Fungal infections following lung transplantation

INTRODUCTION — Lung transplantation is an effective treatment for a wide range of advanced lung diseases. While the survival of lung transplant recipients continues to improve [1], outcomes after lung transplantation remain inferior to other types of solid organ transplantation. Infectious complications contribute substantially to morbidity and mortality following lung transplantation.

Fungal infections are a frequent complication in lung transplant recipients, with one-year cumulative incidence of 8.6 percent [2]. Aspergillus and Candida spp cause the majority of fungal infections in lung transplant recipients; Cryptococcus spp, the agents of mucormycosis, endemic fungi (Histoplasma, Coccidioides, and Blastomyces spp), Scedosporium spp, Fusarium spp, and dematiaceous molds are other important causes (table 1) [3,4].

This topic reviews fungal infections in lung transplant recipients. Bacterial, viral, and mycobacterial infections in lung transplant recipients, as well as the evaluation, treatment, and prophylaxis of infection in solid organ transplant recipients, are reviewed separately. (See "Bacterial infections following lung transplantation" and "Prevention of cytomegalovirus infection in lung transplant recipients" and "Tuberculosis in solid organ transplant candidates and recipients" and "Nontuberculous mycobacterial infections in solid organ transplant candidates and recipients" and "Evaluation for infection before solid organ transplantation" and "Infection in the solid organ transplant recipient" and "Prophylaxis of infections in solid organ transplantation".)

RISK OF INFECTION — Lung transplant recipients are at high risk of infectious complications due to the following factors:

●The high level of immunosuppression required to prevent rejection

●Adverse effects of transplantation on local pulmonary host defenses (loss of lymphatics, reduced mucociliary clearance, decreased cough)

●Constant environmental contact allowing pathogens direct access into the allograft

The likelihood and type of infection varies with the degree of host immunosuppression, timing since transplantation, nature and duration of antimicrobial prophylaxis, local hospital and regional microbiology, and active or latent infections in the donor. Pneumonia is the most common type of infection in lung transplant recipients. Bacterial, viral, fungal, and mycobacterial infections all occur at an increased frequency after lung transplantation. (See "Bacterial infections following lung transplantation" and "Prevention of cytomegalovirus infection in lung transplant recipients" and "Tuberculosis in solid organ transplant candidates and recipients" and "Nontuberculous mycobacterial infections in solid organ transplant candidates and recipients".)

The majority of non-Candida fungal infections are acquired through inhalation. Pretransplant colonization, particularly with filamentous molds (eg, Aspergillus spp), also increases the risk of post-transplant pulmonary fungal infection. (See 'Risk factors' below.)

In addition to the direct morbidity and mortality caused by infectious complications, they may also lead to loss of allograft function and contribute to the development of bronchiolitis obliterans syndrome (BOS) [5]. As an example, in a cohort of 201 lung transplant recipients in which 54 (27 percent) were colonized with Aspergillus spp, such colonization was found to be an independent risk factor for BOS on multivariate analysis (hazard ratio 1.81, 95% CI 1.03-3.19) [6]. In another study, airway colonization with Aspergillus spp, especially those that have smaller conidia, was found to be a risk factor for BOS following lung transplantation [7]. (See "Infection in the solid organ transplant recipient" and "Chronic lung allograft dysfunction: Bronchiolitis obliterans syndrome".)

TIMELINE OF INFECTION — The epidemiology of fungal infections after lung transplant varies by the nature and duration of post-transplant prophylaxis. Candidemia usually occurs during the first month following lung transplantation as a result of intensive care unit exposure, increased antibiotic use, and recent surgery. Aspergillosis occurs a median of 3.2 months following lung transplantation, with 72 percent of cases occurring within the first six months [8].

Non-Aspergillus molds (eg, Scedosporium, Purpureocillium, Scopulariopsis) are frequently isolated from respiratory samples from lung transplant recipients receiving inhaled liposomal amphotericin B prophylaxis (pretransplant 11.9 percent, post-transplant 16.9 percent) but only a minority (2.4 percent) developed an invasive fungal infection [9]. Non-Aspergillus molds may present later than Aspergillus (median 419 days post-transplant compared with 363 days post-transplant) and are associated with significantly higher mortality (60.5 versus 39.5 percent) [10]. The hospital environment itself can also be considered a risk factor for the development of fungal infection after lung transplantation, and center-specific outbreaks have been observed [11].

A general discussion of the pattern of infections seen following solid organ transplantation is discussed in detail separately (figure 1). (See "Infection in the solid organ transplant recipient".)

EVALUATION FOR INFECTION — Evaluation for infection in lung transplant recipients should follow the general guidelines used in other solid organ transplant recipients and consider the diversity of pulmonary infectious diseases including tracheobronchitis, anastomotic infection, cavitary disease, and pleural space infection. (See "Infection in the solid organ transplant recipient".)

