EORTC/MSG) Consensus Group. Clin Infect Dis 2008; 46 (12): 1813–1821. 20. Sopirala MM, Pope-Harman A, Nunley DR, Moffat-Bruce S, Ross P, Martin SI. Multidrug-resistant Acinetobacter baumannii pneumonia in lung transplant recipients. J Heart Lung Transplant 2008; 27 (7): 804–807. 21. Duarte AG, Myers AC. Cough reflex in lung transplant recipients. Lung 2012; 190 (1): 23–27. 22. Shyu S, Dew MA, Pilewski JM, et al. Five-year outcomes with alemtuzumab induction after lung transplantation. J Heart Lung Transplant 2011; 30 (7): 743–754. 23. Espinel-Ingroff A. In vitro fungicidal activities of voriconazole, itraconazole, and amphotericin B against opportunistic moniliaceous and dematiaceous fungi. J Clin Microbiol 2001; 39 (3): 954–958.
24. Cecil JA, Wenzel RP. Voriconazole: a broad-spectrum triazole for the treatment of invasive fungal infections. Expert Rev Hematol 2009; 2 (3): 237–254. 25. Troke P, Aguirrebengoa K, Arteaga C, et al.; Global Scedosporium Study Group. Treatment of scedosporiosis with voriconazole: clinical experience with 107 patients. Antimicrob Agents Chemother 2008; 52 (5): 1743–1750. 26. Schwartz S, Reisman A, Troke PF. The efficacy of voriconazole in the treatment of 192 fungal central nervous system infections: a retrospective analysis. Infection 2011; 39 (3): 201–210. ~ oz P. Central nervous 27. Berenguer J, Diaz-Mediavilla J, Urra D, Mun system infection caused by Pseudallescheria boydii: case report and review. Rev Infect Dis 1989; 11 (6): 890–896. 28. Chakraborty A, Workman MR, Bullock PR. Scedosporium apiospermum brain abscess treated with surgery and voriconazole. Case report. J Neurosurg 2005; 103 (1 Suppl): 83–87. 29. Leechawengwongs M, Milindankura S, Liengudom A, Chanakul K, Viranuvatti K, Clongsusuek P. Multiple Scedosporium apiospermum brain abscesses after near-drowning successfully treated with surgery and long-term voriconazole. Mycoses 2007; 50 (6): 512–516. 30. Meletiadis J, Mouton JW, Meis JF, Verweij PE. In vitro drug interaction modeling of combinations of azoles with terbinafine against clinical Scedosporium prolificans isolates. Antimicrob Agents Chemother 2003; 47 (1): 106–117. 31. Lackner M, de Hoog GS, Verweij PE, et al. Species-specific antifungal susceptibility patterns of Scedosporium and Pseudallescheria species. Antimicrob Agents Chemother 2012; 56 (5): 2635–2642. 32. Cano J, Guarro J, Mayayo E, Fernandez-Ballart J. Experimental infection with Scedosporium inflatum. J Med Vet Mycol 1992; 30 (6): 413–420. 33. Ortoneda M, Capilla J, Pujol I, et al. Liposomal amphotericin B and granulocyte colony-stimulating factor therapy in a murine model of invasive infection by Scedosporium prolificans. J Antimicrob Chemother 2002; 49 (3): 525–529.
