Italian guidelines for diagnosis, prevention, and treatment of invasive fungal infections in solid organ transplant recipients

Use of various induction regimens, of novel immunosuppressive agents, and of newer prophylactic strategies continues to change the pattern of infections among solid organ transplant (SOT) recipients. Although invasive fungal infections (IFIs) occur at a lower incidence than bacterial and viral infections in this population, they remain a major cause of morbidity and mortality worldwide. In March 2008, a panel of Italian experts on fungal infections and organ transplantation convened in Castel Gandolfo (Rome) to develop consensus guidelines for the diagnosis, prevention, and treatment of IFIs among SOT recipients. We discussed the definitions, microbiological and radiological diagnoses, prophylaxis, empirical treatment, and therapy of established disease. Throughout the consensus document, recommendations as clinical guidelines were rated according to the standard scoring system of the Infectious Diseases Society of America and the United Stated Public Health Service.     

Safety of anidulafungin in solid organ transplant recipients

The aim of this study was the evaluation of the safety of anidulafungin in adult solid organ transplantation (SOT) recipients. During the study period (14 months), we included all consecutive SOT recipients from 14 centers who received anidulafungin for at least 48 hours for the treatment of invasive fungal infections (IFIs) or as prophylaxis. Relevant clinical and analytical information on clinical charts was reviewed. Clinical side effects, liver function tests, and serum creatinine levels were assessed at least weekly. The need for the modification of immunosuppressive drugs was also recorded by the investigators. All patients were followed for at least 1 week after the end of treatment (EOT) or until death. Eighty-six SOT recipients were evaluated (56 transplant recipients, 20 lung transplant recipients, 8 kidney transplant recipients, and 2 heart transplant recipients). Sixty-two patients (72%) received anidulafungin for prophylaxis, and 24 (28%) received anidulafungin for the treatment of IFIs [candidemia/invasive candidiasis (16) or invasive aspergillosis (8)]. At the baseline, only 5% of the patients were neutropenic (<500 neutrophils/mL). There was no need for the modification of immunosuppressive drug doses because of anidulafungin therapy. No patient discontinued anidulafungin because of severe adverse effects. While receiving anidulafungin, 1 patient developed mild liver toxicity, but the liver function normalized without the discontinuation of anidulafungin. At EOT, the median serum creatinine, aspartate aminotransferase, and alanine aminotransferase levels were significantly lower than the baseline levels, even in liver transplant recipients and patients who had higher baseline levels of serum creatinine. In conclusion, these results show that anidulafungin is a well-tolerated drug in SOT recipients.     

COVID-19 and solid organ transplantation: Finding the right balance

BackgroundThe COVID-19 pandemic has a great impact on solid organ transplant (SOT) recipients due to their comorbidities and their maintenance immunosuppression. So far, studies about the different aspects of the impact of the pandemic on SOT recipients are limited.ObjectivesThis systematic review summarizes the risk factors that make SOT patients more vulnerable for severe COVID-19 disease or mortality and the impact of immunosuppressive therapy. Furthermore, their clinical outcomes, mortality risk, immunosuppression, immunity and COVID-19 vaccination efficacy are discussed.MethodsA systematic search on PubMed was performed to select original articles on SOT recipients concerning the following four topics: (1) mortality and clinical course; (2) risk factors for mortality and composite outcomes; (3) maintenance immunosuppression; (4) immunity to COVID-19 infection and (5) vaccine immunogenicity. Relevant data were extracted, analyzed and summarized in tables.ResultsThis systematic review includes 77 articles. Mortality was associated with advanced age. Post-transplantation time or comorbidities were variably identified as independent risk factors for mortality or severe disease. However, generally, no comorbidity was reported as a major risk factor. SOT recipients have a higher risk of acute kidney injury, but no higher rate of mortality compared to non-transplanted patients was found. Immunosuppression was individually adjusted, without leading to high rates of graft dysfunction. Generally, no association between type of immunosuppression and mortality was found. SOT patients established humoral and cellular immune responses after COVID-19 disease comparable to immunocompetent people. At last, SOT patients experience a diminished immune response after two-dose vaccination with SARS-COV-2-mRNA-vaccines.ConclusionMore research is needed to address the direct effect of COVID-19 disease on the graft in lung transplant recipients, as well as the factors ameliorating the immune response in SOT recipients.     

