The incidence of invasive aspergillosis among solid organ transplant recipients and implications for prophylaxis in lung transplants

Abstract: Background. Invasive aspergillosis (IA) is associated with significant morbidity and mortality in solid organ transplant recipients but data on the incidence rates stratified by type of solid organ are limited. Objective. To describe the attack rates and incidence of IA in solid organ transplant recipients, and the impact of universal Aspergillus prophylaxis (aerosolized amphotericin B or oral itraconazole) in lung transplant recipients. Patients. The 2046 patients who received solid organ transplants at the Cleveland Clinic Foundation from January 1990 through 1999 were studied. Methods. Cases were ascertained through computerized records of microbiology, cytology, and pathology reports. Definite IA was defined as a positive culture and pathology showing septate hyphae. Probable IA was clinical disease and either a positive culture or histopathology. Disseminated IA was defined as involvement of two or more noncontiguous anatomic sites. Results. We identified 33 cases of IA (28% disseminated) in 2046 patients (attack rate = 1.6%) for an incidence of 4.8 cases per 1000 patient‐years (33 cases/6813 pt‐years). Both the attack and the incidence rates were significantly higher for lung transplant recipients vs. other transplant recipients: lung 12.8% (24 cases/188 patients) or 40.5 cases/1000‐pt year vs. heart 0.4% (3/686) or 1.4 per 1000‐pt year vs. liver 0.7% (3/439) or 2.1 per 1000‐pt year vs. renal 0.4% (3/733) or 1.2 per 1000‐pt year (P < 0.01). The incidence of IA was highest during the first year after transplantation for all categories, but cases occurred after the first year of transplantation only in lung transplant recipients. The attack rate of IA in lung transplant recipients was significantly lower after institution of routine Aspergillus prophylaxis (4.9% vs. 18.2%, P < 0.05). Conclusions. The highest incidence and attack rate of invasive aspergillosis among solid organ transplant recipients occurs in lung transplant recipients and supports the routine use of Aspergillus prophylaxis for at least one year after transplantation in this group.     

Epidemiology of fungal infections in solid organ transplant patients

The epidemiology of fungal infection in solid organ transplant patients is of concern due to the high mortality associated with this complication. Rates of fungal infections vary by type of transplant recipient. Most of these infections occur two to six months after transplantation. Liver transplant recipients are more likely to have early fungal infection which is often due to Candida species. Exogenous and endogenous Candida infection may occur in the immunosuppressed patient in the intensive care unit. Patients with chronic rejection are more likely to have late infection (after six months) which may be due to Aspergillus or endemic fungi such as Cryptococcus. Lung and heart–lung transplant recipients are more predisposed to infection with Aspergillus and other filamentous fungi, due to exposure of the transplanted organ to the external environment. Preventative measures such as environmental controls and chemoprophylaxis may be beneficial in high-risk patients. Emerging fungal pathogens such as the dematiaceous fungi may cause skin or soft tissue infection, or more serious systemic infections. Fungal infection should be ruled out in the solid organ transplant patient with early brain abscess. Characteristic risk factors in high-risk types of solid organ transplant recipients should be recognized for early diagnosis and treatment of these infections associated with high morbidity and mortality.     

Epidemiology and outcome of invasive fungal infections in solid organ transplant recipients

D. Neofytos, J.A. Fishman, D. Horn, E. Anaissie, C.‐H. Chang, A. Olyaei, M. Pfaller, W.J. Steinbach, K.M. Webster, K.A. Marr. Epidemiology and outcome of invasive fungal infections in solid organ transplant recipients.
Transpl Infect Dis 2010: 12: 220–229. All rights reserved Abstract: Contemporary epidemiology and outcomes of invasive fungal infections (IFIs) in solid organ transplant (SOT) recipients are not well described. From March 2004 through September 2007, proven and probable IFIs were prospectively identified in 17 transplant centers in the United States. A total 429 adult SOT recipients with 515 IFIs were identified; 362 patients received a single and 67 patients received ≥2 organs. Most IFIs were caused by Candida species (59.0%), followed by Aspergillus species (24.8%), Cryptococcus species (7.0%), and other molds (5.8%). Invasive candidiasis (IC) was the most frequently observed IFI in all groups, except for lung recipients where invasive aspergillosis (IA) was the most common IFI (P<0.0001). Almost half of IC cases in liver, heart, and lung transplant recipients occurred during the first 100 days post transplant. Over half of IA cases in lung recipients occurred >1 year post transplant. Overall 12‐week mortality was 29.6%; liver recipients had the highest mortality (P=0.05). Organ damage, neutropenia, and administration of corticosteroids were predictors of death. These results extend our knowledge on the epidemiology of IFI in SOT recipients, emphasizing the occurrence of IC early after non‐lung transplant, and late complications with molds after lung transplant. Overall survival appears to have improved compared with historical reports.     