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Epidemiology, clinical manifestations, and outcomes of Scedosporium infections among solid organ transplant recipients L.S. Johnson, R.K. Shields, C.J. Clancy. Epidemiology, clinical manifestations, and outcomes of Scedosporium infections among solid organ transplant recipients. Transpl Infect Dis 2014: 16: 578–587. All rights reserved Abstract: Background. Few studies of Scedosporium infections following solid organ transplantation have been performed in the era of induction immunosuppression and widespread antifungal prophylaxis. Methods. We performed a single-center, retrospective study of transplant recipients from 2000 through 2010 who had a positive Scedosporium culture. Results. Among 27 patients, 67% (n = 18) and 33% (n = 9) were infected with Scedosporium apiospermum and Scedosporium prolificans, respectively. A total of 67% received induction immunosuppression and 74% received prior antifungal therapy. Isolates were broadly resistant to antifungals. Of these patients, 59% (n = 16) were colonized by Scedosporium, and 41% (n = 11) had disease (scedosporiosis). No significant clinical differences were seen between species. Colonization occurred exclusively in the lungs of lung transplant recipients (LTR). Scedosporiosis followed lung transplantation in 55%, and other organ transplants (multivisceral [18%]; and heart, liver, small intestine [9% each]) in 45%. Scedosporiosis was preceded by colonization in 36%. Diseases included pneumonia (64%), mediastinitis (18%), and fungemia/ disseminated infections (18%). The 6-month outcomes were death in 55%, progression in 18%, stability in 9%, and resolution in 18%. Patients who died had earlier onset scedosporiosis post transplant (median: 80.5 vs. 1388 days; P = 0.04), and were more likely to have mediastinitis or disseminated infections than pneumonia (100% vs. 29%; P = 0.06). The 3 patients who developed scedosporiosis >1 year post transplant survived. All patients who survived were treated with a voriconazole-containing regimen. Conclusions. LTR were most susceptible to Scedosporium colonization and scedosporiosis, particularly within the lungs. Death was common with scedosporiosis in the first year after all types of organ transplants, consistent with profound immunosuppression and antifungal resistance, but not encountered thereafter.
Scedosporium species are fungi with a predilection for infecting immunosuppressed patients, including solid organ transplant recipients (SOTR) (1). Like many medically relevant fungi, Scedosporium species are ubiquitous soil organisms, especially in polluted areas (2). The most common species, Scedosporium apiosper-
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L.S. Johnson1, R.K. Shields1,2, C.J. Clancy2 1
Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA, 2Infectious Diseases, Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
Key words: Scedosporium; transplantation; colonization; S. apiospermum; S. prolificans; scedosporiosis Correspondence to: Cornelius J Clancy, MD, Infectious Diseases, Department of Medicine, University of Pittsburgh, Scaife Hall 867, 3550 Terrace Street, Pittsburgh, PA 15261, USA Tel: 412 383 5193 Fax: 412 648 8455 E-mail: [email protected]
Received 5 September 2013, revised 2 January 2014, accepted for publication 1 March 2014 DOI: 10.1111/tid.12244 Transpl Infect Dis 2014: 16: 578–587
mum, was initially thought to be an anamorph of Pseudallescheria boydii, but following a series of reclassifications it was defined as a distinct species in 2008 (3–5). Scedosporium prolificans (formerly Scedosporium inflatum), which shares many common features with S. apiospermum, first appeared in the literature in the
Johnson et al: Scedosporium in transplantation
1980s (6). Both organisms cause diverse diseases (scedosporiosis) that carry mortality rates as high as 80%, particularly with disseminated infections (7, 8). The clinical features of scedosporiosis are similar to those of the more recognized Aspergillus species, and the genera are indistinguishable by routine histopathology of infected tissue (1, 3, 8). Scedosporium species are notable for their resistance to polyene antifungals and variable susceptibility to newer azole agents that are generally effective against Aspergillus (3, 8). Despite the importance of Scedosporium infections, studies among transplant recipients are limited, and much of our understanding comes from case reports and epidemiologic series (8–17). In a series of 7 SOTR with scedosporiosis due to S. apiospermum at our center from 1986 to 1996, the mortality rate was 86% (8). Scedosporiosis was encountered in patients after liver, lung, heart, heart-lung, and kidney transplantation. Disseminated disease, pneumonia, and sinusitis occurred in 43% (3/7), 43% (3/7), and 14% (1/7) of patients, respectively. In a multicenter, retrospective case series and review of the literature through 2003, which included 57 SOTR, the majority of scedosporiosis occurred after kidney (35%), heart (28%), and liver (18%) transplantation (18); 83% of transplant recipients were infected with S. apiospermum, and 55% had disseminated infections. The overall mortality rate was 54%, with worse outcomes among patients with disseminated infections. Patients reported in earlier studies did not receive induction immunosuppression, and mold-active antifungal prophylaxis was employed in a minority. More recently, data from 17 transplant centers between 2004 and 2007 indicated that lung transplant recipients (LTR) were at greatest risk for scedosporiosis, but detailed clinical information was not provided (15). Respiratory tract colonization by Scedosporium has been reported to progress to disseminated disease (16, 17). However, the relationship between colonization and the subsequent development of scedosporiosis following solid organ transplantation is unclear. Our objective in this study was to evaluate the epidemiology, clinical manifestations, and outcomes of Scedosporium colonization and scedosporiosis among SOTR at our center since 2000. During this period, induction immunosuppression and mold-active antifungal prophylaxis were widely employed.