Since pneumonia is the most common type of infection in lung transplant recipients, the diagnostic evaluation of lung transplant patients generally includes early and aggressive evaluation of the lungs as a potential source. (See "Bacterial infections following lung transplantation" and 'Diagnosis' below.)

Pleural effusions diagnosed within the first three months of transplant also warrant further investigation, particularly in patients with systemic signs of infection. Although often presumed to be benign, some pleural effusions in the early post-transplant period represent infection [12].

ASPERGILLOSIS — Aspergillus spp are the most common cause of invasive fungal infection following lung transplantation and occur more often among lung transplant recipients compared with recipients of other organs (40.5 versus 1.2 cases per 1000 patient-years among lung transplant recipients and renal transplant recipients, respectively; 4.8 cases per 1000 patient-years among all solid organ transplant recipients) [13]. Approximately 6 percent (range 3 to 15 percent) of lung transplant recipients develop aspergillosis [8,13-15].

Aspergillus fumigatus is the most common species implicated in invasive aspergillosis, but other species, such as Aspergillus terreus, Aspergillus flavus, and Aspergillus niger, also cause disease [16]. A. terreus is of particular importance because it is resistant to amphotericin B in vitro [17,18]. (See "Epidemiology and clinical manifestations of invasive aspergillosis", section on 'Microbial epidemiology'.)

Risk factors — Lung transplant recipients are at increased risk for invasive aspergillosis and other infections compared with other solid organ transplant recipients because of the higher doses of immunosuppression that are required, as well as other factors that are described above. (See 'Risk of infection' above.)

Specific risk factors for invasive aspergillosis in lung transplant recipients include [8,14,16,19,20]:

●Airway colonization with Aspergillus spp

●Airway ischemia

●Bronchiolitis obliterans (rejection)

Airway colonization with Aspergillus spp occurs in 25 to 30 percent of lung transplant recipients [14] but in approximately 50 percent among those with cystic fibrosis [21]. Cystic fibrosis patients colonized with Aspergillus pretransplant appear to have an elevated risk of Aspergillus tracheobronchitis but not of invasive pulmonary aspergillosis [21-23].

Recipients of single-lung transplants are at risk for aspergillosis in the native lung [8,24]. In a retrospective study, aspergillosis in single-lung transplant recipients was associated with significantly higher mortality than in double-lung and heart-lung transplant recipients [8]. Furthermore, single-lung transplant recipients were more likely to develop invasive aspergillosis late in the post-transplant course. Those who developed invasive aspergillosis were more likely to have chronic obstructive pulmonary disease, which predisposes to colonization with Aspergillus spp.

Risk factors for invasive aspergillosis include rejection, cytomegalovirus disease, high doses of glucocorticoids, renal failure, use of anti-T cell agents (eg, antithymocyte globulin), single-lung transplant, and colonization with Aspergillus at one year post-transplant [24,25]. (See "Infection in the solid organ transplant recipient" and "Epidemiology and clinical manifestations of invasive aspergillosis".)

Clinical manifestations — The most common acute manifestations of invasive aspergillosis in lung transplant recipients are tracheobronchitis, pneumonia, and disseminated disease. In a literature review of 78 cases of aspergillosis in lung transplant recipients, tracheobronchitis was responsible for 37 percent of cases, followed by invasive pulmonary aspergillosis (32 percent), bronchial anastomosis infections (20 percent), and disseminated infection (10 percent) [8]. Other sites of involvement may include the sinuses and/or central nervous system (CNS), and, less commonly, the vertebrae, intervertebral discs, eyes, pleural space, or skin [16]. (See "Epidemiology and clinical manifestations of invasive aspergillosis".)

Tracheobronchial aspergillosis — Tracheobronchial aspergillosis occurs most commonly in lung transplant recipients, typically within three months of transplantation [8,14,26,27].

Tracheobronchial aspergillosis can be asymptomatic and detected only by surveillance bronchoscopy [28]. Reported clinical findings have included fever, cough, wheezing, and/or hemoptysis.

The range of findings in tracheobronchial aspergillosis is varied and includes simple tracheobronchitis, obstructing bronchial aspergillosis, ulcerative tracheobronchitis, necrotizing pseudomembranous tracheobronchitis, and tracheobronchial aspergillosis with bronchopleural fistulae. Tracheobronchial aspergillosis may also progress to invasive and disseminated disease [8]. Tracheobronchial disease can occur early post-transplant at the vulnerable anastomotic site, can be a complication from the use of airway stents, and can lead to airway dehiscence [29,30].

