Cutaneous Toxicities From Transplantation‐Related Medications

Despite the abundance of information on cutaneous malignancies associated with solid organ transplantation in the transplant literature, there is limited information regarding nonmalignant skin changes after transplantation. There are numerous skin toxicities secondary to immunosuppressive and other transplant‐related medications that can vary in presentation, severity, and prognosis. To limit associated morbidity and mortality, solid organ transplant recipient care providers should effectively identify and manage cutaneous manifestations secondary to drug toxicity. Toxicities from the following transplant‐related medications will be discussed: antithymocyte globulins, systemic steroids, cyclosporine, tacrolimus, azathioprine, mycophenolate mofetil, mammalian target of rapamycin inhibitors sirolimus and everolimus, basiliximab and daclizumab, belatacept, and voriconazole.     

Aggressive Cutaneous Squamous Cell Carcinoma Associated with Prolonged Voriconazole Therapy in a Renal Transplant Patient

A 69-year-old man, with a history of end-stage renal disease due to polyarteritis nodosa, followed by invasive pulmonary aspergillosis secondary to cyclophosphamide and corticosteroids, received a renal transplant 2 years ago under prophylactic treatment with voriconazole. Because of the severity of the aspergillosis, it was decided to continue voriconazole for a prolonged period. Eighteen months after transplantation, the patient developed a severe facial phototoxic reaction. A few months later, he developed multiple actinic keratoses and a large, rapidly expanding, poorly differentiated squamous cell carcinoma (SCC) with perineural invasion and metastatic lymph nodes, necessitating radical surgery and radiotherapy. Voriconazole therapy has been suggested to be involved in the development of multi-focal invasive SCC when complicated by a phototoxic reaction. Therefore, an alternative antifungal prophylaxis regimen (for instance with posaconazole) should be considered when evaluating patients for solid organ transplantation who are at high risk for the development of cutaneous malignancies.     

Aspergillus fumigatus spondylodiskitis in renal transplant patient: voriconazole experience

The incidence of invasive aspergillosis has increased after solid organ transplant. However, aspergillus osteomyelitis in vertebrae is rare. We report a case of aspergillus spondylodiskitis after pulmonary aspergillosis in a renal transplant recipient. He was treated by antifungal therapy and surgical intervention. The transplantist should be alert for a diagnosis of aspergillus spondylodiskitis in recipients who developed back pain after aspergillosis infection in other sites.     

Combination antifungal therapy for invasive pulmonary aspergillosis in a heart transplant recipient

Invasive pulmonary aspergillosis is a severe complication after solid organ transplant, with a high mortality rate. We present a 45-year-old male heart transplant recipient who developed fever, progressive worsening of dyspnea, and productive cough without response to antibiotics. Diagnosis of invasive pulmonary aspergillosis was made based on clinical, laboratory, and radiographic findings. The patient was treated successfully with combined antifungal therapy (voriconazole and micafungin). This case report highlights the importance of a high degree of clinical suspicion to allow curative treatment of invasive aspergillosis and the efficiency of new antifungal drugs.     

Fatal case of Aspergillus coinfection in a renal transplant recipient suffering from cytomegalovirus pneumonitis

Cytomegalovirus (CMV) disease is common in postrenal transplant recipients, and may predispose the patients to secondary bacterial or fungal infections. However, simultaneous coinfection is rare and often makes diagnosis difficult. We report a case of CMV pneumonitis in a renal transplant recipient presenting with elevated CMV pp65 antigen level and abnormal chest radiograph. Despite potent and broad-spectrum antimicrobial therapy, his condition deteriorated rapidly - he soon went into respiratory failure, septic shock and died several days later. Transbronchial biopsy and bronchoalveolar lavage obtained before the patient's death showed evidence of invasive pulmonary aspergillosis with concomitant CMV pneumonitis. High index of suspicion and early and empirical initiation of antifungal therapy may be necessary for successful management of fulminant pneumonia in solid organ transplant recipients.     