Prophylactic fluconazole in liver transplant recipients. A randomized, double-blind, placebo-controlled trial

BACKGROUND: Among persons who receive solid organ transplants, liver transplant recipients have the highest incidence of invasive fungal infection; however, no antifungal prophylaxis has been proven to be effective. OBJECTIVE: To evaluate the efficacy and safety of prophylactic fluconazole in liver transplant recipients. DESIGN: Randomized, double-blind, placebo-controlled trial. SETTING: University-affiliated transplantation center. PATIENTS: 212 liver transplant recipients who received fluconazole (400 mg/d) or placebo until 10 weeks after transplantation. MEASUREMENTS: Fungal colonization, proven superficial or invasive fungal infection, drug-related side effects, and death. RESULTS: Fungal colonization increased in patients who received placebo (from 60% to 90%) but decreased in patients who received fluconazole (from 70% to 28%). Proven fungal infection occurred in 45 of 104 placebo recipients (43%) but in only 10 of 108 fluconazole recipients (9%) (P < 0.001). Fluconazole prevented both superficial infection (29 of 104 placebo recipients became infected [28%] compared with 4 of 108 fluconazole recipients [4%]; P < 0.001) and invasive infection (24 of 104 placebo recipients became infected [23%] compared with 6 of 108 fluconazole recipients [6%]; P < 0.001). Fluconazole prevented infection by most Candida species, except C. glabrata. However, infection and colonization by organisms intrinsically resistant to fluconazole did not seem to increase. Fluconazole was not associated with any hepatotoxicity. Patients receiving fluconazole had higher serum cyclosporine levels and more adverse neurologic events (headaches, tremors, or seizures in 13 fluconazole recipients compared with 3 placebo recipients; P = 0.01). Although the overall mortality rate was similar in both groups (12 of 108 [11%] in the fluconazole group compared with 15 of 104 [14%] in the placebo group; P > 0.2), fewer deaths related to invasive fungal infection were seen in the fluconazole group (2 of 108 patients [2%]) than in the placebo group (13 of 104 patients [13%]) (P = 0.003). CONCLUSIONS: Prophylactic fluconazole after liver transplantation decreases fungal colonization, prevents superficial and invasive fungal infections, and has no appreciable hepatotoxicity. Although fluconazole prophylaxis is associated with fewer deaths from fungal infection, it does not improve overall survival. Patients receiving prophylactic fluconazole require close monitoring of serum cyclosporine levels to avoid neurologic toxicity.     

Lung transplant infection

Lung transplantation has become an accepted therapeutic procedure for the treatment of end‐stage pulmonary parenchymal and vascular disease. Despite improved survival rates over the decades, lung transplant recipients have lower survival rates than other solid organ transplant recipients. The morbidity and mortality following lung transplantation is largely due to infection‐ and rejection‐related complications. This article will review the common infections that develop in the lung transplant recipient, including the general risk factors for infection in this population, and the most frequent bacterial, viral, fungal and other less frequent opportunistic infections. The epidemiology, diagnosis, prophylaxis, treatment and outcomes for the different microbial pathogens will be reviewed. The effects of infection on lung transplant rejection will also be discussed.     

