Keywords

1 Introduction

Solid organ transplantation (SOT) for the treatment of end-organ disease has increased over the last three decades. While novel immunosuppressive regimens have improved allograft survival and function, combined with surgical complications, these predispose transplant recipients to infectious complications [1, 2]. Invasive fungal infections (IFIs) are particularly concerning in this population due to the associated high morbidity and mortality [1]. The most common IFIs in SOT recipients are candidiasis, aspergillosis, cryptococcosis, and those caused by endemic fungi such as Blastomyces, Coccidioides, and Histoplasma [3]. The incidence of IFIs varies according to type of organ transplant, and the risk of infection changes over time based on host state of immunosuppression and many fungal factors (e.g., virulence and resistance of fungi) [2, 4]. In this chapter, we review epidemiology, clinical presentation, diagnosis, and treatment of fungal infections due to yeast and endemic fungi in SOT recipients.

2 Epidemiology

The data from the US Transplant-Associated Infection Surveillance Network (TRANSNET) estimated that invasive candidiasis (IC) was the most common (53%) IFI, followed by invasive aspergillosis (19%) in most organ transplants. The exception was for lung transplants where aspergillosis was more common than IC. Cryptococcosis (8%) was the third most common IFI, and endemic fungi accounted for 5.3% of IFIs, whereas other yeasts accounted for less than 3% of the IFIs (Table 13.1) [3].

Table 13.1 Frequency of yeast and endemic fungal infections by type of transplant from the TRANSNET study [3]
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Candida is a normal commensal of humans and becomes pathogenic when the host immune system is compromised. Candida colonization and biofilm formation on human tissues, intravascular catheters, implants, and prosthetic material support IC [5, 6]. Donor-derived infections by Candida have been reported [7]. Among infections caused by Candida species in SOT recipients, C. albicans was the most common isolate (46.3%), followed by C. glabrata (24.4%) and C. parapsilosis (8.1%) [8]. Resistance to azoles and echinocandins is increasing, and previous data suggested that prior exposures to azole or echinocandins lead to the development resistance and increased incidence of infections due to non-albicans Candida in SOT recipients [9,10,11,12]. C. auris is an emerging multidrug-resistant yeast in the healthcare settings in the USA and other parts of the world (Spain, South America, and Asia) [13].

Cryptococcal infections occur due to the inhalation of the aerosolized basidiospores from soil or avian excreta, although rarely it can be transmitted from donor organs and tissue grafts [14]. Most infections are caused by C. neoformans although infections due to C. gattii have emerged in North America since 1999 where it was in the past more typical of tropical and subtropical areas [15]. Cryptococcosis causes approximately 8% of IFIs in SOT recipients [3] and has an overall mortality of 14% at 90 days after diagnosis in this population [16]. The median time to cryptococcosis ranges between 16 and 21 months posttransplantation, although time to onset was earlier (<12 months) in liver and lung transplant recipients possibly related to the more intense immunosuppression they receive compared to other types of transplants [16, 17]. A recent multicenter study suggested that lung transplant recipients are at highest risk of cryptococcosis [18]. When infection occurs in the first 30 days posttransplantation, donor-derived cryptococcosis should be considered [14].

Endemic fungal infections can occur in patients who reside or have resided in endemic areas and occur posttransplantation with a median time of 343 days. Histoplasmosis is caused by H. capsulatum and is endemic to the Ohio and the Mississippi River valleys in the USA and has been isolated in many parts of the world particularly around river valleys. Blastomycosis, caused by B. dermatitidis, is also seen in the Ohio-Mississippi River Valley. Histoplasmosis or blastomycosis occurs only in about 0.5% of transplant patients in endemic areas [19]. Coccidioidomycosis is endemic in the Southwestern United States, New Mexico, western Texas, and some parts of Central and South America [20] and is caused by two species: C. immitis and C. posadasii. The disease may be primary or secondary to reactivation of a latent infection [20] and may occur in up to 8% of transplant patients in endemic areas [21]. Other yeasts or endemic fungi that have been rarely reported in SOT recipients include Trichosporon, Rhodotorula, Malassezia, Hansenula, and paracoccidioidomycosis [22].