Risk factors for invasive aspergillosis in liver transplant recipients

Aspergillosis is a potential, severe, and usually early complication of liver transplantation. New promising strategies, such as detecting Aspergillus antigenemia, have been used for the diagnosis of aspergillosis in immunosuppressed patients, but the impact in solid organ transplantation is not well known. A case-control study in 260 adults who underwent liver transplantation from January 1994 to June 2000 was performed. A case was defined as any liver transplant recipient with a proven or probable diagnosis of invasive aspergillosis. Controls were defined as a liver transplant recipient without aspergillosis infection with a survival longer than two months after transplantation. Clinical and analytical variables, including Aspergillus antigenemia, were compared. A special analysis was performed in patients in whom late aspergillosis developed (after day 100 posttransplantation). Among 260 patients, invasive aspergillosis developed in 15 (5.6%). Median time from transplantation to aspergillosis in 13 patients with sufficient data for analysis was 126 days (range, 22 to 1117). Seven (54%) developed the infection after day 100 posttransplantation. Thirty-eight patients were used as controls. Antigenemia was available in nine of 13 cases and in 33 of 38 controls. By multivariate analysis, retransplantation (OR, 29.9 [95% CI, 2.1 to 425.1]), dialysis requirements after transplantation (OR, 24.5 [95% CI, 1.25 to 354]), and the presence of Aspergillus antigenemia in serum at any time point after transplantation (OR, 50.0 [95% CI, 3.56 to 650]) were independently associated to aspergillosis. In the subgroup of patients that developed late aspergillosis, cytomegalovirus infection (OR, 6.7 [95% CI, 1.0 to 42.5]) was the only independent factor associated. Hepatic and renal dysfunction predispose to Aspergillus infection in liver transplant recipients. Cytomegalovirus infection and increased immunosuppression favor invasive aspergillosis during the late posttransplantation period. Aspergillus antigenemia seems to be a good predictor of invasive aspergillosis. (Liver Transpl 2002;8:1065-1070.)     

Pulmonary Aspergillosis in Solid Organ Transplant Patients: A Report From Iran

Background

Aspergillosis is one of the most important opportunistic infections after organ transplantation. Early diagnosis and initiation of appropriate antifungal therapy are key factors for better prognosis.

Methods

We reviewed the medical records of patients with solid organ transplantation with evidence of Aspergillus infections from December 2001 to January 2008, evaluating patient demographics, time of onset after transplantation, risk factors, radiologic appearance, diagnostic criteria, antifungal therapy, and outcome.

Results

We observed aspergillosis in 8 lung, 3 kidney, and 1 heart recipient, with overall mean age of 40.6 years. Seven cases of Aspergillus tracheobronchitis were diagnosed in lung transplant recipients, all of them in the first 6 months after transplantation. All patients responded to antifungal therapy and bronchoscopic debridement. We observed 5 cases of invasive pulmonary aspergillosis. Three patients survived in response to antifungal treatment. The two patients who died were treated with a combination of itraconazole and amphotericin B, whereas all cured patients had been treated with voriconazole alone or in combination with caspofungin.

Conclusion

It seems that the prognosis of aspergillosis in solid organ recipients is improving with new treatment regimens, particularly if they are used in early stages of infection.     

Cutaneous Fungal Masses From Prior Environmental Injury Following Kidney Transplant: A Case Report

Fungus account for ∼ 5% of all cases infections following solid organ transplant. Fungal infections in the setting of immunosuppression may progress rapidly and present in an atypical pattern. Herein we describe 4 cases of environmental fungal infections acquired decades prior to transplant that developed into localized atypical cutaneous masses following kidney transplant.     

Successful,Combined Long-term Treatment of Cerebral Candidiasis and Aspergillosis in a Liver Transplant Recipient: A Case Report

Invasive fungal infections, of which the most common are candidiasis and aspergillosis, are among the most important and fatal complications in solid organ transplantation. They continue to be a significant cause of morbidity and mortality in patients with involvement of the central nervous system (CNS) because of the poor CNS penetration of antifungal medications. Voriconazole yields fungicidal drug concentrations in the CNS, but its use is limited in solid organ transplant patients because of its metabolic interactions with immunosuppression. Here we report a case of invasive fungal infection in the CNS after an emergency liver transplantation due to hepatitis B virus–related acute liver failure. The patient was managed successfully with a long-term conservative medical treatment.     

