Donor‐Derived Fungal Infections in Organ Transplant Recipients: Guidelines of the American Society of Transplantation,Infectious Diseases Community of Practice†

Donor‐derived fungal infections can be associated with serious complications in transplant recipients. Most cases of donor‐derived candidiasis have occurred in kidney transplant recipients in whom contaminated preservation fluid is a commonly proposed source. Donors with cryptococcal disease, including those with unrecognized cryptococcal meningoencephalitis may transmit the infection with the allograft. Active histoplasmosis or undiagnosed and presumably asymptomatic infection in the donor that had not resolved by the time of death can result in donor‐derived histoplasmosis in the recipient. Potential donors from an endemic area with either active or occult infection can also transmit coccidioidomycosis. Rare instances of aspergillosis and other mycoses, including agents of mucormycosis may also be transmitted from infected donors. Appropriate diagnostic evaluation and prompt initiation of appropriate antifungal therapy are warranted if donor‐derived fungal infections are a consideration. This document discusses the characteristics, evaluation and approach to the management of donor‐derived fungal infections in organ transplant recipients.     

The feared five fungal infections in kidney transplant recipients: A single‐center 20‐year experience

Invasive fungal infections are a feared complication in kidney transplant recipients (KTRs). Here we present the University of Wisconsin experience with 5 invasive fungal infections—aspergillosis, cryptococcosis, histoplasmosis, blastomycosis, and coccidioidomycosis—in KTRs transplanted between 01/01/1994 and 06/30/2014. During this period, there were 128 cases of fungal infections; aspergillosis was the most common (72), followed by cryptococcosis (29), histoplasmosis (14), blastomycosis (10), and coccidioidomycosis (3). The mean interval from transplant to fungal infection was 3.19 ± 3.58 years (range 5 days‐15.8 years). By 6 months postinfection, there were 53 (41%) graft failures and 24 (19%) deaths. Graft failure occurred in 46%, 38%, 21%, 40%, and 67% of patients with aspergillosis, cryptococcosis, histoplasmosis, blastomycosis, and coccidioidomycosis, respectively. Anti‐thymocyte globulin (ATG) induction (HR, 1.49; 95% CI, 1.03‐2.16; P = .04), diabetes (HR, 1.53; 95% CI, 1.05‐2.21; P = .03), and age (HR, 1.47; 95% CI, 1.27‐1.70; P ≤ .001) were associated with an increased risk for infection in univariate analysis. Multivariate adjustment retained ATG induction and older age. A large proportion of kidney transplant recipients with invasive fungal infections suffer graft failure within 3 years. Preventive, therapeutic, and monitoring strategies are needed to improve graft and patient outcomes.     

Chronic graft-versus-host disease in pancreas after kidney transplant recipients – An unrecognized entity

Graft-versus-host disease (GVHD), a common complication after peripheral blood stem cell or bone marrow transplantation, rarely occurs in kidney and pancreas transplant recipients. The true incidence may be confounded by the rarity of the disorder, with a resultant lack of appreciation of the diagnosis as a potential cause of common clinical manifestations such as cytopenias and immune dysfunction. Reports of GVHD in kidney and pancreas transplant recipients almost uniformly describe patients in the early posttransplant period (days to months) with the typical manifestations of acute GVHD involving the skin, liver, and intestines. In contrast, reports of solid organ transplant recipients with clinical features more consistent with chronic GVHD (cGVHD) are lacking, raising concern of underrecognition of this severe complication. Occurrence later after transplant may be even more likely to result in lack of recognition. We report 2 cases of possible cGVHD occurring in recipients of pancreas after kidney transplantation, which were diagnosed at 5.5 and 42 months after pancreas transplant. Both patients presented with severe pancytopenia, multiple opportunistic infections, and features suggestive of cGVHD. Transplant professionals should be aware of the possibility of acute and cGVHD in pancreas after kidney transplant recipients and be able to recognize the clinical manifestations.     