Pulmonary aspergillosis — Pulmonary aspergillosis generally occurs later than tracheobronchial aspergillosis, with median time to diagnosis of six months post-transplant [31]. Symptoms include fever, dry cough, and dyspnea with or without hemoptysis [16]. Physical exam findings are consistent with pneumonia.

Other sites — After the lungs and airways, other common sites of invasive aspergillosis in lung transplant recipients include the sinuses, orbits, and CNS [16]. Rarer manifestations include vertebral osteomyelitis, discitis, endophthalmitis, empyema, retroperitoneal or intra-abdominal abscess, pericarditis, and skin lesions. In a literature review that included 78 lung transplant recipients with aspergillosis, disseminated infection occurred in 10 percent of patients [8].

Diagnosis — Given the increased risk of pulmonary fungal infections in lung transplant recipients, many centers employ frequent early surveillance bronchoscopies to examine the anastomosis as well as fungal staining and culture of bronchoalveolar lavage (BAL) fluid (table 2). Practices for surveillance bronchoscopy vary widely by transplant center. At centers that routinely perform bronchoscopy, the primary purpose is to evaluate for allograft rejection although BAL provides an opportunity for extensive microbiologic sampling of the allograft. In addition, diagnostic bronchoscopies performed based upon clinical need (respiratory symptoms, radiographic abnormalities) are useful for the diagnosis of fungal infection.

The diagnosis of tracheobronchial aspergillosis is made by visualization of erythema, pseudomembranes, or ulcerations on bronchoscopy with confirmation by histopathology and/or fungal culture (picture 1) [32]. Bronchoscopy may also identify airway dehiscence, which can be a complication of tracheobronchial aspergillosis. Chest computed tomography (CT) can help define the extent of lung involvement.  

Although definitive diagnosis of invasive pulmonary aspergillosis requires a biopsy demonstrating tissue invasion, evidence of a mold in the airway is suggestive of invasive infection in the right clinical context, such as when there are chest CT findings that are consistent with invasive infection. In lung transplant recipients, BAL and/or transbronchial lung biopsy is helpful in proving the diagnosis but cultures and/or fungal stains are positive in only 50 to 70 percent of cases [33]. CT scan findings range from consolidation (40 percent) to cavitary lesions (30 percent) to nodular or mass-like lesions (30 percent) (picture 2) [8]. Detection of fungal antigens such as galactomannan has been used to increase the sensitivity of detecting Aspergillus from BAL fluid. However, a positive BAL galactomannan is not specific for invasive disease because poor airway clearance can be associated with colonization alone. (See 'Galactomannan, beta-D-glucan, and PCR' below.)

CT or magnetic resonance imaging of the CNS is advised in lung transplant recipients with invasive pulmonary aspergillosis to evaluate for dissemination among patients where suspicion for CNS disease exists based on a careful neurologic exam or in patients where a neurologic exam may be unreliable. Tracheobronchitis, however, would not warrant CNS imaging unless CNS symptoms or signs were present.

Galactomannan, beta-D-glucan, and PCR — Data are limited regarding the utility of the galactomannan antigenemia assay, the beta-D-glucan assay, or the polymerase chain reaction (PCR) for the diagnosis of invasive aspergillosis in lung transplant recipients. One study evaluated the serum galactomannan assay in 70 lung transplant recipients through prospective monitoring with biweekly monitoring. Using an index cut-off value of ≥0.66, the assay had a sensitivity of 30 percent and a specificity of 95 percent, with false positives typically occurring in the first week post-transplant [34]. None of the four patients with tracheobronchial aspergillosis had a positive serum galactomannan assay.

Another prospective study evaluated the galactomannan assay in 333 bronchoalveolar lavage samples from 116 lung transplant recipients, two of whom had proven invasive aspergillosis, and four of whom had probable invasive aspergillosis [35]. Using an index cut-off value of ≥1, the assay had a sensitivity of 60 percent and a specificity of 98 percent [35].

A retrospective study compared the performance of an Aspergillus real-time PCR assay with the galactomannan assay in 150 BAL specimens from lung transplant recipients who underwent bronchoscopy for surveillance or diagnostic evaluation [36]. Of these, 16 patients had proven or probable invasive pulmonary aspergillosis, 26 had Aspergillus colonization, 11 had non-Aspergillus mold colonization, and 97 were negative controls. The sensitivity and specificity of a pan-Aspergillus spp PCR for diagnosing invasive pulmonary aspergillosis were 100 and 88 percent, respectively. In comparison, the sensitivity and specificity of an A. fumigatus-specific PCR were 85 and 96 percent, respectively, and the sensitivity and specificity of the galactomannan assay (using a cut-off value ≥0.5) were 93 and 89 percent, respectively.

