Zygomycosis and other rare filamentous fungal infections in solid organ transplant recipients.

Fungi cause severe infections in solid organ transplant (SOT) recipients. Recently, a shift towards non-Aspergillus filamentous fungal infections (nAFFI) was noticed. In a series of 2878 SOTs (kidney, pancreas, islets, liver, heart, lung, and bowel) performed between January 1995 and December 2006 at the Innsbruck medical university, eleven cases of nAFFI were diagnosed. The encountered species included Zygomyzetes (n = 8), and Alternaria alternate, Pseudallescheria boydii, Trichoderma spp. (one each); there were three liver and three heart, one intestinal, pancreas, lung, bilateral forearm and renal recipient each. Five patients died from nAFFI (zygomycosis: 4, Pseudallerichia boydii: 1); four were diagnosed postmortem. In five cases infection was surgically treated in combination with antifungals. Risk factors for nAFFI were renal failure (73%) and intensified immunosuppression (73%); two cases were associated with post-transplant lymphoproliferative disorder, one with graft versus host disease. An increase in the incidence of nAFFI was observed parallel to introduction of caspofungin and voriconazole (three cases until 12/2003, seven cases thereafter). NAFFI are increasingly found in SOT recipients. If diagnosed in time, the outcome seems acceptable. Intensified immunosuppression and exposure to antifungals not active against zygomycetes may be risk factors. Surgical therapy may play an important role in these infections.     

COVID-19 in solid organ transplant recipients: a single-center experience

Solid organ transplant (SOT) recipients may be at risk for severe COVID-19. Data on the clinical course of COVID-19 in immunosuppressed patients are limited, and the effective treatment strategy for these patients is unknown. We describe our institutional experience with COVID-19 in SOT. Demographic, clinical, and treatment data were extracted from the electronic patient files. A total of 23 SOT transplant recipients suffering from COVID-19 were identified (n = 3 heart; n = 15 kidney; n = 1 kidney-after-heart; n = 3 lung, and n = 1 liver transplant recipient). The presenting symptoms were similar to nonimmunocompromised patients. Eighty-three percent (19/23) of the patients required hospitalization, but only two of these were transferred to the intensive care unit. Five patients died from COVID-19; all had high Clinical Frailty Scores. In four of these patients, mechanical ventilation was deemed futile. In 57% of patients, the immunosuppressive therapy was not changed and only three patients were treated with chloroquine. Most patients recovered without experimental antiviral therapy. Modification of the immunosuppressive regimen alone could be a therapeutic option for SOT recipients suffering from moderate to severe COVID-19. Pre-existent frailty is associated with death from COVID-19.     

Hematologic complications of anti-CMV therapy in solid organ transplant recipients

Abstract:  Cytomegalovirus (CMV) infection complicates the post-operative course of patients receiving solid organ transplants. While ganciclovir has significantly reduced the direct effects of CMV infection, some patients cannot tolerate the optimal therapeutic exposure required for CMV prevention and treatment. Few reports directly address the incidence, consequences, and risk factors for hematologic toxicities related to ganciclovir therapy. Nevertheless, leukopenia, thrombocytopenia, and anemia occur in 5–50% of patients. Current strategies, focused on ganciclovir dose reduction, may increase the risk of CMV reactivation and drug-resistant disease. The current article reviews the incidence, risk factors, and consequences of ganciclovir-associated hematologic adverse events in transplant recipients. Management strategies, including ganciclovir dose reduction, and the addition of CMV hyperimmune globulin are discussed. Exposing this relatively frequently occurring, but uncommonly discussed, toxicity should lead to better avoidance and treatment strategies, without placing patients at increased risk of CMV disease.     

Graft-vs.-host disease in lung and other solid organ transplant recipients

Graft-vs.-host disease (GVHD) is an uncommon complication of solid organ transplantation. Herein, we report a case of GVHD occurring in a lung transplant recipient and review 29 reported cases of GVHD that complicated thoracic organ, and non-hepatic intra-abdominal organ transplantation. The major presenting clinical symptom of GVHD was skin rash. Less frequent clinical manifestations were cytopenia (16%), diarrhea (11%), and fever (5%). The mainstay of treatment was high-dose corticosteroids. The mortality rate was high (30%). The cause of death was mainly due to infection, suggesting that antimicrobial prophylaxis may improve the outcome of this potentially fatal complication.     