Efficacy and safety of Amphotericin B Lipid Complex Injection (ABLC) in solid-organ transplant recipients with invasive fungal infections

Background: Fungal infections following solid-organ transplantation are a major source of morbidity and mortality. This report describes the efficacy and safety of Amphotericin B Lipid Complex Injection (ABLC) in solid-organ transplant recipients.
Methods: Three open-label, second-line treatment studies evaluated ABLC as a treatment for severe, life-threatening mycoses in patients who were refractory to or intolerant to conventional antifungal (mostly amphotericin B [AmB]) therapy or had pre-existing renal disease.
Results: The 79 solid-organ transplant recipients (25 heart, 20 liver, 17 kidney, 11 lung, 5 multiple, 1 pancreas) who received ABLC in these studies had the following fungal infections: aspergillosis (n=39); candidiasis (n=20); zygomycosis (n=8); cryptococcosis and histoplasmosis (n=3 each); and blastomycosis, cladosporiosis, fusariosis, Bipolaris hawaiiensis , Dactylaria gallopava , and an unspecified fungal infection (n=1 each). The median duration of ABLC therapy was 28 d (1–178 d). The daily dose ranged between 1.6 and 7.4 mg/kg (median, 4.6 mg/kg). The clinical response rate for the patients who could be assessed was 58% (39/67). Clinical response rates for heart, liver, kidney, and lung recipients were 59, 60, 67, and 40%, respectively; response rates for aspergillosis and candidiasis were 47 and 71%, respectively. Forty-six of the 79 patients (58%) survived for more than 28 d after the last dose of ABLC. Mean baseline serum creatinine was 3.2 mg/dL; 64 patients (81%) had stable (n=37) or improved (n=27) serum creatinine at the end of treatment.
Conclusions: ABLC is safe and effective treatment for fungal infections in solid-organ transplant recipients. Its renal-sparing properties are particularly suited for this high-risk population for renal failure.     

Histoplasmosis in transplant recipients

Histoplasma capsulatum is a dimorphic fungus that most often causes asymptomatic infection in the immunocompetent population. In immunocompromised patients, including solid organ transplant (SOT) and hematopoietic cell transplant (HCT) recipients, however, it is likely to cause severe life‐threatening infection. Post‐transplant histoplasmosis (PTH) in SOT is uncommon with an incidence of ≤1% and is even rarer in HCT patients. The majority of PTH in SOT is diagnosed in the first 2 years following transplantation. Histoplasmosis may result from endogenous reactivation of latent infection, de novo post‐transplant acquisition, and donor‐derived infection. Disseminated infection is common. Fever is the most common symptom and clinical features are often nonspecific, but patients with disseminated infection may present with a septic picture. Other features, including pancytopenia and hepatosplenomegaly, may not be prominent early in the course of illness. Contemporary histoplasma antigen assays are the most sensitive tests but cross‐reactivity with antigens of other fungi, including with Aspergillus galactomannan, is not uncommon. Treatment should be continued for at least a year. Histoplasma antigen levels have prognostic value and can be used to monitor the response to therapy. The attributable mortality is approximately 10%. Routine screening of donors and recipients is not currently recommended.     

Caspofungin in the treatment of azole-refractory esophageal candidiasis in kidney transplant recipients

BACKGROUND: Infection is a common cause of morbidity and mortality in kidney transplant recipients. The incidence of esophageal and urogenital candidiasis in kidney and kidney-pancreas transplant recipients has not been well documented. Azoles are safe, effective agents to treat esophageal candidiasis. However, resistance to azoles is now becoming common. This study reports the use of caspofungin for the treatment of azole-resistant esophageal and urogenital candidiasis in kidney transplant recipients. PATIENTS AND METHODS: The incidence of esophageal and urogenital candidiasis was evaluated among 140 kidney transplantations and four combined kidney-pancreas transplants performed over a 2-year period. RESULTS: Twenty-two patients (15.7%) presented with esophageal candidiasis, while seven patients (5%) showed urogenital candidiasis. Thirteen patients with esophageal candidiasis (59%) and four patients (57%) with urogenital candidiasis did not improve after a week of azole treatment. A regimen of caspofungin was started in these patients, who tolerated the treatment. Urogenital candidiasis recurred in two patients 2 and 3 months after the treatment. One patient with esophageal candidiasis did not improve with caspofungin and was switched to amphotericin B therapy. There were no other recurrences of candidiasis among patients treated with caspofungin for a median follow-up of 8 months. CONCLUSIONS: Renal transplant patients remain at high risk for fungal infections. Although the number of patients was limited, the results of this study indicated that caspofungin is an effective, well-tolerated alternative for difficult-to-treat, azole-resistant candida infections in kidney and pancreas transplant recipients. The high costs of the drug limit the use of caspofungin as first-line antifungal therapy, reserving its use to recipients who had undergone unsuccessful azole therapy.     

