Hindawi Publishing Corporation Scientifica Volume 2014, Article ID 821969, 17 pages http://dx.doi.org/10.1155/2014/821969

Review Article Invasive Mold Infections in Solid Organ Transplant Recipients Yoann Crabol1 and Olivier Lortholary1,2 1

Universit´e Paris Descartes, Sorbonne Paris Cit´e, Centre d’Infectiologie Necker Pasteur, Institut Imagine, Hˆopital Universitaire Necker-Enfants Malades, APHP, 75015 Paris, France 2 Institut Pasteur, Unit´e de Mycologie Mol´eculaire, Centre National de R´ef´erence Mycoses Invasives et Antifongiques, CNRS URA3012, 75015 Paris, France Correspondence should be addressed to Olivier Lortholary; [email protected] Received 4 August 2014; Accepted 3 November 2014; Published 23 November 2014 Academic Editor: Maurizio Sanguinetti Copyright © 2014 Y. Crabol and O. Lortholary. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Invasive mold infections represent an increasing source of morbidity and mortality in solid organ transplant recipients. Whereas there is a large literature regarding invasive molds infections in hematopoietic stem cell transplants, data in solid organ transplants are scarcer. In this comprehensive review, we focused on invasive mold infection in the specific population of solid organ transplant. We highlighted epidemiology and specific risk factors for these infections and we assessed the main clinical and imaging findings by fungi and by type of solid organ transplant. Finally, we attempted to summarize the diagnostic strategy for detection of these fungi and tried to give an overview of the current prophylaxis treatments and outcomes of these infections in solid organ transplant recipients.

1. Introduction Solid organ transplantation (SOT) is effective life-sparing modalities for thousands of patients worldwide with organ failure syndromes. Despite important advances in surgical techniques and immunosuppressive regimens, there remain substantial risks for posttransplantation infections. Because of improvement in diagnosis and treatment of other infections, as Cytomegalovirus infections, invasive fungal infections (IFIs) have now become the leading cause of infection-related mortality following transplantation. Although SOT populations are at high risk for IFI, with overall incidence rate of 0.9 to 13.2%, respectively [1, 2], they differ with regard to specific defects in host defense mechanisms. Whereas all SOT recipients have dysfunctional T cells and phagocytes, as a result of immunosuppressive drug therapy, disrupted anatomical barriers and iron overload seem to be specific factors favoring fungal infections in lung and liver transplant recipients, respectively.

Those specific defects might explain differences in type, onset, and outcome of IMIs among those populations as reported in two large multicenter prospective studies in the United States and Canada, the Transplant-Associated Infection Surveillance Network (TRANSNET) and the Prospective Antifungal Therapy Alliance (PATH Alliance) studies. Basically, while yeast is major pathogens among SOT recipients (Candida sp. and Cryptococcus sp. 53% and 8% of IFIs, resp.) [1–3] molds are more prevalent among heart or lung transplants recipients (65% of IFIs). Though rare, endemic fungi (mainly histoplasmosis) represent up to 5.3% of IFIs in endemic areas among SOT recipients [4]. Moreover, median date of diagnosis of IMIs is shorter in liver transplant recipients (99.5 day), compared with 504 days and 382 days in lung and heart transplant recipients. Among IFIs, invasive mold infections (IMIs) carry the worst outcome [1, 2] and represent an increasing source of morbidity and mortality among SOT recipients [5]. 12-week mortality after the diagnosis of IMIs is the highest among liver

2 transplant recipients (47.1%), compared to kidney, heart, and lung recipients (27.8%, 16.7%, and 9.5%, resp.) [6]. We reviewed specific epidemiology, clinical and imaging findings, diagnostic procedures, treatment, and outcome of proven/probable IMIs, as defined by the 2008 EORTC/MSG criteria [7], in SOT recipient.

2. Molds Classification Molds are filamentous fungi that thrive in soil and decomposing vegetation. Usual molds classification relies on the phenotype of hyphae. Septate hyaline hyphae encompass Aspergillus sp. and other Hyalohyphomycosis whereas Mucormycosis, previously termed zygomycosis, belongs to the nonseptate hyaline hyphae. Finally, dematiaceous fungi have melaninlike pigments in the cell walls. They are agents of the phaeohyphomycosis (phaeo is Greek for “dark”). The dematiaceous fungi appear to be especially common in tropical and subtropical regions. Most patients infected with Rhinocladiella mackenziei have been reported from Middle Eastern countries, including Saudi Arabia, Syria, or Kuwait [8].