Emerging Issues With Diagnosis and Management of Fungal Infections in Solid Organ Transplant Recipients

Invasive fungal infections (IFIs) are being increasingly recognized in solid organ transplant (SOT) recipients, and delayed diagnosis can lead to graft loss and death. Therefore, there is a low threshold for prophylaxis and early initiation of empiric antifungal treatment, in this patient population. Meanwhile, the increasing consumption of antifungals is associated with high cost, medication toxicities and the emergence of resistance in Candida species, all of which call for rational use of antifungal agents. The implementation of fungal biomarkers, molecular diagnostic methods and direct detection of volatile fungal metabolites in breath samples could lead to faster diagnosis, early appropriate treatment and improved clinical outcomes, but also aid in the de‐escalation of antifungal treatment. Those novel diagnostic modalities need to be validated specifically in SOT recipients. Infectious diseases consultation can contribute to optimization of care through prompt initiation and appropriate modification of antifungal treatment, management of medication toxicities and drug‐drug interactions, as well as source control. In this review, we conceptually summarize recent advances in the diagnosis and management of IFI in SOT recipients, and highlight the importance of early diagnostic tools and good stewardship of antifungal drugs.     

Emerging fungal infections in solid organ transplant recipients: Guidelines of the American Society of Transplantation Infectious Diseases Community of Practice

These updated AST‐IDCOP guidelines review the epidemiology, diagnosis, and management of emerging fungi after organ transplantation. Infections due to numerous generally innocuous fungi are increasingly recognized in solid organ transplant (SOT) recipients, comprising about 7%‐10% of fungal infections in this setting. Such infections are collectively referred to as emerging fungal infections and include Mucormycetes, Fusarium, Scedosporium, and dematiaceous fungi among others. The causative organisms are diverse in their pathophysiology, uncommon in the clinical setting, have evolving nomenclature, and are often resistant to multiple commonly used antifungal agents. In recent years significant advances have been made in understanding of the epidemiology of these emerging fungal infections, with improved diagnosis and expanded treatment options. Still, treatment guidelines are generally informed by and limited to experience from cohorts of patients with hematological malignancies and/or solid and stem cell transplants. While multicenter randomized controlled trials are not feasible for these uncommon infections in SOT recipients, collaborative prospective studies can be valuable in providing information on the epidemiology, clinical manifestations, treatment strategies, and outcomes associated with the more commonly encountered infections.     

Management of Clostridioides (formerly Clostridium) difficile infection (CDI) in solid organ transplant recipients: Guidelines from the American Society of Transplantation Community of Practice

These updated guidelines from the American Society of Transplantation Infectious Diseases Community of Practice address the prevention and management of Clostridium difficile infection in solid organ transplant (SOT) recipients. Clostridioides (formerly Clostridium) difficile infection (CDI) is among the most common hospital acquired infections. In SOT recipients, the incidence of CDI varies by type and number or organs transplanted. While a meta‐analysis of published literature found the prevalence of postoperative CDI in the general surgical population to be approximately 0.51%, the prevalence of CDI that is seen in the solid organ transplant population ranges from a low of 3.2% in the pancreatic transplant population to 12.7% in those receiving multiple organ transplants. There are no randomized, controlled trials evaluating the management of CDI in the SOT population. Herein is a review and summary of the currently available literature that has been synthesized into updated treatment guidelines for the management of CDI in the SOT population.     

实体器官移植受者移植术后下消化道并发症流行病学及影响因素

实体器官移植(SOT)作为治疗终末期器官衰竭疾病的有效手段,临床开展越来越广泛。随着外科手术技术及术后管理水平的逐年提高及新型免疫抑制剂的应用,SOT受者术后生存率和生存质量不断提高。国外研究发现,SOT受者术后下消化道并发症(如憩室炎、结肠息肉和结直肠癌等)发生率随术后时间延长逐年增加,并成为影响受者生存时间和生存质量的重要因素。但目前国内这方面研究较少,且大多为个案报道。本文旨在对近年来SOT受者移植术后下消化道并发症流行病学及其影响因素相关研究进行综述,以期为临床预防及早期诊治提供依据,改善受者预后。     