Severe Hyperkalemia Complicating Voriconazole Treatment in a Kidney Transplant Recipient With Histoplasmosis: A Case Report

Voriconazole is an antifungal agent that is commonly used in immunocompromised patients who develop fungal infections. We report a case of severe recurrent hyperkalemia that developed after starting voriconazole for the treatment of histoplasmosis in a kidney transplant patient who was maintained on tacrolimus-based immunosuppression. Hyperkalemia developed despite reducing the tacrolimus dose to maintain levels in a low therapeutic range. Although interactions between azoles and calcineurin inhibitors are widely recognized, this is the 1st report describing new-onset hyperkalemia following initiation of voriconazole in a kidney transplant patient receiving tacrolimus.     

Voriconazole in the treatment of invasive aspergillosis in kidney transplant recipients

BACKGROUND: Aspergillosis and other invasive mold infections are severe complications in immunosuppressed patients, and in renal transplant patients it is the most common cause of systemic fungal disease with an incidence ranging from 0.4% to 2.4% with a high mortality of 56% to 100%. We present our experience with voriconazole in a population of kidney transplant recipients with invasive aspergillosis. PATIENTS AND METHODS: From January 2002 to December 2005, 245 kidney transplantations were performed. RESULTS: Four patients (1.6%) presented with clinical and laboratory findings of invasive aspergillosis. Three patients presented with pulmonary aspergillosis, while one patient presented with pulmonary and ocular aspergillosis. All patients underwent a therapy with voriconazole 200 mg twice a day, in combination with caspofungin in one patient. All patients are alive, with no clinical recurrence of aspergillosis at a median follow-up of 13 months. One patient lost her graft due to discontinuation of immunosuppression. CONCLUSIONS: Voriconazole is a potent and well-tolerated antifungal drug that is extremely efficacious in the treatment of invasive aspergillosis in kidney transplant recipients. A careful monitoring of immunosuppressive drugs should be considered to avoid nephrotoxicity.     

Intestinal fungal and parasitic infections in kidney transplant recipients: a multi-center study

Kidney transplant recipients are susceptible to various infections due to the use of immunosuppressive drugs. The present study was performed as studies on the prevalence of intestinal fungal and parasitic infections in kidney transplant recipients are limited. A total of 150 kidney transplant recipients and 225 matched immunocompetent outpatients, who were referred to the laboratory of Noor Hospital, Isfahan, were studied. After recording demographic characteristics, direct test and specific laboratory cultures were carried out on the stool specimens. Patients were instructed on sanitary rules and, during each medical visit, they were reminded of the same. The overall prevalence of intestinal parasitic and fungal infections was 33.3% and 58.7%, respectively, in transplant recipients and 20% and 51%, respectively, in the control group; the difference was not statistically significant. The most prevalent intestinal parasite was Entameba coli, which was seen in 9.3% of the study patients and 6.7% of the controls. The most prevalent fungus was Candida sp., which was seen in 22% of the study patients and 24.4% of the control group. Co-existing infection with two or more fungi was seen in 14.8% and 3.4% in the case and control groups, respectively; P <0.001. Interestingly, there was no significant difference in the prevalence of infection by a single organism between the two groups. However, co-existing infection with two or more species was more prevalent in transplant recipients. We conclude that further investigations are needed to evaluate the pathogenesis of infection with these microorganisms.     