Invasive filamentous fungal infections associated with renal transplant tourism

S. Shoham, F. Hinestrosa, J. Moore Jr, S. O'Donnell, M. Ruiz, J. Light. Invasive filamentous fungal infections associated with renal transplant tourism.
Transpl Infect Dis 2010: 12: 371–374. All rights reserved Abstract: ‘Transplant tourism,’ the practice of traveling abroad to acquire an organ, has emerged as an issue in kidney transplantation. We treated a patient who developed invasive aspergillosis of the allograft vascular anastomosis after receiving a kidney transplant in Pakistan, prompting us to review the literature of invasive mycoses among commercial organ transplant recipients. We reviewed all published cases of infections in solid organ transplant recipients who bought their organs abroad and analyzed these reports for invasive fungal infections. Including the new case reported here, 19 cases of invasive fungal infections post commercial kidney transplant occurring in 17 patients were analyzed. Infecting organisms were Aspergillus species (12/19; 63%), Zygomycetes (5/19; 26%), and other fungi (2/19; 5%). Invasive mold infections were present at the transplanted graft in 6/17 patients (35%) with graft loss or death in 13/17 (76%) of patients and overall mortality (10/17) 59%. Invasive fungal infections, frequently originating at the graft site, have emerged as a devastating complication of commercial renal transplant and are associated with high rates of graft loss and death.     

Trends in invasive disease due to Candida species following heart and lung transplantation

Abstract: Although invasive candidiasis (IC) causes significant morbidity and mortality in patients who undergo heart, lung, or heart–lung transplantation, a systematic study in a large cohort of thoracic organ transplant recipients has not been reported to date. Clinical and microbiological data were reviewed for 1305 patients who underwent thoracic organ transplantation at Stanford University Medical Center between 1980 and 2004. We identified and analyzed 76 episodes of IC in 68 patients (overall incidence 5.2% per patient). The incidence of IC was higher in lung (LTx) and heart–lung transplant (HLTx) recipients as compared with heart transplant (HTx) recipients (risk ratio [RR] 1.7, 95% confidence interval [CI] 1.1–2.7). The incidence of IC decreased over time in all thoracic organ transplant recipients, decreasing from 6.1% in the 1980–1986 time period to 2.1% in the 2001–2004 era in the HTx recipients, and from 20% in the 1980–1986 period to 1.8% in the 2001–2004 period in the LTx and HLTx recipients. The most common site of infection differed between the HTx and LTx cohorts, with bloodstream or disseminated disease in the former and tracheobronchitis in the latter. IC in the first year after transplant was significantly associated with death in both HTx (RR 2.9, 95% CI 1.8–4.6, P=0.001) and LTx and HLTx patients (RR 3.0, 95% CI 1.9–4.6, P<0.001). The attributable mortality from IC decreased during the 25‐year period of observation, from 36% to 20% in the HTx recipients and from 39% to 15% in the LTx and HLTx recipients. There were a significant number of cases caused by non‐albicans Candida species in all patients, with a trend toward higher mortality in the HTx group. In conclusion, the incidence and attributable mortality of IC in thoracic organ transplant recipients has significantly declined over the past 25 years. The use of newer antifungal agents for prophylaxis and treatment, the decrease in the incidence of cytomegalovirus disease, and the use of more selective immunosuppression, among other factors, may have been responsible for this change.     

Epidemiology and prevention of invasive aspergillosis

Aspergillus species are the most common causes of invasive mold infections in immunocompromised persons. This review examines the available information regarding the rising incidence of invasive aspergillosis in different high-risk groups, including persons with acute leukemia, hematopoietic stem cell transplant recipients, and liver and lung transplant recipients. The risk factors for infection in these groups are discussed. Because Aspergillus species are widespread in the environment, it is difficult to link specific sources and exposures to the development of human infections. However, molecular strain typing and other studies indicate that a significant number of Aspergillus infections are now being acquired outside the health care setting, either before patients are admitted to hospital, or after they have been discharged. The role of environmental control measures and antifungal drug prophylaxis in the prevention of hospital- and community-acquired aspergillosis is discussed.     

Necrotizing Microascus tracheobronchitis in a bilateral lung transplant recipient