We searched the University of Pittsburgh Medical Center medical record database for positive culture results for Scedosporium species from patients, who had undergone solid organ transplantation from January 1, 2000 to December 31, 2010. The search included the organism’s previous identifiers, such as Pseudallescheria boydii. Clinical characteristics were reviewed and abstracted from patients’ electronic medical records. Patients were classified as colonized or suffering from scedosporiosis based on clinical course, radiographic findings, histopathology, and, in unclear cases, the consensus classifications of the authors. Patients were defined as having possible, probable, or proven scedosporiosis, in keeping with criteria adapted from the Mycoses Study Group and European Organization for Research and Treatment of Cancer (19). We classified 6-month treatment outcomes for scedosporiosis into the categories of complete resolution, partial resolution, stable, progression of disease, and death. None of the patients identified in this review were included in earlier studies of scedosporiosis that included University of Pittsburgh Medical Center transplant recipients (8, 18). Statistical analyses were performed using the PASW Statistics 18 software program (SPSS Inc, Chicago, Illinois, USA). Comparisons between 2 groups were performed by Wilcoxon rank sum test for continuous variables, and chi-square or Fisher’s exact tests for categorical variables. Significance was defined as P-value ≤0.05 (2-tailed).
Results A total of 27 SOTR had positive Scedosporium cultures, including 17 women and 10 men. The median age was 52 years (range 20–69). Patient demographics are presented in Table 1; 85% (22/27) of patients were LTR; 59% (16/27) of patients were colonized, and the remaining 41% (11/17) had scedopsoriosis. Patients were infected with S. apiospermum in 67% (18/27) and with S. prolificans in 33% (9/27). Among isolates tested, both species were broadly resistant to antifungal agents (Table 2).
Patients colonized by Scedosporium
Materials and methods The University of Pittsburgh Institutional Review Board approved this retrospective study (#PRO09050022).
Sixteen patients were colonized by Scedosporium (excluding those who went on to develop scedosporiosis); 69% (11/16) of colonized patients were women and 31% (5/16) were men. The median age was
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Demographics of patients with (+) Scedosporium cultures Total population: N (%); N = 27
Characteristic
Colonization: N (%); N = 16
Disease: N (%); N = 11
Age at first (+) Scedosporium culture 60 Gender
Race/Ethnicity
Underlying disease Lung transplant COPD1
Other solid organ transplants
Type of transplant Lung
22 (81)
16 (100)
6 (55)
Multivisceral
2 (7)
0
2 (18)
Heart
1 (4)
0
1 (9)
Small intestine
1 (4)
0
1 (9)
Liver
1 (4)
0
1 (9)
1
Including isolated emphysema. One patient also suffered liver cirrhosis. 3 Includes 1 (4%) instance each of hepatitis C, idiopathic dilated cardiomyopathy, and congenital periportal fibrosis. 4 Includes 1 (9%) instance each of hepatitis C, idiopathic dilated cardiomyopathy, and congenital periportal fibrosis. COPD, chronic obstructive pulmonary disease. 2
Table 1
55 years (range 20–69). All colonized patients were LTR who were colonized in the respiratory tract only. Overall, 73% (16/22) of LTR were colonized in the absence of disease. The colonizing isolates were S. apiospermum in 75% (12/16) and S. prolificans in 25% (4/12). Of the colonized patients, 81% (13/16) were treated with antifungal agents. All patients who received antifungals received an azole; 38% (5/13) received
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combination therapy with 2 or more antifungal agents. At 6 months after the first positive culture, 75% (12/16) of patients cleared their colonization (i.e., subsequent cultures did not grow Scedosporium), and 25% (4/12) were still infected (i.e., no documentation of clearance). The 19% (3/16) of colonized patients who were not treated with antifungals had colonization that was diagnosed >1 year after lung transplantation; each patient cleared their colonization.