Renal allograft recipient with co-existing BK virus nephropathy and pulmonary histoplasmosis: report of a case

Renal allograft recipients are prone to opportunistic infections, rarely multiple coexisting infections, due to the immunocompromised state. To the best of our knowledge, no case of a co-existing polyoma virus nephropathy and pulmonary histoplasmosis in a renal allograft recipient has been reported so far in the available literature. A 55-year-old male renal allograft recipient underwent graft biopsy for asymptomatic graft dysfunction. The graft biopsy showed features of polyoma virus nephropathy. Soon after, he developed fever with pulmonary nodules. Fine-needle aspiration from lung nodules showed intracellular yeast forms of histoplasma. The patient responded well to amphotericin B with subsidence of fever. The co-existence of renal allograft-limited infection like polyoma virus and systemic fungal infection such as histoplasmosis should be kept in mind in a transplant recipient with graft dysfunction and non-specific systemic symptoms. Prompt recognition of these infections permits the clinician to institute appropriate therapeutic modification and improved survival.     

Disseminated histoplasmosis 19 years after renal transplantation.

Infections with fungi like Histoplasma are rarely seen in immunocompromized patients. We report the case of a renal transplant recipient who presented with fever and was diagnosed to have disseminated histoplasmosis 19 years after transplant. The pitfalls in making a diagnosis in non-endemic areas are discussed. The literature on renal transplantation recipients with histoplasmosis has been reviewed.     

Bacterial and fungal pneumonias after lung transplantation

OBJECTIVE: The aim of this study was to evaluate the epidemiology of bacterial and fungal pneumonia in lung transplant (LT) recipients and to assess donor-to-host transmission of these microorganisms. MATERIALS AND METHODS: We retrospectively studied all positive cultures from bronchoalveolar lavage (BAL) of 49 lung transplant recipients and their donors from August 2003 to April 2007. RESULTS: There were 108 episodes of pneumonia during a medium follow-up of 412 days (range, 1-1328 days). The most frequent microorganisms were: Pseudomonas aeruginosa (n = 36; 33.3%), Staphylococcus aureus (n = 29; 26.8%), and Aspergillus spp. (n = 18; 16%). Other fungal infections were due to Fusarium spp., Cryptococcus neoformans, and Paracoccidioides brasiliensis. Of the 31 donors with positive BAL, 15 had S. aureus. There were 21 pretransplant colonized recipients (43%) and 16 of them had suppurative underlying lung disease. P. aeruginosa was the most frequent colonizing organism (59% of pretransplant positive cultures). There were 11 episodes of bacteremia and lungs were the source in 5 cases. Sixteen deaths occurred and 6 (37.5%) were due to infection. Statistical analyses showed association between pretransplant colonizing microorganisms from suppurative lung disease patients and pneumonias after lung transplantation (RR = 4.76; P = .04; 95% CI = 1.02-22.10). No other analyzed factor was significant. CONCLUSIONS: Bacterial and fungal infections are frequent and contribute to higher mortality in lung transplant recipients. P. aeruginosa is the most frequent agent of respiratory infections. This study did not observe any impact of donor lung organisms on pneumonia after lung transplantation. Nevertheless, we demonstrated an association between pretransplant colonizing microorganisms and early pneumonias in suppurative lung transplant recipients.     

Multiple Primary Malignancies: The First Case of a Combination of a Gastrointestinal Stromal Tumor and Renal Cell Carcinoma in a Kidney Transplant Recipient

There is limited data on multiple primary malignancies in the kidney transplant population. Gastrointestinal stromal tumors (GISTs) are rare tumors in kidney transplant recipients, with only 5 cases reported in the literature to date. GIST patients are at an increased risk for developing additional malignancies, with other histologic types of gastrointestinal tract malignancies being the most frequent and other types of malignancies rare. There is evidence in the literature suggesting an association between GIST and renal cell carcinomas. We report on the first case of a GIST and a renal cell carcinoma in a kidney transplant recipient and in other solid organ transplant recipients.     