Invasive Aspergillosis in solid‐organ transplant recipients: Guidelines from the American Society of Transplantation Infectious Diseases Community of Practice

These updated AST‐IDCOP guidelines provide information on epidemiology, diagnosis, and management of Aspergillus after organ transplantation. Aspergillus is the most common invasive mold infection in solid‐organ transplant (SOT) recipients, and it is the most common invasive fungal infection among lung transplant recipients. Time from transplant to diagnosis of invasive aspergillosis (IA) is variable, but most cases present within the first year post‐transplant, with shortest time to onset among liver and heart transplant recipients. The overall 12‐week mortality of IA in SOT exceeds 20%; prognosis is worse among those with central nervous system involvement or disseminated disease. Bronchoalveolar lavage galactomannan is preferred for the diagnosis of IA in lung and non‐lung transplant recipients, in combination with other diagnostic modalities (eg, chest CT scan, culture). Voriconazole remains the drug of choice to treat IA, with isavuconazole and lipid formulations of amphotericin B regarded as alternative agents. The role of combination antifungals for primary therapy of IA remains controversial. Either universal prophylaxis or preemptive therapy is recommended in lung transplant recipients, whereas targeted prophylaxis is favored in liver and heart transplant recipients. In these guidelines, we also discuss newer antifungals and diagnostic tests, antifungal susceptibility testing, and special patient populations.     

Skin cancer in transplant recipients: Scientific retreat of the international immunosuppression and transplant skin cancer collaborative and skin care in organ transplant patients—Europe

The International Immunosuppression and Transplant Skin Cancer Collaborative (ITSCC) is an organization of more than 500 physicians and scientists focused on the treatment of cutaneous malignancies following solid organ transplantation and in other forms of immunosuppression. It is well known that solid organ transplant recipients (SOTRs) have an approximate 100‐fold increase in the risk of developing skin cancer with consensus guidelines recommending these patients be managed as high risk for local recurrence and metastasis associated with poor outcomes. In September 2018, ITSCC and its European counterpart, the Skin Care in Organ Transplant Patients—Europe (SCOPE), held their biennial scientific retreat in Essex, MA to discuss novel findings in the pathogenesis of cutaneous malignancy including new treatment and prevention strategies in this at‐risk population for significant morbidity and mortality from their cutaneous disease. This meeting report is a summary of the novel findings discussed.     

Pulmonary Zygomycosis in Solid Organ Transplant Recipients in the Current Era

Fifty-eight solid organ transplant recipients with zygomycosis were studied to assess the presentation, radiographic characteristics, risks for extra-pulmonary dissemination and mortality of pulmonary zygomycosis. Pulmonary zygomycosis was documented in 31 patients (53%) and developed a median of 5.5 months (interquartile range, 2–11 months) posttransplantation. In all, 74.2% (23/31) of the patients had zygomycosis limited to the lungs and 25.8% (8/31) had lung disease as part of disseminated zygomycosis; cutaneous/soft tissue (50%, 4/8) was the most common site of dissemination. Pulmonary disease presented most frequently as consolidation/mass lesions (29.0%), nodules (25.8%) and cavities (22.6%). Patients with disseminated disease were more likely to have Mycocladus corymbifer as the causative pathogen. The mortality rate at 90 days after the treatment was 45.2%. In summary, pulmonary zygomycosis is the most common manifestation in solid organ transplant recipients with zygomycosis, and disseminated disease often involves the cutaneous/soft tissue sites but not the brain.     