Beta-D-glucan is a cell wall component of many fungi. A serum assay for beta-D-glucan is available and can be used to screen for invasive fungal infections, including those caused by Aspergillus spp, Candida spp, Pneumocystis, and other fungi. However, it has not been adequately studied in lung transplant recipients. While we do not routinely use or recommend using beta-D-glucan testing to diagnose aspergillosis, an elevated level corroborates the diagnosis.

These assays are discussed in greater detail separately. (See "Diagnosis of invasive aspergillosis".)

Treatment — Treatment of invasive aspergillosis involves antifungal therapy, most often with voriconazole, although other antifungal agents can be used [37,38]. In addition, immunosuppression should be reduced whenever possible. (See "Treatment and prevention of invasive aspergillosis".)

Tracheobronchial aspergillosis — Treatment of tracheobronchial aspergillosis involves systemic therapy with voriconazole in combination with nebulized amphotericin B; in addition, debridement of the bronchial anastomosis is often necessary when a substantial amount of necrotic tissue is present [29,37]. The use of voriconazole is discussed in the following section. (See 'Pulmonary and disseminated aspergillosis' below.)

Bronchoscopic debridement is an important component of therapy for tracheobronchial aspergillosis when a substantial amount of necrotic debris is present at the bronchial anastomosis, particularly when there is risk of airway obstruction. When there are ulcerations or bronchitis in the absence of devitalized tissue, there is no role for debridement.

Nebulized amphotericin B products may help treat the devascularized anastomotic site when this is the site of infection, although its therapeutic efficacy has not been proven. Anecdotal reports have described the use of combined systemic and inhaled antifungal agents in the treatment of anastomotic infection resulting in resolution of disease [39]. Occasionally, stenting is required to maintain airway patency.

Duration of therapy for tracheobronchial aspergillosis has not been adequately studied and is based on the extent and invasiveness of the infection, the host immune status, and the response to therapy. In uncomplicated cases, at least three months of voriconazole and nebulized amphotericin B or amphotericin B lipid complex are typically given, with longer durations reserved for nonresolving disease [37]. Complicated cases necessitate longer therapy, with consideration of lifelong suppressive therapy, particularly when the bronchial anastomosis is involved. Patients should continue antifungal therapy until tracheobronchial aspergillosis has completely resolved [37].

Pulmonary and disseminated aspergillosis — Voriconazole is the treatment of choice for invasive aspergillosis and is recommended for this indication in the 2016 Infectious Diseases Society of America (IDSA) guidelines on the treatment of aspergillosis [37]. We typically use combination therapy with voriconazole plus an echinocandin in lung transplant recipients with severe invasive aspergillosis. Similarly, the IDSA guidelines recommend consideration of such combination therapy in the setting of severe disease. Data supporting this practice are limited; combination therapy has been best studied in those with hematologic malignancy or profound and persistent neutropenia (not specifically in lung transplant recipients) [37]. Some experts prefer monotherapy with voriconazole. (See "Treatment and prevention of invasive aspergillosis", section on 'Dosing and drug effects'.)

An important consideration when giving voriconazole (or other azoles) to solid organ transplant recipients is its significant interactions with calcineurin inhibitors (eg, tacrolimus, cyclosporine) and mTOR inhibitors (eg, sirolimus, everolimus). Azoles increase levels of these immunosuppressants. Thus, dose reduction of these immunosuppressants and careful monitoring of serum concentrations of both azoles and immunosuppressants are needed when azoles are used. Because interaction between voriconazole and sirolimus can be extreme, this combination is usually avoided. We also suggest checking a voriconazole trough concentration during the first week of therapy (eg, between days 4 and 7) in all patients receiving treatment for invasive aspergillosis; the goal concentration is >1 mcg/mL and <5.5 mcg/mL. (See "Pharmacology of azoles", section on 'Drug interactions' and "Pharmacology of azoles", section on 'Voriconazole'.)

The treatment of invasive aspergillosis is discussed in greater detail separately. (See "Treatment and prevention of invasive aspergillosis".)

Outcomes — Historically, there was a high mortality with invasive aspergillosis (over 50 percent) in lung transplant recipients, but this varies depending upon the site of infection and has likely been reduced with the availability of newer antifungal azoles [8,28]. The mortality is lower in those with tracheobronchitis compared with invasive pulmonary infections [14].

OTHER FUNGAL INFECTIONS — In addition to Aspergillus spp, other important causes of invasive fungal infection in lung transplant recipients include Candida spp, Cryptococcus spp, endemic fungi, and the agents of mucormycosis; rarer causes are Fusarium spp, Scedosporium spp, and dematiaceous molds (table 1) [3,4,40].