3 Timing and Risk Factors for Fungal Infections

The timing of IFIs posttransplantation is typically divided into three intervals based on the risk and type of IFIs: early (0–1 month), intermediate (1–6 months), and late (>6 months). Infections in the early interval are similar to that in non-immunocompromised patients postoperatively, usually due to surgical complications, nosocomial, or donor-derived infections [3]. Candida species are the common cause of IFIs in the early period. The intermediate interval has the most frequent IFIs as immunosuppression plays a major role, while the effects of surgical and nosocomial factors decrease. IC is less common, while mold infections due to aspergillosis, mucormycosis, scedosporiosis, or other molds predominate [3]. By late stage when 80% of SOT recipients are maintained on minimal chronic immunosuppression, the risk of IFIs declines [2]. The predominant fungal pathogens in this interval are Cryptococcus and endemic fungi, but mold infections such as aspergillosis and mucormycosis are possible and may occur at any time posttransplantation [3, 17].

The net state of immunosuppression is an important determinant of the overall risk of infection and involves a number of host and environmental factors. Host factors include underlying immune defects; extrinsic factors such as loss of integrity of mucocutaneous barriers and surgical complications; dose, duration, and sequence of immunosuppressive therapy; and environmental exposures to specific pathogens (Table 13.2) [23, 24]. Other risk factors that are specific to the type of organ transplant include the type of anastomosis or drainage, intensity of immunosuppression especially in the immediate posttransplantation period, and postoperative complications (anastomotic leak, ischemia, thrombosis, fluid collection, and the presence of foreign bodies) (Table 13.3) [2, 23,24,25,26,27,28,29,30,31,32,33,34,35,36].

Table 13.2 Risk factors of yeast and endemic fungal infections in SOT recipients and “net state of immunosuppression” [23, 24]
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Table 13.3 Specific risk factors of yeast and endemic fungal infections per type of solid organ transplant [3, 23, 26,27,28,29,30,31,32,33,34,35,36]
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Several immunosuppressive agents are used in SOT recipients including cyclosporine, tacrolimus, mycophenolate mofetil, azathioprine, as well as antithymocyte globulin (ATG) or monoclonal antibodies such as alemtuzumab, basiliximab, or rituximab in order to avoid or minimize the use of glucocorticoids [36, 37]. Calcineurin inhibitors (CNIs) (such as cyclosporine and tacrolimus) have synergistic antifungal activity against C. neoformans isolates, and thus, cryptococcal disease in SOT recipients manifests with skin and soft tissue disease rather than CNS disease owing to the antifungal activity of tacrolimus at 37–39 °C and the lower skin temperatures [38]. Episodes of rejection pose a particular risk for IFIs as patients receive pulse doses of glucocorticoids, intensified immunosuppressive therapy, ATG, and monoclonal antibodies as well as they experience high rates of cytomegalovirus (CMV) reactivation which can contribute to IFIs and immunosuppression [37].

Donor-derived yeast infections have been reported due to Candida and Cryptococcus among other fungi. Also, Candida contamination of preservation fluid has been associated with posttransplantation infections in renal and liver transplant recipients [39, 40]. In a study of graft-site infections in renal transplant recipients, the incidence was 1 case per 1000 grafts [41]. A recent case of C. auris was transmitted during lung transplantation [42]. Of note, early cases of cryptococcosis were reported posttransplantation especially in liver transplant recipients that were attributed to unrecognized pretransplant or donor-derived infections [14]. Donor-derived infections due to Histoplasma and Coccidioides but not Blastomyces have been reported [43].

4 Clinical Manifestations

4.1 Infections Due to Candida

Candida colonizes skin, respiratory, gastrointestinal, and genitourinary tracts. Colonization usually precedes IC, and the infection depends on the breach of integrity of mucocutaneous barriers, the virulence of infecting strain, and the intensity of immunosuppression [4]. Candidemia is the most common form of IC in SOT recipients (64%), followed by urinary tract infections (11%) and peritonitis (9%) [3, 11]. Candidemia may occur due to translocation across damaged intestinal barriers or from central venous catheters (CVC) [2, 44]. Intra-abdominal infections are particularly common among liver, pancreas, and small bowel transplant recipients [3]. Intra-abdominal manifestations include biliary, perirenal, and peritoneal infections. Bilomas, in liver transplant recipients, may result from Candida and can lead to the loss of liver transplant function [4, 45].

Candida may cause anastomotic tracheobronchitis in lung transplant recipients and sternal wound infections in heart and lung transplant recipients [46]. Asymptomatic Candida colonization is common in renal transplant recipients; however, the need for indwelling catheters can result in ascending renal parenchymal infection or ureteral fungal balls due to Candida species [26]. Of note, infections of allograft vascular anastomosis have been reported in renal [41], pancreatic [47], heart, and lung transplants [48].