Use of sodium-glucose co-transporter 2 inhibitors in solid organ transplant recipients with pre-existing type 2 or post-transplantation diabetes mellitus: A systematic review

IntroductionSodium-Glucose Co-Transporter 2 (SGLT2) inhibitors have demonstrated kidney, cardiovascular and mortality benefits in the general population; however, the evidence is limited in solid organ transplant recipients. The aim of this systematic review was to evaluate the current efficacy and safety data of SGLT2 inhibitors in adult kidney, heart, lung, and liver transplant recipients with pre-existing type 2 or post-transplantation diabetes mellitus.MethodWe searched MEDLINE, MEDLINE Epub, CENTRAL, CDSR, EMBASE, CINAHL, and sources of unpublished literature. All primary interventional and observational studies on SGLT2 inhibitors in transplant recipients were included. Clinical outcomes included mortality, cardiovascular and kidney events, and adverse events such as graft rejection. Surrogate markers including hemoglobin A1c (HbA1c) and weight reduction were also evaluated.ResultsOf the 17 studies that were included in this systematic review, there were 15 studies on kidney transplant recipients (n = 2417 patients) and two studies on heart transplant recipients (n = 122 patients). There was only one randomized controlled trial which evaluated 49 kidney transplant patients over 24 weeks. Overall, studies were heterogeneous in study design, sample size, duration of diabetes, time to SGLT2 inhibitor initiation post-transplantation (ranging from 0.88 to 11 years post kidney transplant; five to 5.7 years post heart transplant) and follow-up (ranging from 0.4 to 5.25 years in kidney transplant patients; 0.75 to one year in heart transplant patients). Only one retrospective study evaluated mortality as a part of a composite outcome in kidney transplant patients; however, study limitations restrict generalizability of results. Overall, studies could not confirm clinical cardiovascular and kidney benefits in the transplant population. Findings suggested that SGLT2 inhibitors may improve glycemic control; however, they are associated with urinary tract infection. Diabetic ketoacidosis and acute kidney injury also occurred in these studies, with precipitating factors such as infection and acute heart failure exacerbation.ConclusionsWhile SGLT2 inhibitors are promising agents with expanding indications in the non-transplant population, these agents may not be suitable for all solid organ transplant recipients, and close monitoring (e.g. for urinary tract infections) and patient education (e.g. sick day management) are essential if these agents are initiated. Evidence is based on short-term findings and suggests an association with hemoglobin A1c reduction and increased adverse events. Further long-term randomized controlled trials are needed to evaluate the effect of SGLT2 inhibitors on clinically important outcomes, including mortality reduction, in solid organ transplant recipients.     

Fungal infections in renal transplant recipients.

Infection continues to be a major source of morbidity and the major source of mortality in renal transplant recipients who are susceptible to opportunistic infections. We recently reviewed all renal transplant recipients who had fungi cultured during a three year period. C. albicans and T. glabrata were cultured most frequently. Deep fungal infections occurred in many patients and were frequently observed late in the course of bacterial and viral infections. Ten patients had fungemia, and primary fungal pneumonia occurred in eight patients. Three patients had fungal infection of the central nervous system. Three of eight patients with fungal pneumonia and eight of ten patients with fungemia died as a result of their fungus infections. These patients frequently had poor renal function and were receiving high steroid doses or had recently been treated for kidney rejection. One patient with fungal pneumonia and six patients with fungemia had the fungus cultured from a superficial site. Several patients developed fungal infections late in the course of viral or bacterial infections. Amphotericin-B and 5-fluorocytosine remain the mainstays of antifungal therapy.     

Are heart transplant recipients more likely to develop skin cancer than kidney transplant recipients?

Abstract Non‐melanoma skin cancer is frequent in organ transplant recipients. The risk of post‐transplant cutaneous squamous cell carcinoma in Norwegian heart transplant recipients (n = 148) and kidney transplant recipients (n = 1020) on triple immunosuppressive therapy with cyclosporine, azathioprine, and prednisolone, transplanted between 1983 and 1992, were studied. After adjustment for age at transplantation in multivariable Cox models, heart transplant recipients had a significantly 2.8‐times higher risk of developing squamous cell carcinoma relative to kidney transplant recipients. The risk relative to the general population (standardized incidence ratio) was higher in heart transplant recipients than in kidney transplant recipients. The results indicate that heart transplant recipients are more likely to be diagnosed with skin cancer than kidney transplant recipients, probably due to the higher doses of cyclosporine and azathioprine after heart transplantation used at our center in the study period.     