Candidiasis — Candidiasis usually manifests as candidemia during the first month following transplantation as a result of intensive care unit exposure and the recent transplant surgery. In addition to candidemia, other manifestations include invasive disease, pleural space infections, incision site infections, and local anastomotic site infections [39,41]. In a survey of bloodstream infections following lung transplantation, Candida was the second most common isolate [41]. Despite frequent oropharyngeal colonization and isolation from sputum or bronchoalveolar lavage specimens, invasive pulmonary disease caused by Candida spp is exceedingly rare. (See "Clinical manifestations and diagnosis of candidemia and invasive candidiasis in adults" and "Candida infections of the abdomen and thorax".)

Cryptococcosis — Both pulmonary, central nervous system, and disseminated cryptococcal infection may occur in lung transplant recipients (image 1). The 12-month cumulative incidence of cryptococcosis following solid organ transplantation is estimated at 0.2 percent [2]. The risk of cryptococcosis is estimated to be highest in lung transplantation recipients (0.66 percent) compared with liver, heart, and kidney transplantation (0.44, 0.42, and 0.32 percent, respectively; hazard ratio 2.10, 95% CI 1.21-3.60) [42]. The median time to onset of disease after lung transplantation was approximately 190 days (range 7.5 to 1816).

Immune reconstitution inflammatory syndrome (IRIS) following initiation of treatment of cryptococcal disease in solid organ transplant recipients has been reported and should be considered as a potential complication of cryptococcosis [43]. Reduction of immunosuppression may have contributed to the development of IRIS in some cases. Cryptococcal cellulitis has been reported in lung transplant recipients [44]. (See "Cryptococcus neoformans infection outside the central nervous system" and "Epidemiology of pulmonary infections in immunocompromised patients" and "Cryptococcus neoformans: Treatment of meningoencephalitis and disseminated infection in patients without HIV", section on 'Immune reconstitution inflammatory syndrome'.)

Mucormycosis — Mucormycosis is another cause of invasive fungal infections in immunocompromised hosts. Presentation in lung transplant recipients typically consists of pulmonary disease, although bronchial anastomosis infection and gastrointestinal disease have also been reported (image 2) [3,45,46].

Mucormycosis is characterized by infarction and necrosis of host tissues that results from invasion of the vasculature by hyphae. The progression is usually fast and the outcome in patients with pulmonary mucormycosis is poor, with mortality rates as high as 87 percent. Treatment of mucormycosis involves a combination of surgical debridement of involved tissues and antifungal therapy. (See "Mucormycosis (zygomycosis)", section on 'Treatment'.)

Endemic fungi — Endemic fungi that cause infection following solid organ transplantation include Histoplasma capsulatum, Coccidioides immitis, and, rarely, Blastomyces dermatitidis [47]. Infections with endemic fungi may occur as a result of reactivation of dormant infection, new acquisition from the environment, or transmission from donors from endemic areas. (See "Infection in the solid organ transplant recipient".)

When endemic fungal infection occurs in solid organ transplant recipients, severe pneumonia and disseminated disease are more likely and the mortality is higher compared with immunocompetent hosts [48]. (See "Pathogenesis and clinical features of pulmonary histoplasmosis" and "Clinical manifestations and diagnosis of blastomycosis" and "Management considerations, screening, and prevention of coccidioidomycosis in immunocompromised individuals and pregnant patients" and "Primary pulmonary coccidioidal infection".)

Pneumocystis jirovecii — Approximately 5 to 15 percent of patients who undergo solid organ transplantation develop Pneumocystis jirovecii (formerly P. carinii) pneumonia (PCP) in the absence of prophylaxis [49-52]. The rates are highest among lung and heart-lung transplant recipients [49,50,53,54].

The period of highest risk for PCP following solid organ transplantation is from one to six months following transplantation if prophylaxis is not given. The incidence of PCP has decreased dramatically due to nearly universal prophylaxis, which is typically given indefinitely. (See "Epidemiology, clinical manifestations, and diagnosis of Pneumocystis pneumonia in patients without HIV".)

PROPHYLAXIS

Invasive fungal infections

Approach to prophylaxis — We provide antifungal prophylaxis for most patients in the early post-transplant period because the risk of fungal infection during this period and its associated morbidity is high [55]. However, providing antifungal prophylaxis to all patients is not universal practice [56-60]. The American Society of Transplantation recommends either a universal prophylaxis or pre-emptive monitoring strategy for invasive aspergillosis in lung transplant recipients. Although data to guide the best approach are limited [38,61], most centers in the United States use universal prophylaxis [62].

Our approach to prophylaxis is as follows:

●We use inhaled liposomal amphotericin B for all patients because the potential benefit of decreased fungal infection appears to outweigh the risks. Typically, we use inhaled amphotericin B lipid complex in extubated patients, dosed at 100 mg nebulized daily for four days post-transplant and then 50 mg nebulized weekly until hospital discharge [63,64].