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Antifungal resistance among Scedosporium isolates Species and antifungal agent, criterion for resistance
% resistant (no. resistant/ no. tested)
Scedosporium apiospermum Amphotericin B, MIC ≥1 lg/mL
100 (6/6)
Posaconazole, MIC ≥0.5 lg/mL
100 (4/4)
Terbinafine, MIC ≥1 lg/mL
86 (6/7)
Voriconazole, MIC ≥1 lg/mL
80 (4/5)
Scedosporium prolificans Amphotericin B, MIC ≥1 lg/mL
67 (2/3)
Posaconazole, MIC ≥0.5 lg/mL
86 (6/7)
Terbinafine, MIC ≥1 lg/mL Voriconazole, MIC ≥1 lg/mL
100 (3/3) 86 (6/7)
MIC, minimum inhibitory concentration.
Table 2
Patients with scedosporiosis Disease due to Scedosporium species developed in 11 patients. Table 3 compares the clinical characteristics of patients who were colonized with those who developed scedosporiosis. Clinical data on the cases of scedosporiosis are presented in Table 4. Of the patients with scedosporiosis, 55% (6/11) were women and 45% (5/11) were men. The median age was 48 years (range 23–65). LTRs were 55% (6/11), and 18% (2/11) were multivisceral transplant recipients. The rate of scedosporiosis among LTR was 0.6% (6/944). The remaining patients were heart, liver, or small intestine transplant recipients (9% each; 1/11). Overall, 27% (6/22) of LTR and 100% (5/5) of other transplant recipients, who were infected with Scedosporium, developed scedosporiosis (P = 0.006). Scedosporiosis was caused by S. apiospermum in 55% (6/11) and by S. prolificans in 45% (5/11) of patients. Of patients with scedosporiosis, 36% (4/11) were previously colonized by the same species (3 LTR and 1 liver transplant recipient); 3 of these patients were colonized before transplantation (2 LTR and 1 liver transplant recipient). All 4 colonized patients developed disease despite receiving preemptive therapy with voriconazole, alone or in combination with another agent. Of LTR, 33% (2/6) had diseases that were considered likely to stem from seeding at the time of surgery, based on the recovery of Scedosporium from recipients’ explanted lungs at the time of transplant, and from an intra-thoracic site of infection within 90 days of trans-
plant. The median time to scedosporiosis post transplantation, among the patients colonized before transplantation, was 15 days (range 4–90 days). Among the patients who were not colonized pretransplant, the median time to scedosporiosis post transplantation was 217 days (range 6–45,914 days; P = 0.11). The diseases caused by Scedosporium were pneumonia (64%; 7/11), mediastinitis (18%; 2/11), and fungemia/disseminated infections (18%; 2/11). Both patients with disseminated infections were multivisceral transplant recipients infected with S. prolificans. Respiratory symptoms, such as cough, dyspnea, or respiratory failure, were the initial presenting symptoms in 73% (8/11) of patients. Other initial presentations were diabetic ketoacidosis, heart failure, and gastrointestinal distress (9% each; 1/11). None of the patients had a sepsis-like syndrome, which has been reported in previous studies of stem cell transplant recipients (3, 4). Concurrent positive cultures for other pathogens were found in 82% (9/11) of patients. Six-month outcomes were death, progression of disease, stable disease, and complete resolution in 55% (6/11), 18% (2/11), 9% (1/11), and 18% (2/11) of patients, respectively. The median time to death among patients who died was 45.5 days (range 25–88 days) following the diagnosis of scedosporiosis. Patients who died had earlier disease onset post transplantation (median 80.5 days [range 0–327] vs. 1388 days [range 4–4591]; P = 0.04). All 3 patients who developed scedosporiosis >1 year post transplant were alive 6 months after their diagnosis. Patients with pneumonia were more likely to be alive at 6 months than patients with mediastinitis or disseminated infections (71% (5/7) vs. 0% (0/4), P = 0.06). Both patients who resolved their infections at 6 months were infected with S. apiospermum. Antifungal therapy consisted of regimens that included voriconazole (91%, 10/11), amphotericin B (64%, 7/11), caspofungin (55%, 6/11), terbinafine (55%, 6), and posaconazole (9%, 1/11). All patients who were alive at 6 months received voriconazole. Four patients received adjuvant surgical treatment; all died.