Solid organ transplantation in survivors of hematopoietic cell transplantation: a single institution case series and literature review

Beitinjaneh A, Burns LJ, Majhail NS. Solid organ transplantation in survivors of hematopoietic cell transplantation: a single institution case series and literature review.
Clin Transplant 2010: 24: E94–E102.
© 2009 John Wiley & Sons A/S. Abstract: For selected hematopoietic cell transplant (HCT) survivors with severe organ dysfunction, solid organ transplantation (SOT) may offer the best chance for better quality of life and extended survival. However, SOT following HCT has not been well described. We report our institutional experience of SOT in 12 HCT recipients and present a review of the published literature of this procedure in HCT survivors. Our experience with transplanted organs included kidney (n = 7), lung (n = 3), liver (n = 2) and heart (n = 1). Age at HCT ranged from 2 to 56 yr. Median time between HCT and SOT was 7.9 yr (range 1.2–15.9 yr). Among the 11 patients with post‐SOT follow‐up information, 10 had normal function of the transplanted solid organ at the time of last contact or death. Infections and secondary malignancy were the most common complications. Four other institutional experiences with kidney transplant, 21 case reports of liver transplant, 11 case reports of lung transplant and one cardiac transplant are also summarized. SOT is feasible for selected HCT survivors with organ failure and may be associated with favorable long‐term survival and graft function. More research is needed to further delineate the subset of survivors who will benefit the most from SOT with the least risk of complications.     

The Role of Antiviral Prophylaxis for the Prevention of Epstein–Barr Virus–Associated Posttransplant Lymphoproliferative Disease in Solid Organ Transplant Recipients: A Systematic Review

The role of antiviral prophylaxis for the prevention of posttransplant lymphoproliferative disease (PTLD) remains controversial for solid organ transplantation (SOT) recipients who are seronegative for Epstein–Barr virus (EBV) but who received organs from seropositive donors. We performed a systematic review and meta‐analysis to address this issue. Two independent assessors extracted data from studies after determining patient eligibility and completing quality assessments. Overall, 31 studies were identified and included in the quantitative synthesis. Nine studies were included in the direct comparisons (total 2366 participants), and 22 were included in the indirect analysis. There was no significant difference in the rate of EBV‐associated PTLD in SOT recipients among those who received prophylaxis (acyclovir, valacyclovir, ganciclovir, valganciclovir) compared with those who did not receive prophylaxis (nine studies; risk ratio 0.95, 95% confidence interval 0.58–1.54). No significant differences were noted across all types of organ transplants, age groups, or antiviral use as prophylaxis or preemptive therapy. There was no significant heterogeneity in the effect of antiviral prophylaxis on the incidence of PTLD. In conclusion, the use of antiviral prophylaxis in high‐risk EBV‐naive patients has no effect on the incidence of PTLD in SOT recipients.     

Risk Classification for Respiratory Viral Infections in Adult Solid Organ Transplantation Recipients

IntroductionMolecular testing such as nasopharyngeal viral polymerase chain reaction (PCR) (NVP) is available now in most hospitals and widely used to identify respiratory viral infections (RVIs) in solid organ transplantation (SOT) recipients.Materials and MethodsA retrospective multicenter study at 8 hospitals from March 1, 2016, to April 30, 2019. We included all adult SOT recipients who were admitted to the hospitals and had their first NVP post transplantation.ResultsA total of 102 adult SOT recipients were enrolled. NVP test was positive in 33 (32.4%) SOT recipients and negative in 69 (67.6%). Median age was more than 60 years old with female predominance in both groups. The majority of patients who had positive NVP were hospitalized either in fall or winter seasons (91%). RVI symptoms were documented in about 73% of the positive NVP group. Rhinovirus was the most common identified virus (48.4%). On logistic regression analysis, clinical presentation in fall or winter seasons, presenting with upper respiratory infection (URI) symptoms and taking prednisone ≥10 mg/d were significantly associated with positive NVP. This model classified patients into 3 categories of risk for RVIs—low (none of the variables), 0%; intermediate (1 variable), 6.5%; and high (≥2 variables), 55.4% with P < .001 for all predictors.ConclusionSOT recipients who are taking prednisone (≥10 mg) and have URI symptoms in fall or winter seasons are more likely to have RVIs     