Epidemiology of laboratory-confirmed influenza among kidney transplant recipients compared to the general population—A nationwide cohort study

Seasonal influenza causes morbidity and mortality after organ transplantation. We quantified the detection of laboratory-confirmed influenza among kidney transplant recipients compared to the general population in a nationwide cohort. All laboratory-confirmed cases of influenza and hospitalizations due to influenza among all kidney transplant recipients in our country between 1995 and 2017 were captured with database linkage from statutory national registries. Data from the general population of Finland, population 5.5 million, were used for comparisons. Annual incidences of influenza and hospitalizations due to influenza, and standardized incidence ratios (SIR) were calculated. Altogether 3904 kidney transplant recipients with a total follow-up of 37 175 patient-years were included. Incidence of laboratory-confirmed influenza was 9.0 per 1000 patient years in 2003–2019, and 18.0 per 1000 patient years during 2015–2019. The risk of laboratory-confirmed influenza was significantly higher among kidney transplant recipients compared to the general population (SIR 5.1, 95% CI 4.5–5.7). SIR for hospitalization due to influenza was 4.4 (95% CI 3.4–4.7). Mortality of the hospitalized patients was 9%, and 5% of the patients with laboratory-confirmed influenza. Detection of laboratory-confirmed influenza is increased fivefold and risk of hospitalization due to influenza more than fourfold among kidney transplant recipients compared to the general population.     

Elevated Incidence of Posttransplant Erythrocytosis After Simultaneous Pancreas Kidney Transplantation

Posttransplant erythrocytosis (PTE) poses a potential risk of thrombosis in kidney transplantation. Clinical observation of our systemically drained simultaneous kidney pancreas transplant (S‐SPK) patients showed a higher incidence of PTE and need for phlebotomies. To evaluate the incidence of PTE we analyzed hematocrit (Hct) levels and frequency of phlebotomies in 94 SPK as compared to 174 living donor (LD) recipients and 53 type‐I diabetic with kidney transplant only. For study purposes we defined PTE as Hct >50% or the necessity for phlebotomies. Kaplan–Meier plots and Cox proportional hazard models were used to examine the association between the transplant type and PTE. We found an increased incidence of PTE in SPK compared to LD (p < 0.001). In the multivariate model, SPK had a 5‐fold risk for the development of PTE (AHR 5.3, 95% CI 1.8, 15.9). The incidence of therapeutic phlebotomy was 13% among SPK patients and 4% in LD kidney recipients; 19 patients altogether. A total of 64 units were phlebotomized (48‐SPK and 16‐LD). Type I diabetic patients with a kidney transplant showed a 0% incidence of PTE. We observed a greater incidence of PTE and phlebotomies in S‐SPK compared to LD with kidney only transplant recipients.     

Cytotoxic T-lymphocyte antigen 4 gene polymorphisms and susceptibility to acute allograft rejection

BACKGROUND: Cytotoxic T-lymphocyte antigen 4 (CTLA4) has been shown to play a critical role in the down-regulation of the immune response. We retrospectively examined the association between acute rejection and two polymorphisms in the CTLA4 gene, the dinucleotide (AT)n repeat polymorphism in exon 3 and the single nucleotide polymorphism A/G at position 49 in exon 1, in a cohort of liver and kidney transplant recipients. METHODS AND RESULTS: A total of 207 liver and 167 renal transplant recipients were analyzed. In the case of the (AT)n repeat polymorphism we found an increased incidence of acute rejection in association with allele 3 and 4 in both liver and kidney (P=0.002 and 0.05, respectively). In addition, in liver transplant recipients, allele 7 was associated with acute rejection independent of ethnicity (P<0.05). Allele 1 was less frequently observed in African American as compared with Caucasian liver and kidney transplant recipients, with a frequency of 33.8% and 69%, respectively (P<0.0001). Those patients with allele 1 had a tendency toward a lower rate of rejection at 42% versus 57.8% (P=0.058), suggesting a potential protective effect of allele 1. Analysis of the A/G single nucleotide polymorphism demonstrated no association between either allele and the incidence of acute rejection in the patients studied. CONCLUSION: These initial observations provide the necessary basis to further investigate the risk stratification of transplant recipients based on specific CTLA4 gene polymorphisms.