Discussion Scedosporiosis was associated with poor outcomes among SOTR at our center. The 6-month mortality rate was 55%, which is consistent with an earlier case series and review of the literature of scedosporiosis following organ transplantation (18). At the same time, our
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Clinical characteristics of patients with (+) Scedosporium cultures Total (N = 27): N (%)
Clinical characteristic
Colonization (N = 16): N (%)
Disease (N = 11) N (%)
Induction immunosuppression None Alemtuzumab
8 (30)
6 (38)
2 (18)
15 (56)
10 (63)
5 (45)
Anti-thymocyte globulin
3 (11)
0
3 (27)
Unknown
1 (4)
0
1 (9)
Maintenance immunosuppression Tacrolimus, mycophenolate mofetil, prednisone Others Documented previous rejection
22 (81)
15 (94)
7 (64)
4 (19)
1 (6)
4 (36)
9 (33)
5 (31)
4 (36)
CMV infection
14 (52)
8 (50)
6 (55)
Concurrent (+) cultures for other fungi1
15 (56)
5 (31)
10 (91)
Concurrent (+) cultures for other pathogens1
12 (44)
4 (25)
9 (82)
Prior antifungals
20 (74)
11 (69)
Median time in days to first (+) Scedosporium culture post transplant (range)
373 ( 2683 to 4584)
643 (6 to 2933)
9 (82) 34 ( 2683 to 4584)
1
From the same date as a (+) Scedosporium culture. CMV, cytomegalovirus.
Table 3
findings highlight several new insights into both disease and colonization by Scedosporium. First, 86% of positive cultures for Scedosporium species occurred in LTR, including 55% and 100% of scedosporiosis and colonization in the absence of disease, respectively. In the previous study of transplant recipients, only 14% of patients had undergone lung transplantation, and colonization was not assessed (18). The susceptibility of LTR is in keeping with a recent epidemiologic survey of fungal infections following transplantation (15). Second, the respiratory tract was the predominant site of Scedosporium infection: pneumonia accounted for 64% of scedosporiosis, and colonization was diagnosed exclusively in the respiratory tract. Disseminated disease occurred in at least 50% of transplant patients in earlier studies (8, 18), but in only 18% of our patients. Third, early-onset scedosporiosis following transplantation was associated with increased mortality in our patients, which is not noted elsewhere. Patients who died had scedosporiosis diagnosed at median 80.5 days, and those who survived had Scedosporium diagnosed at median 1388 days post transplant; 75% of patients with scedosporiosis within the first year of transplantation died, compared with none of the patients with later-onset disease. Finally, early-onset scedosporiosis often occurred after colonization by Scedosporium.