4.2 Infections Due to Cryptococcus

The two major sites of cryptococcosis in SOT recipients are the lungs and the central nervous system (CNS). Other sites that can be involved include the skin and soft tissues, bones, joints, liver, kidney, and prostate [49]. Isolated pulmonary infection is seen in 33% of SOT recipients [16]. Lung disease ranges from asymptomatic colonization to pneumonia leading to respiratory failure [49]. Endobronchial disease is an increasingly recognized disease [50]. Extrapulmonary dissemination was seen in 61% of SOT recipients, and liver transplant recipients have a sixfold higher risk for dissemination [16]. Cryptococcal meningitis was seen in 44% of SOT recipients with cryptococcosis and had a mortality of 26% [18]. Predictors of CNS involvement in SOT recipients include late-onset disease >24 months posttransplantation, altered mental status, and serum cryptococcal antigen (CrAg) titer >1:64 [51].

Skin manifestations are diverse and may include nodules, papules, pustules, abscess, and necrotizing cellulitis commonly in the lower extremities [52]. The use of calcineurin inhibitors is associated with fewer CNS infections and more cutaneous manifestations [17]. Immune reconstitution inflammatory syndrome (IRIS) is an uncommon manifestation and results from rapid reduction of immunosuppressive therapy when initiating antifungal therapy in SOT recipients and mimics worsening cryptococcosis or antifungal failure [53]. It may present as lung nodules, hydrocephalus, cerebral mass lesions, aseptic meningitis, lymphadenitis, or cellulitis [52, 53].

4.3 Infections Due to Endemic Fungi

Infections due to endemic fungi result from environmental exposures and enter into the body through the lungs. Pneumonia is common, and fulminant multilobar pneumonia, acute respiratory distress syndrome (ARDS), and respiratory failure are feared complications [20]. The most common presentation of blastomycosis in SOT is pneumonia, but extrapulmonary dissemination of the skin, musculoskeletal system (MSK), genitourinary, or CNS disease is seen in almost 50% of SOT recipients [3, 19, 54]. Clinical manifestations of coccidioidomycosis range from pneumonia to disseminated disease. Extrapulmonary disseminated disease in SOT recipients involves the skin, MSK, and CNS and occurs in about 1–5% [55]. Those of African, Filipino, or Native American descent, males, pregnant women, and immunosuppressed are at increased risk [55]. Histoplasmosis can involve any organ but most commonly presents with disseminated disease in SOT patients. Clinical findings usually underestimate the severity and burden of disease [19].

4.4 Infections Due to Other Yeasts

Other yeasts that are rare in SOT recipients include Trichosporon, Rhodotorula, and Malassezia. T. asahii is associated with intravenous catheter-related infections [56]. Rhodotorula and Malassezia have been associated with fungemia and disseminated disease [22]. Table 13.4 outlines the clinical manifestations of yeast infections in SOT recipients [3, 14, 17,18,19,20, 52, 53, 57,58,59,60,61,62].

Table 13.4 Clinical manifestations of yeast and endemic fungal infections in SOT recipients [3, 14, 17,18,19,20, 52, 53, 57,58,59,60,61,62]
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5 Diagnosis and Monitoring

Diagnosis of IFIs in SOT recipients is challenging due to their nonspecific signs and symptoms owing to impaired inflammatory responses as a result of immunosuppression and the lack of highly sensitive and specific diagnostic modalities. Early diagnosis is key to successful outcomes, and physicians should have a high index of suspicion based on risk factors and epidemiology of these pathogens [23]. IFIs are categorized into proven, probable, and possible based on specific cytologic/histopathologic findings and host, clinical, radiographic, and microbiological criteria [63].

Histopathological demonstration of tissue invasion by fungal elements helps to establish proven disease, and special stains may be utilized. Isolation of Candida from blood cultures (which has a sensitivity of 50–70% [35]) or sterile sites is indicative of true infection, while Candida isolated from nonsterile sites usually represents colonization which could indicate infection in the right context but also is a risk factor for future invasive candidiasis [41]. Diagnosis of anastomotic tracheobronchitis in lung transplant recipients is to be based on direct visual examination, histopathological confirmation, and positive cultures [64]. Otherwise, the recovery of Candida species in sputum rarely indicates disease in the lungs [35, 64]. Isolation of other yeasts such as C. neoformans, H. capsulatum, B. dermatitidis, and C. immitis even without clinical findings suggests disease and calls for additional testing. SOT recipients suspected to have cryptococcosis should undergo evaluation with a lumbar puncture (LP), blood and urine cultures, and bronchoalveolar lavage (BAL) with or without biopsy [58]. Species identification and drug susceptibilities help to decide on antifungal therapy and to predict clinical outcomes.