Invasive fungal infections are a major cause of mortality among solid organ transplant recipients. Scopulariopsis species and their teleomorph Microascus are molds found in soil and decaying organic matter. We report here the case of a woman who underwent bilateral lung transplantation for severe emphysema. On day 25 after transplantation, endobronchial green‐black lesions were detected during routine endoscopy. Endobronchial swabs, biopsies, and bronchoalveolar lavage samples were positive for Microascus cirrosus. This fungal infection developed despite voriconazole given for previous persistent invasive aspergillosis. Treatment consisted of a combination of antifungal medication (voriconazole, terbinafine, amphotericin B, and caspofungin) and endoscopic resection of necrosed bronchial mucosa. A favorable clinical outcome was achieved after 7 weeks of treatment. Seven cases of Scopulariopsis/Microascus infection have been previously described in solid organ transplant recipients. Only two survived after treatment with an antifungal combination therapy including echinocandins, posaconazole, and terbinafine. In immunocompromised patients, infection by Microascus species is a rare but life‐threatening event because of innate resistance to most common antifungal drugs. Our patient was successfully cured by combined therapy including intravenous voriconazole and caspofungin, oral terbinafine, and inhaled voriconazole and amphotericin B administered for 7 weeks in association with iterative endoscopic debridement to reduce fungal inoculum.     

Very early‐onset of Cryptococcus neoformans disease following liver transplantation: Report of two cases and a review of the literature

Cryptococcosis is the third most common invasive fungal infection following solid organ transplantation, and mortality is high. Most cases occur late and are due to reactivation of latent infection; however, very early reactivation and donor‐derived transmission can occur. Routine screening pre‐transplant and antifungal prophylaxis for cryptococcosis post‐transplant in solid organ transplantation are not standard practice. We present two cases of very early‐onset Cryptococcus neoformans disease following liver transplantation to highlight the need to consider individualized pre‐transplant screening and be aware that reactivation of Cryptococcosis neoformans can occur in the immediate post‐transplant period.     

Fungal infections in lung transplantation

Lung transplant is a potential life-saving procedure for chronic lung diseases. Lung transplant recipients (LTRs) are at the greatest risk for invasive fungal infections (IFIs) among solid organ transplant (SOT) recipients because the allograft is directly exposed to fungi in the environment, airway and lung host defenses are impaired, and immunosuppressive regimens are particularly intense. IFIs occur within a year of transplant in 3–19% of LTRs, and they are associated with high mortality, prolonged hospital stays, and excess healthcare costs. The most common causes of post-LT IFIs are Aspergillus and Candida spp.; less common pathogens are Mucorales, other non-Aspergillus moulds, Cryptococcus neoformans, Pneumocystis jirovecii, and endemic mycoses. The majority of IFIs occur in the first year following transplant, although later onset is observed with prolonged antifungal prophylaxis. The most common manifestations of invasive mould infections (IMIs) include tracheobronchial (particularly at anastomotic sites), pulmonary and disseminated infections. The mortality rate of tracheobronchitis is typically low, but local complications such as bronchomalacia, stenosis and dehiscence may occur. Mortality rates associated with lung and disseminated infections can exceed 40% and 80%, respectively. IMI risk factors include mould colonization, single lung transplant and augmented immunosuppression. Candidiasis is less common than mould infections, and manifests as bloodstream or other non-pulmonary invasive candidiasis; tracheobronchial infections are encountered uncommonly. Risk factors for and outcomes of candidiasis are similar to those of non lung transplant recipients. There is evidence that IFIs and fungal colonization are risk factors for allograft failure due to chronic rejection. Mould-active azoles are frontline agents for treatment of IMIs, with local debridement as needed for tracheobronchial disease. Echinocandins and azoles are treatments for invasive candidiasis, in keeping with guidelines in other patient populations. Antifungal prophylaxis is commonly administered, but benefits and optimal regimens are not defined. Universal mould-active azole prophylaxis is used most often. Other approaches include targeted prophylaxis of high-risk LTRs or pre-emptive therapy based on culture or galactomannan (GM) (or other biomarker) results. Prophylaxis trials are needed, but difficult to perform due to heterogeneity in local epidemiology of IFIs and standard LT practices. The key to devising rational strategies for preventing IFIs is to understand local epidemiology in context of institutional clinical practices.     

Antifungal prophylaxis in lung transplantation

Fungal infections are among the most serious complications of lung transplantation. The 1-year cumulative incidence of invasive fungal infections in lung transplant recipients is 6 to 10%, which is higher than most other solid organ transplant recipients. Aspergillus spp. are the most common etiologic agents, but Candida spp., non-Aspergillus mycelial fungi, Cryptococcus, Pneumocystis, and endemic mycoses can cause active infections in this population. Clinical manifestations of fungal infection in lung transplant recipients are protean, and include invasive pulmonary disease, airway and anastomotic infections, posttransplant empyemas, and disseminated infections. Most centers employ either universal or targeted antifungal prophylaxis in some form, but the agents, doses, durations, and monitoring strategies vary widely from one center to another. This review discusses the salient fungal organisms responsible for infection in lung transplant recipients and management strategies for prevention.     