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In many regards, our new findings should not be surprising. It is widely recognized that LTR are at particular risk for respiratory tract infections by environmental molds. This susceptibility is a result of the continuous exposure of the transplanted organ to the external environment, the frequent need for prolonged mechanical ventilation (20), impaired mucociliary clearance (21), and profound immune suppression (22). Moreover, patients awaiting lung transplantation are commonly colonized with fungi as a result of their underlying diseases. Scedosporium colonization of the respiratory tract, for example, is well recognized among patients with chronic obstructive pulmonary disease and cystic fibrosis (11, 16, 17), which were the most common indications for transplantation in our series. Fungal colonization among LTR, in turn, is a risk factor for subsequent invasive pulmonary infections. Increased mortality with early-onset scedosporiosis is not unexpected during the period of most intense immunosuppression. In each of these aspects, our findings with Scedosporium colonization and disease are similar to the experience with Aspergillus species, and are consistent with pathogenesis that generally stems from inhalation of airborne conidia by highly susceptible hosts. Scedosporium infections among other SOTR differed from lung transplantation in several ways. Whereas the recovery of Scedosporium from the respiratory tract
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41/F
3
4
24/F
59/F
2
6
26/M
1
26/F
65/M
Pt
5
Age years/ gender
Lung
Lung
Lung
Lung
Lung
Lung
Transplant type
Shortness of breath, chest pain, fever
Diabetic ketoacidosis
Failure to wean from ventilator
Hypoxia
Dyspnea; productive cough
Respiratory distress, tachycardia, atrial flutter
Initial clinical manifestations
73
90
15
1388
4591
2841
Time to disease (days)
Clinical information on patients with scedosporiosis
Pneumonia (proven)
Mediastinitis/ sternal osteo (proven)
Pneumonia, wound infection (proven1)
Pneumonia (probable)
Pneumonia (probable)
Pneumonia (probable)
Disease type
S. apiospermum
S. prolificans
S. apiospermum
S. prolificans
S. prolificans
S. apiospermum
Scedosporium species
(+)
Pseudomonas aeruginosa (BAL); Pseudomonas mirabilis (sputum)
None
Rhizopus, K. pneumonia (BAL)
Klebsiella pneumoniae (BAL)
Mycobacterium fortuitum (BAL)
Stenotrophomonas maltophilia (BAL, wash)
Concurrent cultures
Death
Death
Surgery2 + posaconazole, terbinafine, voriconazole
Progression of disease
Progression of disease
Stable
Complete resolution
6-month outcome
Surgery + terbinafine, voriconazole
Amphotericin, caspofungin, fluconazole, terbinafine, voriconazole
Amphotericin, terbinafine, voriconazole
Terbinafine, voriconazole
Voriconazole
Treatment
Surgical biopsies revealed Scedosporium. Autopsy report attributed cause of death to Enterococcus faecium pneumonia, pulmonary and myocardial infarction. The patient was colonized prior to disease
Surgical biopsies revealed Scedosporium. Death due to mycotic pseudoaneurysm. The patient was colonized at time of transplant, and disease was likely to stem from surgical seeding
Scedosporium and Rhizopus both grew from respiratory culture. Tissue pathology was consistent with Scedosporium. The patient was colonized at time of transplant, and disease was likely to stem from surgical seeding
The patient died 9 months after diagnosis due to unknown causes
The patient was also treated for M. fortuitum pneumonia. Scedosporium was cultured from multiple respiratory samples
Discharged home
Comments
Johnson et al: Scedosporium in transplantation
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584
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23/F
48/M
10
11
Liver
Heart
Small intestine
Multivisceral
Multivisceral
Transplant type
Worsening of baseline bronchiectasis
Heart failure
Non-productive cough, fever, chills
Respiratory difficulty, stridor
Abdominal discomfort
Initial clinical manifestations
4
Pneumonia (probable)
Mediastinitis (proven)
Pneumonia (probable)
3273
0
Disseminated (proven)
Disseminated (proven)
Disease type
107
34
Time to disease (days)
S. apiospermum
S. apiospermum
S. apiospermum
S. prolificans
S. prolificans
Scedosporium species
(+)
P. aeruginosa (BAL)
None
Citrobacter freundii (sputum)
Staphylococcus aureus, E. faecium, Klebsiella oxytoca, P. aeruginosa (various autopsy sites)
Enterococcus cloacae, E. faecium (autopsy abscess)
Concurrent cultures
Death
Surgery2 + amphotericin, caspofungin
Table 4
2
Complete resolution
Death
Surgery + caspofungin, terbinafine, voriconazole
Caspofungin, voriconazole
Death
Death
6-month outcome
Amphotericin, caspofungin, voriconazole
Amphotericin, caspofungin, voriconazole
Treatment
Probable infection with Scedosporium; proven invasive fungal infection. Mediastinal exploration. 3 Time from second transplant; 837 days from first. M, male; F, female; BAL, bronchoalveolar lavage; CNS, central nervous system; MRI, magnetic resonance imaging.