Sensitivity of Histoplasma urine and serum antigen exceeds 90% in immunocompromised patients with disseminated disease and is at least 59% in pulmonary disease [65]. Similarly, Blastomyces Ag detection assays in urine, blood, or BAL have a sensitivity of >90%. Ag detection assays for Histoplasma and Blastomyces in BAL may cross-react with each other [66]. IgM (detected by tube precipitin method, immunodiffusion, latex agglutination, and enzyme immune assay (EIA)) and IgG complement-fixing antibody serology tests for Coccidioides are very sensitive and specific to diagnose coccidioidomycosis and to define the severity of disease [55]. Diagnosis and management of suspected meningeal coccidioidomycosis require an LP and cerebrospinal fluid (CSF) analysis for CSF complement-fixing IgG antibodies [20]. Table 13.5 shows the different laboratory and radiographic diagnostic modalities for yeast infections [20, 35, 49, 58, 64, 67,68,69].

Table 13.5 Diagnosis of yeast and endemic fungal infections in SOT recipients [20, 35, 49, 58, 64, 67,68,69]
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6 Treatment and Prevention

6.1 Prophylaxis and Prevention

Preventive strategies have been developed in SOT patients at high risk of opportunistic IFIs [70]. There is no current recommendation to start universal prophylaxis to prevent IC in SOT recipients, and a targeted approach is based on type of transplant and other risk factors [35]. Similarly, there is no recommendation to start primary antifungal prophylaxis for cryptococcosis. However, secondary prophylaxis is recommended in some cases [49]. Primary or secondary antifungal prophylaxis for blastomycosis in SOT recipients is not currently recommended [20]. Table 13.6 shows different antifungal prophylaxis recommendations in SOT recipients [20, 35, 71,72,73,74,75,76,77].

Table 13.6 Antifungal prophylaxis of yeast and endemic fungi recommendations in SOT recipients [20, 35, 71,72,73,74,75,76,77]
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6.2 Treatment of Yeast and Endemic Fungal Infections in SOT Recipients

The choice of antifungal therapy in the treatment of candidemia should be based on the Candida species in cultures and their susceptibilities, azole exposure in the last 90 days, and history of intolerance to antifungal agents [78]. Early antifungal therapy for suspected candidemia has been associated with better outcomes in patients with candidemia [79, 80]. Fluconazole can be used as first-line in patients with mild-moderate disease and who are unlikely to have infections with fluconazole-resistance Candida species [64]. The use of an echinocandin is now strongly recommended in the treatment of candidemia [64], especially in SOT patients with hemodynamic instability or with previous exposures to azoles or colonized with Candida species resistant to azoles [81]. Liposomal amphotericin B (AmB) or an azole should be used when other IFIs are suspected due to the limited activity of echinocandins, but the use of AmB is limited but its toxicities. Monitoring drug levels is important as azoles are potent inhibitors of liver cytochrome P-450 CYP3A4 and can increase the levels of CNIs, everolimus, and sirolimus [35, 82]. Patients with candidemia should have repeated blood cultures every 48–72 h until it is cleared, and central venous catheters should be removed as soon as possible. It is also strongly recommended to do a dilated fundoscopic exam in these patients [64]. Management of anastomotic tracheobronchitis should include using inhaled or systemic AmB. Treatment of other manifestations of IC is outlined in Table 13.7.

Table 13.7 Recommendations for the treatment of yeast and endemic fungal infections in SOT recipients [20, 35, 49, 58, 64, 75,76,77, 83]
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Guidelines for the treatment of cryptococcosis in SOT patients are mostly based on clinical trial data among HIV patients [49, 58]. In order to choose the right antifungal therapy, it is essential to define the extent and severity of disease as well as the net state of immunosuppression. Identifying localized pulmonary from disseminated disease and sites of involvement including CNS helps to define the extent of disease. When meningeal disease is suspected, an LP should be done for CSF analysis, CSF CrAg, and opening pressure. This can also have therapeutic implications to relieve elevated intracranial pressure (ICP) to ≤20 cm.

Patients with localized pulmonary cryptococcal disease, even if asymptomatic, should be treated with fluconazole for 6–12 months. Treatment of severe, diffuse pulmonary disease or disseminated disease should follow the treatment of cryptococcal meningoencephalitis [49]. Similar to cryptococcosis, treatment for blastomycosis [75], coccidioidomycosis [77], and histoplasmosis [76] is based on IDSA guidelines and is based on the site of involvement and severity of disease. Table 13.7 shows the treatment recommendations of IFIs in SOT recipients [20, 35, 49, 58, 64, 75,76,77, 83].