●We add an azole for most patients to prevent infection with Candida spp, particularly surgical site infections (eg, empyema); use of inhaled amphotericin alone is rare.

Azole selection varies based on risk factors for mold infection (eg, a history of mold infection or current of past colonization with mold). (See 'Risk factors for mold infection' below and 'Systemic azoles' below.)

•For patients without risk factors for mold infection, we generally use fluconazole for three months following transplantation. However, if the chest is left open, we use an echinocandin (micafungin, caspofungin, anidulafungin) or fluconazole until the chest is closed.

•For patients with risk factors for mold infection, we use a broader spectrum azole (eg, voriconazole, posaconazole, isavuconazole). While voriconazole is most often used, selection varies based on patient comorbidities.

For patients with a history of mold colonization or infection, we begin prophylaxis when the patient is listed for transplant and continue for at least three months post-transplant. Longer or shorter durations might be appropriate, depending on the clinical context and burden of disease.

●We reinitiate antifungal prophylaxis for patients receiving immunosuppression augmentation with thymoglobulin, alemtuzumab, or high-dose glucocorticoids [37].

In addition to nebulized or systemic antifungal prophylaxis, nystatin suspension (5 cc swish and swallow four times daily for six months following transplantation) is often used to reduce gastrointestinal colonization with Candida spp. We use nystatin in patients who are not receiving a systemic antifungal agent.

The approach to universal prophylaxis varies among centers and not all use inhaled amphotericin in addition to systemic antifungal agents. Transplant centers that use a pre-emptive approach typically perform fungal culture and galactomannan testing on bronchoalveolar lavage fluid obtained on routine bronchoscopy for the first three to four months following transplantation.

Risk factors for mold infection — The most important risk factors for mold infection in the early post-transplant period are:

●A history of mold infection or colonization

●Detection of mold in the airway at the time of transplantation

●Detection of mold in the airway on post-transplant surveillance bronchoscopy

Several other patient groups may be at higher risk for fungal infections after lung transplantation [61]. These include recipients of a single-lung transplant, patients with early airway ischemia, patients whose sinuses are colonized with mold, patients with concurrent cytomegalovirus infection, patients with rejection requiring increased immunosuppression (eg, antithymocyte globulin), patients with delayed sternal closure, patients requiring renal replacement therapy, patients on extracorporeal membrane oxygenation, and patients with acquired hypogammaglobulinemia (immunoglobulin [Ig]G <400 mg/dL.) In such individuals, systemic antifungal prophylaxis is likely warranted. Further study is necessary to better define the benefits of antifungal prophylaxis in these patient groups.

Antifungal agents and their efficacy

Inhaled amphotericin B — We prefer inhaled lipid complex amphotericin B (eg, liposomal amphotericin B, amphotericin B lipid complex) to inhaled amphotericin B deoxycholate since the former agent appears to be associated with a lower rate of adverse effects and also has a longer half-life and improved lung deposition. Because inhaled therapy has minimal side effects and coverage against a broad range of fungal pathogens, we use this agent in nearly all patients in the early post-transplant period.

Efficacy data are limited in observational studies, which show reduced rates of invasive fungal infection with nebulized amphotericin use [19,63,65-67]. However, reduced infection rates were not observed in all studies [68] and there are disadvantages to utilizing inhaled therapy alone. At least one center that practices this approach reported a relatively high incidence of fungal pleural space infections in the early post-transplant period, suggesting that a disadvantage of inhaled therapy is the failure to prevent systemic fungal infections, including pleural space infections [12,57].

Systemic azoles — Fluconazole is active against many Candida spp but has limited to no activity against molds. Thus, we use fluconazole for patients without risk factors for mold.

For patients who have respiratory tract colonization with mold (especially Aspergillus spp), we use an oral azole that has activity against molds, such as voriconazole, isavuconazole, or posaconazole.

●Voriconazole is given as a loading dose of 6 mg/kg intravenously (IV; or 400 mg orally) every 12 hours for two doses, then 4 mg/kg IV (or 200 mg orally) every 12 hours.

●Isavuconazole is given as a loading dose of 372 mg by mouth (isavuconazonium sulfate 372 mg IV) every eight hours for six doses, then 372 mg once daily.

●Posaconazole is given as a loading dose of 300 mg (by mouth/IV) twice daily for two doses, then 300 mg once daily. When administering posaconazole orally, we use the delayed-release formulation because it is better absorbed than other formulations. However, the extended-release form cannot be given to intubated patients; while the liquid form can be given via an endotracheal tube, absorption is erratic. In these cases, at our center, we either use the IV formulation of posaconazole or switch to another azole.