3. Epidemiology of Invasive Molds Infections among Solid Organ Transplants 3.1. Epidemiology. The epidemiology of IMIs in transplant recipients differs based on geography, host variables, preventive strategies, and methods of diagnosis (see Tables 1 and 2). Of the 1,208 cases of proven or probable IFI in SOT recipients in TRANSNET, 45 cases of Mucorales, Fusarium spp., or Scedosporium spp. infection were detected, making these molds the most frequently identified molds after Aspergillus (227 cases) within this patient population. The Mucorales (28 patients, 62.2%) were the most common of these molds, followed by Scedosporium spp. (11 patients, 24.4%) and Fusarium spp. (6 patients, 13.3%). In 10 years of single-center experience recent report, the overall incidence for IMIs among lung, kidney, liver, and heart transplant recipients was 49, 2, 11, and 10 per 1000 person-years, respectively [6]. Among SOT recipients, 17 (37.8%) infections occurred within the first 6 months and 15 (33.3%) occurred >2 years after transplant [2]. Moreover, breakthrough invasive mold infections are an emerging issue among transplant recipients and have been described with the prophylactic or curative use of voriconazole [9], posaconazole [10], caspofungin [11], or polyene [12] antifungal agents. Beside increased minimum inhibitory concentration that remains rare, mechanisms of breakthrough encompass low antifungal serum trough because of noncompliance, insufficient absorption or drugdrug interaction, and low local antifungal concentration because of biofilm or insufficient tissue penetration to critical body site [13]. 3.2. Invasive Aspergillosis. The proportion of SOT patients within cohorts of patients with invasive aspergillosis (IA) ranges from 8.7% to 44% [14–16]. Overall cumulative incidence of IA ranges from 0.1 to 3.5% in American or European

Scientifica series of adult and paediatric SOT recipients depending on the type of transplant [2, 15, 17–20]. Indeed, among heart, lungs, liver, and kidney SOT patients, the IA incidence was 4.8% (7/146), 4.1% (7/172), 0.8% (9/1067), and 0.3% (11/3157), respectively. The 12-month cumulative incidence of aspergillosis is 2.4%, 0.8%, 0.3%, and 0.1% after lung, heart, liver, and kidney, respectively. In a five-year surveillance of IA in a university hospital, a significant decrease (from 24 to 4 per 100,000 patient days) of IA during the investigation period (2003–2007) was noticed after implementation of a standardized antimycotic prophylaxis protocol [16]. 3.3. Mucormycosis. The proportion of SOT patients within recent cohorts of patients with mucormycosis varied from 3% to 10% [21–23]. Recently published estimated incidence of mucormycosis in SOT recipients has ranged from 0.4% to 16.0%, depending on the procedure and the geographical area [5, 22, 24]. The TRANSNET study found that the 12-month cumulative incidence of mucormycosis was 0.07% in SOT recipients, with mucormycosis accounting for 2% of invasive fungal infections [25], which is concordant with other studies [2, 3, 26]. Postmortem prevalence evaluation shows that mucormycosis is 10–50-fold less frequent than candidiasis or aspergillosis with a frequency of 1–5 cases per 10 000 autopsies [27, 28]. However, world distribution of mucorales may vary depending on countries. Of note, a study from Iran showed that mucormycosis was the most frequent invasive fungal infection in patients receiving SOT [29]. In the past 2 decades, mucormycosis has emerged as an important invasive fungal infection in SOT and HSCT recipients [21, 30, 31] and an increasing incidence from 0.7/million in 1997 to 1.2/million in 2006 was reported in a population-based study in France [5]. 3.4. Other Molds. Data regarding epidemiology of hyalohyphomycosis and phaeohyphomycosis are scarcer. Among 162 S. prolificans infections cases retrieved from literature, 8.6% had received solid organ transplantation [32]. Among 73 patients with invasive fusariosis identified through the voriconazole clinical database and the French National Reference Center for Mycoses and Antifungals database, only one was a SOT recipient (kidney) [33]. 12-month cumulative scedosporiosis and fusariosis incidence among SOT were 0.024 and 0.012%, respectively, in the TRANSNET study [25]. In a retrospective analysis of 101 cases of primary central nervous system phaeohyphomycosis, 15% had received a solid organ transplant [34]. A 0.7% overall incidence of phaeohyphomycosis among SOT has been recently reported in a retrospective single-center study in New Orleans, USA [8]. 3.5. Risk Factors 3.5.1. General Risk Factors. Environmental and immune system related risk factors for IMIs have already largely been reviewed by Pagano et al. [35] and Shoham [36]. Moulds are ubiquitous saprophytes present in air, soil, and water that might peak after seasonal periods of dry weather