1
52/M
9
7
51/F
54/M
Pt
8
Age years/ gender
Table 4 Continued
The patient was colonized prior to transplant. Discharged home
Surgical biopsy revealed Scedosporium infection mixed with Candida parapsilosis. Death due to failure of transplanted heart
Scedosporium grew from BAL and sputum cultures. The patient suffered CNS symptoms and MRI revealed brain lesions consistent with abscesses. Death due to cardiac arrest and anoxic brain injury
Autopsy-proven scedosporiosis of the pericardium, eyes, dermis, heart, kidneys, and pancreas
Autopsy-proven scedosporiosis of the heart, pericardium, pleura, kidneys, and brain
Comments
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Johnson et al: Scedosporium in transplantation
represented colonization rather than disease in 72% of LTR, positive cultures in other patients were always associated with scedosporiosis or colonization that led to scedosporiosis. Among LTR, 83% with scedosporiosis had pneumonia, while non-LTR had diseases ranging from pneumonia to mediastinitis to fungemia and disseminated infections. Both patients with fungemia underwent multivisceral transplantation and died from widely disseminated scedosporiosis that did not involve the lung parenchyma. Indeed, a strong trend was seen toward improved survival among patients with pneumonia, compared to those with mediastinitis or fungemia, an observation that is consistent with previous studies describing better outcomes in transplant recipients with localized rather than disseminated infections (18). The high mortality rates with scedosporiosis, particularly among patients with early-onset and more extensive disease, underscore the inadequacy of current treatment regimens. The size of our study precludes us from drawing definitive conclusions about treatment. In general, previous studies have shown that voriconazole is active against S. apiospermum in vitro, but S. prolificans is less responsive (23, 24). Our voriconazole resistance data are potentially biased by the fact that isolates were only tested if requested by clinicians. Nevertheless, the high levels of resistance to voriconazole and other agents among tested isolates may stem from the widespread prior receipt of antifungal therapy. In comparison, only 18% of transplant recipients received prior antifungals in the earlier review (18). Voriconazole appeared to have some role in treatment, as all of our surviving patients received a voriconazole-containing regimen. This finding is tempered by the facts that resolution of disease was achieved in only 18% of patients, choices of antifungal regimens may have been biased by the severity of patients’ illnesses, and voriconazole was often employed in combination with other agents. Several clinical studies, including the previous review of transplant recipients, showed improved outcomes among patients treated with voriconazole (18, 25, 26). Of course, noncurative antifungal therapy may still be beneficial by arresting disease progression and facilitating surgical resections or other interventions. Indeed, previous studies reported lower mortality from scedosporiosis among transplant recipients who underwent surgical interventions (12, 18, 27–29). In our experience, however, all patients who underwent surgery died, which may reflect the use of surgery in more extensive infections. In fact, the benefits of surgery for scedosporiosis are most striking for well-localized lesions, particularly in the central nervous system (18, 28, 29).