Risk of colorectal neoplasia in patients with solid organ transplantation

The incidence of colorectal adenomas and advanced neoplasia in the transplant population has not been well characterized. The aim of this study was to determine whether or not there was an increased incidence of colorectal adenomas and advanced neoplasia in solid organ transplantation (SOT) recipients compared with an average-risk population. We reviewed 360 patients with solid organ transplants who underwent colonoscopy between February 1995 and July 2008, and 360 age- and gender-matched patients in an average-risk population. The mean duration from transplantation to colonoscopy in the SOT group was 40.4 ± 34.0 months. Ninety-three (25.8%) adenomas were detected in the SOT group, while 98 (27.2%) adenomas were detected in the control group (p = 0.763). There was a statistically significant difference (p < 0.0001) in the number of patients with advanced neoplasia in the SOT group (24 patients [6.7%]) compared with the control group (3 patients [0.8%]). The independent risk factors of advanced neoplasia were old age (odds ratio [OR], 1.067; 95% CI, 1.019-1.118) and transplantation (OR, 6.069; 95% CI, 1.455-25.314). In summary, there was a significant increase in the incidence of advanced colorectal neoplasia in SOT recipients. The reason for this finding is unclear, and studies with a larger number of patients are needed to further evaluate this group.     

SARS-CoV-2 in Solid Organ Transplant Recipients: A Structured Review of 2020

BackgroundThe severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic is challenging health systems all over the world. Particularly high-risk groups show considerable mortality rates after infection. In 2020, a huge number of case reports, case series, and consecutively various systematic reviews have been published reporting on morbidity and mortality risk connected with SARS-CoV-2 in solid organ transplant (SOT) recipients. However, this vast array of publications resulted in an increasing complexity of the field, overwhelming even for the expert reader.MethodsWe performed a structured literature review comprising electronic databases, transplant journals, and literature from previous systematic reviews covering the entire year 2020. From 164 included articles, we identified 3451 cases of SARS-CoV-2–infected SOT recipients.ResultsInfections resulted in a hospitalization rate of 84% and 24% intensive care unit admissions in the included patients. Whereas 53.6% of patients were reported to have recovered, cross-sectional overall mortality reported after coronavirus disease 2019 (COVID-19) was at 21.1%. Synoptic data concerning immunosuppressive medication attested to the reduction or withdrawal of antimetabolites (81.9%) and calcineurin inhibitors (48.9%) as a frequent adjustment. In contrast, steroids were reported to be increased in 46.8% of SOT recipients.ConclusionsCOVID-19 in SOT recipients is associated with high morbidity and mortality worldwide. Conforming with current guidelines, modifications of immunosuppressive therapies mostly comprised a reduction or withdrawal of antimetabolites and calcineurin inhibitors, while frequently maintaining or even increasing steroids. Here, we provide an accessible overview to the topic and synoptic estimates of expectable outcomes regarding in-hospital mortality of SOT recipients with COVID-19.     

Efficacy and safety of caspofungin in solid organ transplant recipients

Efficacy and safety data for the echinocandins in solid organ transplant (SOT) recipients are limited. We reviewed data from three clinical trials that enrolled SOT patients receiving caspofungin therapy for an invasive fungal infection (IFI). Caspofungin was administered at doses ranging from 50 to 100 mg/day. Efficacy was assessed in all patients at the end of caspofungin therapy (EOT). Adverse events (AE) and laboratory data were collected from all patients. We identified data from 22 SOT patients (aged 34-67 years) with proven invasive candidiasis (IC; 6 patients) or proven or probable invasive aspergillosis (IA; 16 patients) who received at least one dose of caspofungin therapy. All patients with IC received caspofungin as primary therapy. Caspofungin success against IC at EOT was 83% (5 of 6), with responses seen across Candida spp. Success by SOT type was: kidney 4 of 5 and liver 1 of 1. All 16 patients with IA (all pulmonary) received caspofungin as salvage therapy. Caspofungin success against IA at EOT was 50% (8 of 16), with responses seen for both definite (3 of 4) and probable IA (5 of 12). Success by SOT type was: heart 2 of 2, heart/lung 0 of 2, kidney 3 of 3, liver 1 of 3, and lung 2 of 6. The outcome was not influenced by caspofungin dose. Caspofungin, dosed for 2 to 162 (mean 36.8) days, was well tolerated. No patient had a serious drug-related adverse event or discontinued caspofungin due to toxicity. Based on these limited data, caspofungin appears to be an effective and well-tolerated option for the treatment of IC and IA in SOT recipients.     