When azoles are used, the clinician must be aware of their significant interactions with calcineurin inhibitors (tacrolimus, cyclosporine) and mTor inhibitors (eg, everolimus, sirolimus) and reduce the dose of the immunosuppressant agent accordingly. We also perform therapeutic drug monitoring to ensure adequate absorption.

A small retrospective study evaluated the use of antifungal prophylaxis in lung transplant recipients [69]. The 65 patients who received universal voriconazole prophylaxis had significantly lower rates of invasive aspergillosis at one year post-transplant than the 30 patients who received targeted itraconazole prophylaxis (with or without inhaled amphotericin) for pre- or post-transplant Aspergillus colonization except A. niger (1.5 versus 23 percent). One downside of long-term voriconazole prophylaxis is that can increase the risk of skin cancer in lung transplant recipients [70].

Posaconazole and isavuconazole are two additional azoles with activity against Aspergillus spp and other molds. In a cohort study evaluating 300 lung transplant recipients, isavuconazole appeared to be as effective as voriconazole for prevention of invasive fungal infections but was better tolerated. The breakthrough infection rate was 8 percent for both azoles; 11 percent of patients receiving isavuconazole stopped prophylaxis prematurely due to adverse effects compared with 35 percent of patients receiving voriconazole [71].

At our center, we tend to use isavuconazole in lung transplant recipient who are risk for QTc prolongation and recipients with renal impairment. Most clinical trials of isavuconazole have not shown QTc prolongation unlike other azoles [72,73]. Compared with IV voriconazole and posaconazole, isavuconazole’s prodrug, isavuconazonium sulfate, does not contain cyclodextrin, which can accumulate with renal impairment and cause toxicity [74]. A potential downside is that isavuconazole may be less effective against Candida spp when compared with other azoles [75].

Posaconazole has not been directly compared with voriconazole or isavuconazole in lung transplant recipients, but observational data suggest it is also effective and well tolerated [71,76].

Pneumocystis pneumonia — Because the risk of P. jirovecii (formerly P. carinii) pneumonia (PCP) in the allografted lung is high, indefinite prophylaxis is recommended for all recipients.

A retrospective study evaluated 25 cases of PCP among 1299 solid organ transplant recipients at a single center between 1987 and 1996 [77]. The incidence of PCP was highest among lung transplant recipients compared with other organ recipients (22 versus 4.8 cases per 1000 person-transplant years) and did not decline after the first year following transplantation, in contrast with recipients of other organs. No patients developed PCP while receiving prophylaxis but the duration of prophylaxis was shorter for the recipients of certain organs than is standard (eg, lung transplant recipients received prophylaxis for one year; liver transplant recipients did not routinely receive prophylaxis until five years into the study). A subsequent multicenter study evaluating PCP episodes between 2010 and 2017 found that the annual incidence was 2.7 cases per 1000 person-transplant years [78]. Sixty-five percent of the patients were not on PCP prophylaxis when they developed PCP infection.

The incidence of PCP among solid organ transplant recipients has decreased dramatically due to nearly universal prophylaxis. In a meta-analysis of 12 randomized controlled trials that included 1245 immunocompromised patients without HIV infection who had undergone autologous hematopoietic stem cell or solid organ transplantation or had a hematologic malignancy, trimethoprim-sulfamethoxazole (TMP-SMX) prophylaxis was associated with a 91 percent reduction in the occurrence of PCP (relative risk [RR] 0.09, 95% CI 0.02-0.32) [79]. Mortality due to PCP was also significantly reduced (RR 0.17, 95% CI 0.03-0.94), although all-cause mortality was not. No differences in efficacy were found between once-daily and thrice-weekly administration schedules for TMP-SMX. (See "Treatment and prevention of Pneumocystis pneumonia in patients without HIV", section on 'Prophylaxis'.)

Although PCP prophylaxis is highly effective, some cases have still been reported in the setting of prophylaxis. For example, in a series of 609 bronchoscopies performed (surveillance and clinically indicated) in lung and heart-lung transplant recipients at a single center from 1994 to 2002, 23 samples were positive for P. jirovecii, 15 of which were from patients receiving prophylaxis [80]. Seven of these 15 patients were taking inhaled pentamidine, which is less effective than TMP-SMX. Furthermore, two samples were positive in samples obtained from surveillance bronchoscopies, which could have represented colonization rather than infection.

TMP-SMX is recommended for all patients who can tolerate it, given its excellent efficacy and its broad spectrum against a range of organisms in addition to P. jirovecii (eg, Toxoplasma gondii, Listeria spp, Nocardia spp, Streptococcus pneumoniae) [81]. The usual dosing of TMP-SMX for lung transplant recipients is one double-strength tablet daily or three times per week, continued indefinitely. Daily dosing is needed for patients at increased risk of toxoplasmosis (donor seropositive/recipient seronegative). For those who are allergic to TMP-SMX, desensitization should be attempted when possible. Alternative regimens are discussed separately. (See "Treatment and prevention of Pneumocystis pneumonia in patients without HIV" and "Prophylaxis of infections in solid organ transplantation".)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Infections in solid organ transplant recipients".)