De novo coccidioidomycosis among solid organ transplant recipients 1 or more years after transplant

Solid organ transplant recipients who contract coccidioidomycosis are at risk for complicated, protracted, disseminated, and severe disease. To date, no studies have described outcomes for patients who develop coccidioidomycosis only after the first posttransplant year. This study was a joint project of Mayo Clinic Hospital, Phoenix, Arizona, and the University of Arizona/Banner University Medical Center, Tucson, Arizona. We retrospectively reviewed electronic health records for patients with a history of solid organ transplant between January 1, 1998, and October 11, 2014, who developed coccidioidomycosis after the first transplant year. We identified 91 patients. Of those, 37/91 (40.7%) had pulmonary coccidioidomycosis (29/37 [78.4%] were symptomatic); and 5/91 (5.5%) had extrapulmonary disease (all were symptomatic). One patient (1.1%) died. Coccidioidomycosis was evident in 2/91 (2.2%) patients within 3 months of antirejection treatment. Many of the patients (51/91 [56.0%]) had asymptomatic coccidioidomycosis, 27 (27.9%) of whom were followed up closely but did not receive antifungal medication and had no sequelae. Although solid organ recipients taking low‐level immunosuppression after the first posttransplant year appeared to have less symptomatic, disseminated, or fatal coccidioidal infection than historical cohorts, this remains an important infection with morbidity and mortality even after the first posttransplant year.     

COVID‐19 in solid organ transplant recipients: A single‐center case series from Spain

The clinical characteristics, management, and outcome of coronavirus disease 2019 (COVID‐19) caused by severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) after solid organ transplant (SOT) remain unknown. We report our preliminary experience with 18 SOT (kidney [44.4%], liver [33.3%], and heart [22.2%]) recipients diagnosed with COVID‐19 by March 23, 2020 at a tertiary‐care center at Madrid. Median age at diagnosis was 71.0 ± 12.8 years, and the median interval since transplantation was 9.3 years. Fever (83.3%) and radiographic abnormalities in form of unilateral or bilateral/multifocal consolidations (72.2%) were the most common presentations. Lopinavir/ritonavir (usually associated with hydroxychloroquine) was used in 50.0% of patients and had to be prematurely discontinued in 2 of them. Other antiviral regimens included hydroxychloroquine monotherapy (27.8%) and interferon‐β (16.7%). As of April 4, the case‐fatality rate was 27.8% (5/18). After a median follow‐up of 18 days from symptom onset, 30.8% (4/13) of survivors developed progressive respiratory failure, 7.7% (1/13) showed stable clinical condition or improvement, and 61.5% (8/13) had been discharged home. C‐reactive protein levels at various points were significantly higher among recipients who experienced unfavorable outcome. In conclusion, this frontline report suggests that SARS‐CoV‐2 infection has a severe course in SOT recipients.     

Patterns of kidney injury in pediatric nonkidney solid organ transplant recipients

The incidence of acute kidney injury (AKI) and its impact on chronic kidney disease (CKD) following pediatric nonkidney solid organ transplantation is unknown. We aimed to determine the incidence of AKI and CKD and examine their relationship among children who received a heart, lung, liver, or multiorgan transplant at the Hospital for Sick Children between 2002 and 2011. AKI was assessed in the first year posttransplant. Among 303 children, perioperative AKI (within the first week) occurred in 67% of children, and AKI after the first week occurred in 36%, with the highest incidence among lung and multiorgan recipients. Twenty‐three children (8%) developed CKD after a median follow‐up of 3.4 years. Less than 5 children developed end‐stage renal disease, all within 65 days posttransplant. Those with 1 AKI episode by 3 months posttransplant had significantly greater risk for developing CKD after adjusting for age, sex, and estimated glomerular filtration rate at transplant (hazard ratio: 2.77, 95% confidence interval, 1.13‐6.80, P trend = .008). AKI is common in the first year posttransplant and associated with significantly greater risk of developing CKD. Close monitoring for kidney disease may allow for earlier implementation of kidney‐sparing strategies to decrease risk for progression to CKD.     

Fungal infection in cardiothoracic transplant recipients: outcome without systemic amphotericin therapy

Transplant recipients require immunosuppression to prevent allograft rejection, placing them at risk of opportunistic infections including fungal infection. Difficulties in managing fungal infections include: establishing diagnosis, poor treatment response, drug interactions and toxicity. We report our single centre experience of treating fungal infections using systemic non-Amphotericin current generation antifungals. Patients receiving inpatient antifungal therapy from September 2005 to December 2010 were identified from pharmacy records. Fungal infections were retrospectively classified according to European Organization for Research and Treatment of Cancer (EORTC) criteria. Treatment outcomes were classified in a manner similar to those used in clinical trials. Two hundred and forty-nine recipients received antifungal treatment, 204 lungs and 45 hearts. One hundred and one patients received Voriconazole, 82 Caspofungin and 65 received both agents. One patient was unsuccessfully treated with additional Amphotericin. Treatment duration varied from 1.5 to 12 weeks. One hundred and sixty-five patients had a complete response, 24 had a partial response and in 60 patients treatment was unsuccessful. The response to systemic non-Amphotericin based antifungal therapy was high. We propose that diagnostic criteria without positive identification of a fungus allow treatment to be started early with few clinically relevant side effects.     