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CNS (%)

Disseminated (%)

In HM: Multiple bilateral patchy nodular condensations, alveolar infiltrates or, most commonly, consolidation without cavitation

In HM: Pulmonary nodules in 82% Reversed halo sign 0% Halo sign or =1.0 yielded a sensitivity of 60%, a specificity of 98%, and positive and negative likelihood ratios of 28 and 0.40, respectively [69]. In a recent Brazilian study, Nucci et al. reviewed the records of 18 patients with invasive fusariosis and GM evaluation. The sensitivity and specificity of GM were 83% and 67%, respectively. GM was positive before the diagnosis of invasive fusariosis in 73% of the cases at a median of 10 days [70]. In patients with a possible invasive fungal infection, negative galactomannan test results in serum and BAL increase the likelihood of invasive mucormycosis [71, 72]. Conversely, a positive GM or 1,3-𝛽-d-glucan result does not exclude the diagnosis of mucormycosis, because of the cooccurrence of fungal infections (up to 45% in a single-center study) [42]. The 1,3-𝛽-d-glucan (BG), a cell wall component of most fungal species, can be detected in blood during IFD. The BG test is used as a diagnostic tool for the detection of a broad spectrum of fungal pathogens, with the exception of

Scientifica Mucorales and C. neoformans. This test is currently used in combination with classical clinical, radiological, and microbiological findings. It was included in the updated consensus definition of probable IFD by the EORTC/MSG consensus [7]. In 2012, a meta-analysis reported the performance of BG antigenemia assays for the diagnosis of IFD in patients with hematological malignancies, including allogeneic HSCT [73]. This paper highlighted the fact that two consecutive positive BG tests strongly suggested the diagnosis of probable IFD according to a very high specificity (99%) and positive predictive value. Thus, following two positive BG tests, a preemptive antifungal therapy should be started. However, despite the excellent specificity of the assay, the sensitivity of BG remains low, and a negative result could not rule out the diagnosis of fungal disease. Matrix-assisted laser desorption ionization time-of-flight (MALDI-TOF) mass spectrometry provides protein spectra from crude extracts or intact cells. Each bacterial or fungal species can be identified within minutes by comparison of its own characteristic spectrum with that in a reference spectra library, at least for common fungal species. Fungi such as Aspergillus, Fusarium [74], Lichtheimia species [75], or Scedosporium [76] were thus identified with MALDI-TOF mass spectrometry. A range of different PCR assays (conventional, nested, and real-time) has been developed, targeting different gene regions (mainly 18S, 28S, internal transcribed spacer, and D1/D2 of the rRNA or 𝛽-tubulin), including a variety of amplicon detection methods. These molecular assays provide high potential in terms of sensitivity and specificity but vary widely in their feasibility. According to recent recommendations from European Society of Clinical Microbiology and Infectious Diseases (ESCMID) and European Confederation of Medical Mycology (ECMM), regarding diagnosis of IMIs, molecular methods are recommended for accurate identification of mucormycosis and phaeohyphomycosis, especially in case of outbreak and to a less extent for hyalohyphomycosis identification. In the TRANSNET study, over 10% of the isolates associated with IA in transplant recipients were found to be cryptic species and molecular identification methods were essential in distinguishing them [77]. Level of evidence for fungal detection by use of PCR methods is still lower and not supported by current recommendations. Harmonization of PCR-based techniques is necessary before any clear recommendations can be made regarding their clinical utility. However, results are promising, especially for Aspergillus and Mucorales. Luong et al. compared the performance of publicly available panAspergillus specific real-time polymerase chain reaction (PCR) assays with the Platelia galactomannan (GM) assay in 150 bronchoalveolar lavage (BAL) samples from lung transplant recipients. The sensitivity and specificity of panAspergillus PCR and GM (>0.5) for diagnosing IPA were 100% and 88% and 93% and 89%, respectively. Positive results for both BAL PCR and GM testing improved the specificity to 97% with minimal detriment to sensitivity (93%) [78]. An inhouse seminested PCR that targets the 18S ribosomal DNA of Mucorales was evaluated on fresh tissue specimens obtained from 46 patients with a haematological malignancy and 15