Incidence and clinical predictors of primary opportunistic deep cutaneous mycoses in solid organ transplant recipients: a multicenter cohort study

Tessari G, Naldi L, Piaserico S, Boschiero L, Nacchia F, Forni A, Rugiu C, Faggian G, Dall’Olio E, Fortina AB, Alaibac M, Sassi F, Gotti E, Fiocchi R, Fagioli S, Girolomoni G. Incidence and clinical predictors of primary opportunistic deep cutaneous mycoses in solid organ transplant recipients: a multicenter cohort study.
Clin Transplant 2010: 24: 328–333. © 2009 John Wiley & Sons A/S. Abstract: Background: Primary opportunistic deep cutaneous fungal
infections may cause significant morbidity and mortality in solid organ transplant recipients (OTR), but no data exist about their incidence, timing, and clinical predictors in a long‐term follow‐up. Patients and methods: A series of 3293 consecutive OTR including 1991 kidney, 929 heart, and 373 liver transplant recipients were enrolled. Patients were regularly followed up since time at transplantation (mean 5.5 yr ±5.9 SD) and primary opportunistic fungal infections registered. Persons‐year at risk (PYs), incidence rates (IR), incidence rate ratios (IRR), and 95% confidence intervals were computed. Results: Twenty‐two cases of deep cutaneous mycoses were detected, (IR 1.2 cases per 1000 PYs) after a mean follow‐up time since transplantation of 2.5 yr ± 2.0 SD (median 1.8 yr). Six patients had subsequent systemic involvement and three patients died of systemic dissemination. A higher risk for mycoses was observed in the first two yr after transplantation, (IRR 35.9, p < 0.0001), in renal transplant recipients (IRR 5.1 p = 0.030), and in patients transplanted after the age of 50 (IRR 11.5 p = 0.020). Conclusions: Primary deep cutaneous opportunistic mycoses in OTR occur mainly in the first two yr after transplantation, in renal transplant recipients, and in older patients.     

Late-Onset Allograft Aspergillosis in an HIV-Positive Renal Transplant Recipient: A Case Report

Aspergillus infection of the allograft in renal transplant patients is rare and associated with a high mortality. We report a case of a 21-year-old, human immunodeficiency virus–positive, deceased-donor kidney recipient who presented 1 year after transplant with oliguric kidney injury. A nuclear medicine renal scan revealed absence of flow to the transplanted kidney, and a urine fungal culture was positive for Aspergillus flavus. The diagnosis was confirmed with the presence of fungal hyphae along with thrombosis in the vascular structures in renal allograft pathology. We found no evidence of disseminated aspergillosis or involvement of any other organ in the patient. To our knowledge, this case is the first reported in the literature of late-onset non-disseminated renal-limited aspergillosis in a human immunodeficiency virus–positive renal transplant patient.     

Myocardial Metastasis of Cutaneous Squamous Cell Carcinoma in a Renal Transplant Recipient

Myocardial metastasis from a cutaneous squamous cell carcinoma (SCC) is rare. Herein we have presented a case of metastasis from cutaneous SCC to the myocardium in a renal transplant recipient, which was confirmed by a cardiac fine-needle biopsy. Postmortem examination revealed disseminated metastatic disease involving myocardium, lungs, thyroid, skin, and peritoneum secondary to cutaneous SCC likely related to immunosuppression. At 46 years of age, he received a renal transplant for chronic renal failure caused by chronic glomerulonephritis. He started to develop multiple nonmelanoma skin cancers 4 years later. At least 23 invasive SCCs and 14 basal cell carcinomas were excised. His immunosuppressive regimen consisted of cyclosporine (150 mg), azathioprine (75 mg), and prednisone (10 mg daily), which was not modified despite multiple nonmelanoma skin cancers. Our case report further illustrates the potentially aggressive and fatal nature of cutaneous SCCs that can develop in organ transplant recipients. It argues for modification of the immunosuppressive regimen in such patients. The management of renal transplant patients with nonmelanoma skin cancers remains difficult and complex.     