CMV-hyperimmune globulin for preventing cytomegalovirus infection and disease in solid organ transplant recipients: a meta-analysis

Abstract. Objective: The goal of this meta-analysis was to investigate the impact of cytomegalovirus hyperimmune globulin (CMVIG) on cytomegalovirus (CMV) infection, CMV disease, and mid-term survival in solid organ transplant recipients. Methods: Medline, EMBASE, and the Cochrane databases were searched since their inceptions until 2006. Inclusion criteria comprised: prospective randomized trials, in solid organ transplantation which received CMV prophylaxis including CMVIG on one of the treatment arms. Random effects models were used to calculate pooled risk ratios (RR) and meta-regression was employed to explain study heterogeneity. Stratified analyses were conducted and Funnel plot was used to assess publication bias. Results: Literature searches identified 11 randomized trials (698 patients; median follow-up: 12 months, range: 3–22 months) including six randomized trials (302 patients) after kidney transplantation. The analysis demonstrated a beneficial effect of the prophylactic use of CMVIG on total survival [RR (95% confidence interval; CI): 0.67 (0.47–0.95)] and prevention of CMV-associated death [RR (95% CI): 0.45 (0.24–0.84)] in solid organ transplant recipients but not kidney transplant recipients [RR (95% CI): 0.35 (0.12–1.04)]. CMV disease was significantly reduced in all recipients receiving prophylactic CMVIG [RR (95% CI): 0.697 (0.57–0.85)]. CMVIG had no impact on CMV-infections and clinically relevant rejections. Conclusions: Prophylactic administration of CMVIG after solid organ transplantation is associated with improved total survival, reduced CMV disease, and CMV-associated deaths.     

Group milleri streptococci: significant pathogens in solid organ recipients

Group milleri streptococci (GMS) comprise a heterogeneous group of streptococci including the species intermedius, constellatus and anginosus. They may cause chronic intra-abdominal and intrathoracic abscesses, which are difficult to treat. This is a retrospective analysis including 45 transplant recipients in whom GMS were isolated. The epidemiology, clinical significance and the impact on the outcome in all transplant patients with infections caused by GMS during a 4-year period (2001-2004) was evaluated. The 45 solid organ recipients (88 isolates) included 34 liver-, four kidney/pancreas-, one kidney-, two small bowel-, three combined liver/kidney- and one combined kidney/small bowel transplant recipient. In 42 cases GMS caused intra-abdominal infection, in two cases pleural empyema and in one case soft tissue infection. Only a single isolate of GMS was cultured from blood. In 54 of the 88 specimens (61%), which grew GMS, other pathogens were also isolated. GMS frequently caused recurrent cholangitis (n = 17) associated with anastomotic and nonanastomotic biliary strictures. These cases were managed by repeated stenting or surgical intervention and prolonged antibiotic therapy. No patient died directly related to GMS infection and all except one case responded to combined surgical/antibiotic treatment. One pancreas graft was lost because of erosion haemorrhage associated with an abscess. GMS were susceptible to penicillin G, carbapenems and clindamycin, whereas cephalosporins and quinolones showed intermediate activity or resistance in some cases, and GMS in general were found resistant to aminoglycosides. GMS may cause serious infections in transplant recipients which are difficult to treat. Their prevalence in transplant surgical site infections thus far may have been underestimated.     

Evaluation of the coagulation and inflammatory responses in solid organ transplant recipients and donors

Abstract: New strategies that modify the coagulation/inflammatory cascades may be applicable to solid organ transplant (SOT) recipients in the treatment of complications. However, data on kinetics of post‐SOT cascades are needed before considering these strategies. Prospectively collected pre‐transplant serum measurements of inflammatory (high‐sensitive C‐reactive protein, HS‐CRP) and coagulation (d ‐Dimer, DD; protein C, PC) markers were compared to post‐operative (day 1–90) values in deceased‐donor liver (DDLT) and renal (DDRT) transplant recipients, living‐related renal recipients (LRT) and donors (LRD). A total of 85 SOT were enrolled: 25 DDLT, 32 DDRT/LRT, 28 LRD. HS‐CRP increased in all groups, mainly immediate post‐SOT and in LRDs. DD had a similar pattern mainly in LRT and LRD. PC increased significantly over time in the DDLT group ( p < 0.01). Compared to those with no complications (infection, rejection or thrombosis), day 30 HS‐CRP (p = 0.04) and DD (p = 0.06) were elevated in the DDRT/LRT group with complications; PC was decreased at day 7 (p = 0.04) and day 30 (p = 0.009) in DDLT and DDRT/LRT groups with complications, respectively. In conclusion, activation of the inflammatory/coagulation cascades occurs after SOT and is least pronounced in DDLT. This activation diminishes over time unless transplant complications occur. Our results support further research in approaches to altering these cascades in SOT recipients.     

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.     

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.