9 patients with solid-organ transplantation. Seminested PCR detected Mucorales in all specimens with nonseptate hyphae (𝑛 = 13, sensitivity 100%) whereas culture remained negative in five cases [79]. Both formalin-fixed paraffin-embedded and fresh or frozen tissue samples can be used, with a lower yield using the former [80]. Mucorales-specific T cells were investigated in 28 hematologic patients during the course of their treatment. Mucorales-specific T cells could be detected only in patients with Mucormycosis, both at diagnosis and throughout the entire course of the disease, but neither before nor for long after resolution of the infection. This assay might be a promising surrogate diagnostic marker of mucormycosis [81]. Positron emission tomography using 18 F-fluorodeoxyglucose (18 F-FDG PET) has proven useful for more accurate evaluation of IFD extent [82]. It can detect small infectious foci before the onset of the anatomical abnormalities assessed by conventional radiological tools but is limited by the size of the lesions (35% between baseline and week 1 predicted a probability of a satisfactory clinical response. Conversely, every 0.1-unit increase in the GM between baseline and week 2 increased the likelihood of an unsatisfactory clinical response by 21.6%. However, resolution of GM to a normal level is not sufficient as a sole criterion for discontinuation of antifungal therapy. 7.2.2. Scedosporium. In vitro and in vivo data show that P. apiospermum is resistant to amphotericin B and flucytosine and demonstrates variable susceptibility to itraconazole, voriconazole, posaconazole, and micafungin. S. prolificans is resistant to caspofungin, polyenes, and azoles. Voriconazole demonstrated the strongest in vitro activity on both of these species [97]. A recent in vitro study suggests synergistic activity of the antibacterial agent colistin with voriconazole against Scedosporium spp. [98]. Success of combinations therapy of azole and terbinafine has been reported in small case series [99, 100]. 7.2.3. Fusariosis. In immunocompromised patients, voriconazole and lipid-based amphotericin B formulations have been reported with success [33, 101] and are supported as first line therapy by ESCMID and ECMM. Posaconazole is recommended as salvage therapy [102]. Data on combination therapy for fusariosis are limited to a few case reports. 7.2.4. Mucormycosis. Immediate treatment initiation in case of mucormycosis is strongly supported to increase survival rates. Indeed, in an uncontrolled study in patients