Nosocomial infections within the first month of solid organ transplantation

Infections remain a common complication of solid organ transplantation. Early postoperative infections remain a significant cause of morbidity and mortality in solid organ transplant (SOT) recipients. Although significant effort has been made to understand the epidemiology and risk factors for early nosocomial infections in other surgical populations, data in SOT recipients are limited. A literature review was performed to summarize the current understanding of pneumonia, urinary tract infection, surgical‐site infection, bloodstream infection, and Clostridium difficult colitis, occurring within the first 30 days after transplantation.     

A multicenter study of histoplasmosis and blastomycosis after solid organ transplantation

S.A. Grim, L. Proia, R. Miller, M. Alhyraba, A. Costas‐Chavarri, J. Oberholzer, N.M. Clark. A multicenter study of histoplasmosis and blastomycosis after solid organ transplantation.
Transpl Infect Dis 2011. All rights reserved Aim. A review of the clinical presentation, diagnosis, treatment and outcomes of 30 solid organ transplant recipients (SOTRs) with histoplasmosis or blastomycosis from 3 Midwestern academic medical centers. Background. The endemic fungal pathogens, Histoplasma capsulatum and Blastomyces dermatitidis, may cause severe infection in SOTRs. In this report, we describe the clinical presentation, diagnosis, treatment, and outcomes of these endemic fungal infections (EFIs) among SOTRs at 3 academic transplant centers. Methods. A retrospective review was conducted of SOTRs with histoplasmosis or blastomycosis from 3 Midwestern medical centers in the United States. Data collected included demographics, immunosuppression, clinical presentation, method of diagnosis, antifungal treatment, response to therapy, and patient and graft survival. Results. Between 1996 and 2008, 30 transplant recipients with histoplasmosis or blastomycosis were identified, giving a cumulative incidence of infection of 0.50% (30/5989); 73% of the study patients were renal transplant recipients, and the median time to disease onset after transplantation was 10.5 months. The lungs were the most common site of infection (83%), and 60% had disseminated disease. Urine antigen testing was positive in all patients in whom it was performed (23/23). Initial antifungal therapy consisted of amphotericin B in 70%, and 87% received azoles, typically itraconazole (83%). Two patients developed relapsed infection and 7 patients had graft failure after EFI. Overall mortality was 30%, with an attributable mortality of 13%. Conclusions. As in several previous single‐center studies, the incidence of post‐transplant histoplasmosis and blastomycosis was <1%, but often resulted in disseminated infection. In this cohort, EFI was associated with a high rate of allograft loss and overall mortality.     

Scedosporium prolificans pericarditis and mycotic aortic aneurysm in a lung transplant recipient receiving voriconazole prophylaxis

Despite the adoption of antifungal prophylaxis, fungal infections remain a significant concern in lung transplant recipients. Indeed, some concern exists that such prophylaxis may increase the risk of infection with drug‐resistant fungal organisms. Here, we describe a case of disseminated Scedosporium prolificans infection, presenting as pericarditis, which developed in a lung transplant patient receiving prophylactic voriconazole for 8 months. The epidemiology and clinical presentation of S. prolificans infections are reviewed, and controversies surrounding antifungal prophylaxis and the development of resistant infections are discussed.     

Linezolid in the treatment of vancomycin-resistant Enterococcus faecium in solid organ transplant recipients: report of a multicenter compassionate-use trial