Determining the conversion ratios for oral versus sublingual administration of tacrolimus in solid organ transplant recipients

Tacrolimus is utilized as maintenance immunosuppression in solid organ transplant (SOT). Current literature has reported conflicting conversion ratios when transitioning between oral and sublingual tacrolimus, and the exact conversion ratio has not been fully established in SOT. The purpose of this study was to determine the conversion ratios between oral and sublingual tacrolimus needed to achieve equivalent whole blood concentrations in heart, kidney, liver, and lung transplant recipients. A retrospective, single‐center analysis was conducted at Mayo Clinic in Florida. One hundred and eighteen hospitalized SOT recipients who received oral and sublingual tacrolimus during the same inpatient admission from June 1, 2012, through June 1, 2017, were reviewed. The median conversion ratio of sublingual to oral tacrolimus was 1.34 (IQR: 1.03‐1.93) in all SOT, 1.25 (IQR: 1.08‐1.64) in heart transplant, 1.23 (IQR: 1.1‐2.06) in kidney transplant, 1.64 (IQR: 1.27‐2.29) in liver transplant, and 1.34 (IQR: 0.94‐1.93) in lung transplant. A slightly higher dose of oral tacrolimus is needed in the majority of solid organ recipients in our population when converting between sublingual to oral tacrolimus administration.     

COVID‐19 in a high‐risk dual heart and kidney transplant recipient

The severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) is rapidly infecting people worldwide, resulting in the infectious disease coronavirus disease 19 (COVID‐19) that has been declared a pandemic. Much remains unknown about COVID‐19, including its effects on solid organ transplant (SOT) recipients. Given their immunosuppressed state, SOT recipients are presumed to be at high risk of complications with viral infections such as SARS‐CoV‐2. Limited case reports in single SOT recipients, however, have not suggested a particularly severe course in this population. In this report, we present a dual‐organ (heart/kidney) transplant recipient who was found to have COVID‐19 and, despite the presence of a number of risk factors for poor outcomes, had a relatively mild clinical course.     

Bloodstream infections among solid organ transplant recipients: Epidemiology,microbiology, associated risk factors for morbility and mortality

Bloodstream infections (BSIs) remain important causes of morbidity and mortality among solid organ transplant (SOT) recipients and still threaten the success of SOT. In general, among SOT recipients, risk factors for BSIs are associated with prior ICU admission, catheterization, older recipient or donor age…etc. Pulmonary focus, nosocomial source of BSIs, lack of appropriate antibiotic therapy and other variables have significant impacts on BSIs-related mortality in SOT. Most of BSIs in SOT are caused by gram-negative bacteria. However, all aspects including microbiological spectrum, morbidity and mortality rates, risk factors of BSIs and BSIs-related death depend on the type of transplantation. The purpose of this review is to summarize the epidemiology, microbiologic features including antimicrobial resistance of organisms, and associated risk factors for morbidity and mortality of BSIs according to different type of transplantation to better understand the characteristics of BSIs and improve the outcomes after SOT.     