A case of primary cutaneous aspergillosis in a renal transplant recipient

Opportunistic fungal infections are life-threatening complications which are a major cause of morbidity and mortality in immunocompromized hosts such as those who have undergone organ transplantation. Aspergillosis comprises a spectrum of disease caused by a ubiquitous saprophytic mold. Invasive aspergillus is a serious life-threatening complication in immunocompromised hosts. Primary cutaneous aspergillosis occurs relatively less frequently and is poorly characterized. We report a case of cutaneous aspergillosis in a 51-year-old renal transplant recipient, which was successfully treated with local excision and concomitant antifungal therapy. CASE: A 51-year-old male renal transplant recipient presented with cutaneous nodules on the dorsum of the right hand. He underwent renal transplantation for end-stage renal disease due to adult dominant polycystic kidney disease (ADPKD) 3 years prior. Initially he suffered an acute rejection episode that was treated with steroid pulse and OKT3 therapy. Eventually he was stabilized on a combination of tacrolimus, prednisone, and mycophenolate mofetil. Three years after transplantation, he developed painless multiple (largest one 5 x 3 cm sized) nodules on the dorsum of his right hand. He was afebrile with no systemic symptoms. A skin biopsy showed a dense solid infiltration of giant cells, histiocytes, and lymphoplasma cells admixed with intra- and extracellular fungal hyphae and spores. The hyphae were septate and acute angle branching, which was consistent with aspergillosis. Oral itraconazole 200 mg/d for 5 weeks was ineffective. Treatment with liposomal amphotericin B for 4 weeks was initiated and MMF was discontinued. The medication was well tolerated with no hepatotoxic effects. Although new lesions did not appear, existing ones did not significantly improve after 4 weeks of treatment. Therefore, most lesions were excised surgically and liposomal amphotericin B continued for 2 weeks followed by treatment with oral fluconazole for 2 months. Ten moths later there was no evidence of recurrence.     

Multiple Atypical Fibroxanthomas in a Cardiac Transplant Recipient

BACKGROUND: Solid organ transplant recipients have an increased incidence of multiple cutaneous neoplasms. OBJECTIVE: We hope to draw attention to the potential risk for organ transplant recipients to develop atypical fibroxanthomas. METHODS: A review of the patient's medical record was performed and summarized as a case report. RESULTS: We present the case of a cardiac transplant recipient who developed three atypical fibroxanthomas. This is the first reported case of multiple atypical fibroxanthomas in an organ transplant recipient. CONCLUSION: Atypical fibroxanthomas are uncommon cutaneous malignancies for which transplant recipients may be at increased risk.     

Cryptococcosis in Organ Transplant Recipients: An Overview

Cryptococcosis is the third most common invasive fungal infection in organ transplant recipients after candidiasis and aspergillosis. Reports indicate that cryptococcosis usually presents as symptomatic disease, and despite therapy the mortality remains high. In addition, some data suggest that there might be differences in the incidence and clinical manifestations of cryptococcosis, depending on the specific transplant organ. The incidence of cryptococcosis in our transplant center is significantly higher in heart transplant recipients than in other transplant groups (p=0.0001). Although the primary risk factor contributing to cryptococcosis in organ transplant recipients is probably the immunosuppressive therapy used to prevent allograft rejection, environmental factors may also play a role. This is indicated by studies that demonstrate differences in the rate of cryptococcosis according to geographic region. Moreover, data point out differences in the isolation of the fungus from soil samples with higher concentrations of Cryptococcus in areas frequented by birds or contaminated by bird droppings. Therefore, it is prudent to recommend that organ transplant recipients avoid birds or areas contaminated with bird droppings. The current review provides an overview of the changes in the incidence, clinical manifestations, and management of cryptococcosis in organ transplant recipients.     

Etiology of increased cancer incidence after solid organ transplantation

Over the past decades, there has been an encouraging increase in survival after solid organ transplantation. However, with longer life spans, more transplant recipients are at risk of dying with functioning grafts from illnesses such as cancer and cardiovascular conditions. Malignancy has emerged as an important cause of death in transplant recipients and is expected to become the leading cause of death in transplanted patients within the next decade. While it is known that solid organ transplant recipients have a three to five-fold increased risk of developing cancer compared with the general population, the mechanisms that lead to the observed excess risk in transplant recipients are less clear. This review explores the etiology of the increased cancer incidence in solid organ transplant including the effect of immunosuppressants on immunosurveillance and activation of oncogenic viruses, and carcinogenic effects of these medications; the role of chronic stimulation of the immune system on the development of cancer; and the impact of pre-existing cancer risk factors and factors related to end-stage organ disease on the cancer excess incidence in solid organ transplant recipients.