Scientifica with haematological malignancy the 12-week mortality rate increased twofold with medical treatment deferred for >6 days from onset of symptoms [103]. Liposomal amphotericin B is the drug of choice and the dose should be at least 5 mg/kg/day, as suggested by murine model [104], uncontrolled retrospective study [105], or analysis of registry [23, 30]. Lanternier et al. evaluated the feasibility and efficacy of high dose (10 mg/kg/day) of liposomal amphotericin B for the initial treatment of mucormycosis. Treatment was feasible in more than half of the patients despite frequent (40%) renal toxicity. At week 12 the response rate was 45% [106]. In a retrospective study, combination therapy with an amphotericin B formulation and caspofungin has been described as successful in a limited number of predominantly diabetic patients with rhinocerebral mucormycosis [107]. Preclinical data indicate that the combination of a lipid formulation of amphotericin B and posaconazole is unlikely to be effective [108]. The duration of acute phase treatment is not defined. Minimum treatment duration should be 6– 8 weeks or until resolution of all associated symptoms and findings. Maintenance therapy has to be considered in persistently immunocompromised transplant recipients. After the infection has stabilized, the standard treatment recommendation is oral posaconazole (800 mg/day) [71]. For salvage treatment posaconazole 200 mg four times daily, yielding the highest exposure, is strongly recommended, with response rate ranging from 60 to 80% [109, 110]. New posaconazole formulations, delayed-release tablet and an IV formulation recently approved by the US Food and Drugs Administration, might enhance its effectiveness. 7.2.5. Phaeohyphomycosis. Because of lack of clinical trials and varied resistance patterns among species, there are no standardized therapies for infections caused by phycomycetes. However, voriconazole, posaconazole, itraconazole, and in some cases amphotericin B demonstrate the most consistent in vitro activity against this group of fungi. Voriconazole may have advantages for central nervous system infections because of its ability to achieve good cerebrospinal fluid levels with brain/plasma ratios ≈3.0 at steady state [111], unlike itraconazole. Combination antifungal therapy for cerebral abscesses and for disseminated infections in immunocompromised patients has been suggested [112]. As an example, in a retrospective review of 101 cases of primary central nervous system phaeohyphomycosis, including 15 SOT recipients, treatment with the combination of amphotericin B, 5-FC, and itraconazole was associated with improved survival, compared with other medical regimens, with 17% mortality versus 74% mortality [34]. 7.3. Surgery. Of major importance, extensive early surgical debridement is generally recommended in combination with antifungals, at least during non-Aspergillus mold infections. Indications for surgery are summarized in Table 3. Whereas no well-designed randomized clinical efficacy trial has been published to date, the highest level of evidence for the need of surgery has been provided in mucormycosis. In

11 this setting, surgery was reported to be an independent predictor of successful therapy and survival in SOT recipients with pulmonary or rhino-orbital-cerebral mucormycosis [105, 113]. In a retrospective study on 30 patients combined with a literature analysis of 225 patients with mucormycosis, surgical debridement of lung involvement was associated with a decrease of mortality from 62% to 11% [114]. In a recent retrospective case series of 22 consecutive rhino-orbital- cerebral mucormycosis adults, none versus 75% died, on day 90 with or without local control, respectively [115]. Indications of surgery in IA depend on multiple variables, severity of lesion, surgical judgment, and the ability of the patient to tolerate the operative procedure, as well as the potential role of alternative medical therapy [60]. For Scedosporium, surgical resection remains the key to a successful outcome if the lesions are localized and is sometimes the only available therapy regarding pan-resistance to antifungal treatment. In addition to antifungal treatment, the optimal management of patients with fusariosis includes surgical debridement of infected tissues and/or nails [116] and removal of venous catheters in confirmed catheter-related fusariosis. For cutaneous and CNS phaeohyphomycosis, complete excision is superior to aspiration and is generally required for the disease to resolve [34]. 7.4. Improvement of Immune and Metabolic Factors. Paramount to the successful treatment of IMIs in SOT recipients is improvement of immune and metabolic factors, by administering tapering doses of steroids and immunosuppressive agents, when feasible, and by controlling hyperglycemia, especially in the case of mucormycosis [71]. Moreover, neutropenic patients who are not receiving a colonystimulating factor may benefit from the addition of granulocyte colony-stimulating factor or granulocyte-macrophage colony-stimulating factor [71, 117, 118]. 7.5. Other Approaches. The role of newer generation iron chelation agents (e.g., deferasirox) is controversial. Indeed, the iron chelator deferasirox protects mice from mucormycosis and enhanced the efficacy of liposomal amphotericin B [119]. In contrast, a recent double-blinded, randomized, placebo-controlled but small size study (𝑛 = 20) mostly in haematological patients has failed to demonstrate a benefit of combination therapy of L-AMB with deferasirox. Instead, patients with mucormycosis treated with deferasirox had a higher mortality rate at 90 days. Population imbalances in this small study make generalizable conclusions difficult [120]. For these reasons, in haematological patients with mucormycosis, adjunctive treatment with deferasirox is discouraged, whereas in other patient groups it is recommended with marginal strength by ESCMID and ECMM. Other therapeutic approaches, such as hyperbaric oxygen therapy [121], lovastatin [122], or the use of new antifungal agents active against Mucorales, such as isavuconazole, have not been clinically validated.