SUMMARY AND RECOMMENDATIONS

●Important pathogens − Aspergillus and Candida spp cause the majority of fungal infections in lung transplant recipients. Cryptococcus spp, the agents of mucormycosis, Scedosporium spp, and endemic fungi (Histoplasma, Blastomyces, and Coccidioides spp) are other important causes (table 1). (See 'Introduction' above.)

●Risk of infection − Lung transplant recipients are at high risk for infectious complications due to the high level of immunosuppression required to prevent rejection, the adverse effects of transplantation on local pulmonary host defenses (eg, reduced mucociliary clearance), and constant environmental contact allowing pathogens direct access into the allograft. (See 'Risk of infection' above.)

●Clinical features and diagnosis of aspergillosis

•Manifestations of invasive aspergillosis − The most common acute manifestations of invasive aspergillosis in lung transplant recipients are tracheobronchitis, pneumonia, and disseminated disease. (See 'Clinical manifestations' above.)

•Diagnosis of tracheobronchial aspergillosis − The diagnosis of tracheobronchial aspergillosis is made by visualization of erythema, pseudomembranes, or ulcerations on bronchoscopy with confirmation by histopathology and/or fungal culture. (See 'Diagnosis' above.)

•Diagnosis of pulmonary aspergillosis − Although definitive diagnosis of invasive pulmonary aspergillosis requires a biopsy demonstrating tissue invasion, this is not always necessary or practical. More commonly, the diagnosis of pulmonary aspergillosis is made presumptively by chest computed tomography in combination with bronchoscopy with fungal stains and cultures performed on bronchoalveolar lavage fluid. (See 'Diagnosis' above.)

●Treatment of aspergillosis

Tracheobronchial aspergillosis − For patients with tracheobronchial aspergillosis, we recommend systemic therapy with voriconazole (Grade 1B). In addition, we suggest nebulized amphotericin B (Grade 2C). Bronchoscopic debridement is an important component of therapy in patients with a substantial amount of necrotic debris at the bronchial anastomosis, particularly when there is risk of airway obstruction. (See 'Tracheobronchial aspergillosis' above.)

•Invasive aspergillosis − Voriconazole is the treatment of choice for invasive aspergillosis. We typically use combination therapy with voriconazole plus an echinocandin in lung transplant recipients with severe invasive aspergillosis. (See 'Treatment' above and "Treatment and prevention of invasive aspergillosis".)

•Important drug interactions − When voriconazole (or another azole) is used, the clinician must be aware of its significant interactions with calcineurin inhibitors (eg, tacrolimus, cyclosporine) and mTor inhibitors (eg, sirolimus, everolimus) and reduce the dose of the immunosuppressant agent or change therapy accordingly. (See "Pharmacology of azoles", section on 'Drug interactions' and "Pharmacology of azoles", section on 'Voriconazole'.)

●Antifungal prophylaxis in the early post-transplant period

•Our approach − We provide antifungal prophylaxis for most patients in the early post-transplant period because the risk of fungal infection during this period and its associated morbidity is high. However, providing antifungal prophylaxis to all patients is not universal practice. The American Society of Transplantation recommends either a universal prophylaxis or pre-emptive monitoring strategy for invasive aspergillosis in lung transplant recipients; data to guide the best approach is limited. (See 'Invasive fungal infections' above and 'Approach to prophylaxis' above.)

•Antifungal selection − We use inhaled liposomal amphotericin B for all patients because the potential benefit of decreased fungal infection appears to outweigh the risks. We add an additional systemic agent depending on the patient’s operative risk factors (eg, whether the chest was open) and risk factors for specific mold infections. (See 'Approach to prophylaxis' above and 'Risk factors for mold infection' above.)

●Pneumocystis prophylaxis − We recommend Pneumocystis jirovecii (formerly P. carinii) pneumonia prophylaxis for all lung transplant recipients (Grade 1A). The duration of prophylaxis is typically lifelong. We recommend trimethoprim-sulfamethoxazole (Grade 1A). The usual dosing is one double-strength tablet daily or one double-strength tablet three times per week, continued indefinitely. (See 'Pneumocystis pneumonia' above.)

ACKNOWLEDGMENTS — The UpToDate editorial staff acknowledges David Zaas, MD, Kieren A Marr, MD, and Cameron Wolfe, MBBS (Hons), MPH, who contributed to earlier versions of this topic review.