Solid organ transplantation after hematopoietic stem cell transplantation in childhood: A multicentric retrospective survey

We report data obtained from a retrospective multicenter pediatric survey on behalf of the European Society for Blood and Marrow Transplantation (EBMT). Information on solid organ transplantation (SOT) performed in pediatric recipients of either autologous or allogeneic hematopoietic stem cell transplantation (HSCT) between 1984 and 2016 was collected in 20 pediatric EBMT Centers (25.6%). Overall, we evaluated data on 44 SOTs following HSCT including 20 liver (LTx), 12 lung (LuTx), 6 heart (HTx), and 6 kidney (KTx) transplantations. The indication for SOT was organ failure related to intractable graft‐vs‐host disease in 16 children (36.3%), acute or chronic HSCT‐related toxicity in 18 (40.9%), and organ dysfunction related to the underlying disease in 10 (22.8%). The median follow‐up was 10.9 years (95% confidence interval: 1.7‐29.5). The overall survival rate at 1 and 5 years after SOT was 85.7% and 80.4%, respectively: it was 74% and 63.2% after LTx, 83.2% after HTx, and 100% equally after LuTx and KTx. This multicenter survey confirms that SOT represents a promising option in children with severe organ failure occurring after HSCT. Additional studies are needed to further establish the effectiveness of SOT after HSCT and to better understand the mechanism underlying this encouraging success.     

Clinical outcomes of polyvalent immunoglobulin use in solid organ transplant recipients: A systematic review and meta‐analysis – Part II: Non‐kidney transplant

Immunoglobulin (IG) is commonly used to desensitize and treat antibody‐mediated rejection in solid organ transplant (SOT) recipients. The impact of IG on other outcomes such as infection, all‐cause mortality, graft rejection, and graft loss is not clear. We conducted a similar systematic review and meta‐analysis to our previously reported Part I excluding kidney transplant. A comprehensive literature review found 16 studies involving the following organ types: heart (6), lung (4), liver (4), and multiple organs (2). Meta‐analysis could only be performed on mortality outcome in heart and lung studies due to inadequate data on other outcomes. There was a significant reduction in mortality (OR 0.34 [0.17‐0.69]; 4 studies, n = 455) in heart transplant with hypogammaglobulinemia receiving IVIG vs no IVIG. Mortality in lung transplant recipients with hypogammaglobulinemia receiving IVIG was comparable to those of no hypogammaglobulinemia (OR 1.05 [0.49, 2.26]; 2 studies, n = 887). In summary, IVIG targeted prophylaxis may decrease mortality in heart transplant recipients as compared to those with hypogammaglobulinemia not receiving IVIG, or improve mortality to the equivalent level with those without hypogammaglobulinemia in lung transplant recipients, but there is a lack of data to support physicians in making decisions around using immunoglobulins in all SOT recipients for infection prophylaxis.     

Health-related quality of life,uncertainty and coping strategies in solid organ transplant recipients during shielding for the COVID-19 pandemic

Strict isolation of vulnerable individuals has been a strategy implemented by authorities to protect people from COVID-19. Our objective was to investigate health-related quality of life (HRQoL), uncertainty and coping behaviours in solid organ transplant (SOT) recipients during the COVID-19 pandemic. A cross-sectional survey of adult SOT recipients undergoing follow-up at our institution was performed. Perceived health status, uncertainty and coping strategies were assessed using the EQ-5D-5L, Short-form Mishel Uncertainty in Illness Scale (SF-MUIS) and Brief Cope, respectively. Interactions with COVID-19 risk perception, access to health care, demographic and clinical variables were assessed. The survey was completed by 826 of 3839 (21.5%) invited participants. Overall, low levels of uncertainty in illness were reported, and acceptance was the major coping strategy (92%). Coping by acceptance, feeling protected, self-perceived susceptibility to COVID-19 were associated with lower levels of uncertainty. Health status index scores were significantly lower for those with mental health illness, compromised access to health care, a perceived high risk of severe COVID-19 infection and higher levels of uncertainty. A history of mental health illness, risk perceptions, restricted healthcare access, uncertainty and coping strategies was associated with poorer HRQoL in SOT recipients during strict isolation. These findings may allow identification of strategies to improve HRQoL in SOT recipients during the pandemic.     

Impact of COVID-19 in solid organ transplant recipients

The coronavirus disease 2019 (COVID-19) pandemic caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) exploded onto the world stage in early 2020. The impact on solid organ transplantation (SOT) has been profound affecting potential donors, candidates, and recipients. Importantly, decreased donations and the pressure of limited resources placed on health care by the pandemic also disrupted transplant systems. We address the impact of COVID-19 on organ transplantation globally and review current understanding of the epidemiology, outcomes, diagnosis, and treatment of COVID-19 in SOT recipients.