Abstract: Vancomycin‐resistant Enterococcus faecium (VRE) is increasing in incidence in solid organ transplant recipients and has a high (up to 83%) associated mortality rate. Until recently, there have been no consistently effective antimicrobial therapies for VRE infection. Linezolid is a new antibiotic that belongs to the class of oxazolidinones approved by the FDA for the treatment of VRE infections, including those with bacteremia. Here, we report the experience with linezolid in an open‐label, compassionate‐use trial at 53 US centers for the treatment of documented VRE infections in patients with solid organ transplants. Eighty‐five patients with solid organ transplants and documented VRE infections were studied. Blood cultures were positive for VRE in 43 patients, while 42 patients had other, non‐rectal, sites of infection. Fifty‐three patients responded well to treatment, with clinical resolution of the infection (62.4% survival rate). Of these, 47 had documented negative cultures post therapy. The mean duration of therapy for cured patients was 23.5 days. Thirty‐two (37.6%) patients died, 28 due to sepsis and organ failure (32.9% failure rate), and 4 due to unrelated causes. Mortality rates for patients with bacteremia were comparable to mortality rates observed with patients who had positive cultures from other sites. Adverse reactions to linezolid included thrombocytopenia (4.7%), decreased leukocyte count (3.5%), and an increase in blood pressure (1.2%), none of which led to discontinuation of therapy. Linezolid appears to be a safe and effective treatment option for VRE, even in the presence of bacteremia, and may lead to decreased mortality in solid organ transplant recipients with VRE infection.     

Nontuberculous mycobacterial and Aspergillus infections among cadaveric lung transplant recipients in Japan

Background

Lung transplantation is an effective treatment modality for respiratory failure. Chronic lung infections, including infections caused by nontuberculous mycobacteria (NTM) and Aspergillus, are difficult to control, and uncontrolled infections are relative contraindications for lung transplantation. However, few reports have documented the incidence and outcome of these infections in lung transplant recipients.

Toxoplasmosis in non‐cardiac solid organ transplant recipients: A case series and review of literature

The risk of toxoplasmosis in high‐risk cardiac transplant recipients is well recognized prompting universal donor and candidate screening with administration of targeted post‐transplant chemoprophylaxis in high‐risk (D+/R?) cardiac transplant patients. In contrast, until recently, there have been neither well‐defined recommendations nor consensus regarding toxoplasmosis preventive strategies among non‐cardiac solid organ transplant recipients. We report 3 cases of post‐transplant toxoplasmosis in non‐cardiac transplant recipients (one lung and two liver); all 3 infections presumed to be donor‐derived. Not surprisingly, pre‐transplant Toxoplasma serology was negative in all the patients. None of the patients were on trimethoprim‐sulfamethoxazole (TMP‐SMX) prophylaxis at the time of diagnosis of toxoplasmosis. The median time from transplant to onset of infection was 90 days (range: 30‐120 days). Clinical presentations included cerebral (n = 1) and disseminated infections (n = 2). Two of the 3 patients, both with disseminated infection died (mortality ~ 67%).     

Aspergillus vertebral osteomyelitis and ureteral obstruction after liver transplantation

L.‐P. Zhu, X.‐S. Chen, J.‐Q. Wu, F.‐F. Yang, X.‐H. Weng. Aspergillus vertebral osteomyelitis and ureteral obstruction after liver transplantation.
Transpl Infect Dis 2011: 13 : 192–199. All rights reserved Abstract: Aspergillus osteomyelitis has been reported as a result of dissemination in solid organ transplant recipients. Vertebral osteomyelitis is one of the most common forms of Aspergillus osteomyelitis. An Aspergillus fungal ball is a rare cause of ureteral obstruction. We describe an unusual case of simultaneous vertebral osteomyelitis and ureteral obstruction caused by A. flavus in a hepatic transplant recipient, who was successfully treated with sequential intravenous and oral itraconazole solution.     

Disseminated histoplasmosis in a kidney transplant patient

Patients with impaired cell‐mediated immunity have a higher risk of developing histoplasmosis; however, histoplasmosis after solid organ transplantation is rare. In Thailand, histoplasmosis cases are sporadic, and most cases are associated with human immunodeficiency virus (HIV) infection. Herein, we report a case of disseminated histoplasmosis in a kidney transplant Thai recipient diagnosed by fungal staining of fungal culture from bronchoalveolar lavage and bone marrow biopsy. Liposomal amphotericin B was given followed by oral itraconazole. The patient's clinical condition was improved; however, his graft function was irreversibly declined. The majority of histoplasmosis cases after solid organ transplant presented with disseminated disease with pulmonary involvement. Even in a non‐endemic area of histoplasmosis, suspected cases should be early diagnosed and promptly managed in order to reduce morbidity and mortality, especially in cell‐mediated immunity defect patients like solid organ transplant recipients.