In considering our outcomes, it is important to note that 63% of patients with scedosporiosis received induction immunosuppression with alemtuzumab or anti-thymocyte globulin. In contrast, none of the transplant recipients in the previous multicenter study received induction therapy (18). It is possible that the intensity of immunosuppression among our patients increased the risk of scedosporiosis and accounted, at least in part, for the high mortality rates in the first several months following transplantation. At the same time, the mortality rate was lower than that reported for SOTR at our center in 1986–1996, prior to use of induction agents (8). As such, these data may attest to improvements in disease recognition and treatment. Based on our experience and other publications, we advocate treatment comprised of prompt surgical resection, where feasible, in conjunction with voriconazole. Combining voriconazole with terbinafine or an echinocandin has been shown to be synergistic in vitro (30), and should be considered in more extensive disease, or for S. prolificans infections. Posaconazole has activity against Scedoporium in vitro (31), but its role as an alternative to voriconazole is unclear. Our poor outcomes, despite antifungal therapy and surgery, illustrate the importance of disease prevention among these high-risk patients. Several approaches to prevention were undertaken in our population. First, voriconazole prophylaxis was routine for 3–6 months after lung transplantation, with additional courses in response to augmented immune suppression for acute cellular rejection and at the discretion of clinicians. Despite concerns that prophylaxis may select for voriconazole-resistant fungi like Scedosporium, only 6 cases of scedosporiosis were encountered among LTR during the study period. It is not possible to determine if the practice contributed to the rate of respiratory tract colonization that was observed or if, in at least some instances, prophylaxis prevented or delayed the onset of scedosporiosis to periods of less intense immune suppression. Second, colonization was treated aggressively with antifungal agents. Of patients who were colonized with Scedosporium at some point after transplantation, 85% (17/20) were treated with voriconazole and/or other agents, with mixed results: 53% (9/17) cleared colonization, 24% (4/17) maintained colonization in the absence of disease, and 24% (4/17) progressed to disease. The 3 patients colonized before transplantation each developed early-onset scedosporiosis despite antifungal therapy. Based on this experience, our current practice among candidates before transplantation is to treat colonization with a voriconazole-containing regimen and document microbiologic clearance.
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Among patients colonized in the first several months after transplantation, approaches are individualized, but we err on the side of preemptive antifungal therapy, as the impact of early-onset scedosporiosis is generally dire. At later time points, we advocate treatment for cases in which disease is suspected clinically. In the absence of signs or symptoms of disease, our experience indicates that antifungal therapy is not absolutely necessary in LTR. In contrast, the recovery of Scedosporium in cultures from non-LTR triggers a low threshold for treatment, as colonization of these patients did not occur in the absence of scedosporiosis. Our series was too small to draw conclusions about the relative virulence of species, but the trend toward more severe disease and worse outcomes with S. prolificans is similar to previous clinical reports (18). These findings are consistent with data from animal studies (32, 33). Of note, the vast majority of our patients with scedosporiosis were also infected with other potential pathogens. Patients fulfilled criteria for proven or probable invasive fungal infections, but the recovery of multiple potential pathogens emphasizes the poor states of health, high levels of immune suppression, and general susceptibility to infections. It is important to acknowledge that our study has shortcomings common to retrospective, single-center studies. Despite these shortcomings, the data are useful because of the limited number of transplant recipients previously reported in the literature. In particular, recent data on scedosporiosis that account for advances in induction immunosuppression and antifungal prophylaxis are lacking. Although some of our findings may be particular to our program, insights such as the susceptibility of LTR and the importance of respiratory tract colonization and disease are likely to be broadly relevant. Further reports on transplant recipients with Scedosporium colonization or scedosporiosis will be valuable for corroborating or expanding upon our findings and offering contrasts to our experience.
Acknowledgements: Thanks: We thank Lloyd Clarke for his help in data collection and retrieval. Funding: This study was funded in part by the National Institutes of Health through Grant Numbers KL2 RR024154 and KL2TR000146 to R.K.S. Author contributions: L.S.J. is primarily responsible for data collection, review and analysis, and writing the manuscript. R.K.S. independently reviewed cases, and assisted with data review and analysis, and in drafting
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and editing the manuscript. C.J.C. is responsible for data collection, review and analysis with L.S.J.; he independently reviewed cases, and was the primary editor of drafts of the manuscript provided by L.S.J. Conflicts: The authors do not have conflicts of interest.
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