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8. Prophylaxis Due to the lack of clinical trials and to the epidemiological differences in IFD in different transplant programs, there are no definitive recommendations for the prevention of IFD in SOT. Because of overlapping epidemiology, prevention strategies for invasive candidosis and aspergillosis must be combined in certain transplant populations. According to recent ESCMID Study Group for Infections in Compromised Hosts (ESGICH) recommendations [123], there are the following. (i) Universal prophylaxis against Aspergillus is indicated in lung or lung/heart transplant recipients. The efficacy and advantages of using nebulized lipid formulations of amphotericin B have been demonstrated. Local irritation symptoms occur in fewer than 10% of patients, and the use of salbutamol or halving the drug concentration can improve the symptoms. Alternatively, antifungal prophylaxis can be performed with azoles such as itraconazole or voriconazole. However, long term voriconazole related hepatotoxicity and skin cancer are limiting issues. (ii) No antifungal prophylaxis is required in kidney transplant recipients. (iii) In the other settings, prophylaxis against Aspergillus should only be discussed in case of specific risk factors, such as acute rejection, poor initial allograft function, hemodialysis, anastomotic problems, need for reintervention, CMV disease, excessive Aspergillus spp. in the air of the centre, or overimmunosuppression. Echinocandins, without renal toxicity and few drug-drug interaction favors over L-amphotericin B in high risk liver, pancreas or intestinal transplant recipients. Itraconazole has been shown to be effective among high risk heart transplants. There is no agreement about the prevention strategy for late IA (>90 days after transplant). In patients with risk factor of late IA as chronic rejection, allograft dysfunction due to HCV (in liver transplant), hemodialysis, overimmunosuppression, and transplant-related neoplasms prophylaxis should be considered.

9. Prognosis and Outcomes While not as high as among patients with neutropenia, twelve-week overall mortality in SOT with IMIs remains significant and ranges from 29.4% to 35.6% (compared to 46% among patients with neutropenia [63]) according to large available PATH, SAIF, or TRANSNET studies [14, 15, 124]. Furthermore, fungal species, disease extension, type of transplant procedure, time to IMIs, underlying organ damage, and treatment highly impacted mortality rate. The overall mortality rate among SOT recipients with mucormycosis is generally 38%–48% [22, 44]. In the PATH alliance database, mucormycosis was associated with the worst IMIs outcome, with more than 55% mortality rate by 12 weeks. In a review of 20 cases of fusariosis among SOT

recipients, 8 (40%) died. Finally, the outcome of S. prolificans infection is very poor, because no drug appears to be effective. In SOT patients, renal or hepatic insufficiency, malnutrition, central nervous system disease, and disseminated disease independently predicted poor outcomes [24, 124]. Moreover, among SOT patients with IA who received antifungal therapy, use of amphotericin B preparation as part of initial therapy was associated with increased risk of death [124]. Interestingly, in heart transplant recipients, there was a trend toward lower related death in early versus late cases of IA (26% versus 63%) [20]. In the TRANSNET study, liver transplant recipients were more likely to die after IA [3]. These data were confirmed in a recent retrospective single-center analysis among 106 patients with IMIs, where the 12-week mortality among liver, kidney, heart, and lung recipients was 52.4%, 47.1%, 27.8%, 16.7%, and 9.5%, respectively [6].

10. Conclusion Although their outcomes have improved in the current era, IMIs remain a significant and severe posttransplant complication in SOT recipients. Epidemiology of IMIs is changing with an increasing rate of late infection and breakthrough of emerging molds species sometimes resistant to antifungal prophylaxis. Since early diagnosis and treatment are critical, there is a need for prospective validation of the new diagnostic tools already available. Preventive strategies as patient education and information regarding environmental risk factor, special attention to health care related infections, and proper handling of immunosuppressive drugs are crucial, while waiting for more evidence based recommendations regarding optimal antifungal prophylaxis. Patient’s tailored surgical and medical antifungal treatments, taking account of transplant procedure and toxicities risks, drug-drug interactions, fungal species identification, and in some cases antifungal susceptibility are of major importance. Follow- up biomarkers or PET-CT seems to be promising tools to guide treatment.

Conflict of Interests The authors declare that there is no conflict of interests regarding the publication of this paper.

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