Severe COVID‐19 in a renal transplant recipient: A focus on pharmacokinetics

The current coronavirus disease 2019 (COVID‐19) pandemic requires extra attention for immunocompromised patients, including solid organ transplant recipients. We report on a case of a 35‐year‐old renal transplant recipient who suffered from a severe COVID‐19 pneumonia. The clinical course was complicated by extreme overexposure to the mammalian target of rapamycin inhibitor everolimus, following coadministration of chloroquine and lopinavir/ritonavir therapy. The case is illustrative for dilemmas that transplant professionals may face in the absence of evidence‐based COVID‐19 therapy and concurrent pressure for exploration of experimental pharmacological treatment options. However, the risk‐benefit balance of experimental or off‐label therapy may be weighed differently in organ transplant recipients than in otherwise healthy COVID‐19 patients, owing to their immunocompromised status and potential drug interactions with immunosuppressive therapy. With this case report, we aimed to achieve increased awareness and improved management of drug‐drug interactions associated with the various treatment options for COVID‐19 in renal transplant patients.     

COVID‐19 pneumonia in a kidney transplant recipient successfully treated with tocilizumab and hydroxychloroquine

Coronavirus disease 2019 (COVID‐19) pneumonia has been poorly reported in solid organ transplanted patients; prognosis is uncertain and best management unclear. We describe the case of a 61‐year‐old kidney transplant recipient with several comorbidities who was hospitalized and later received a diagnosis of COVID‐19 pneumonia; the infection was successfully managed with the use of hydroxychloroquine and a single administration of tocilizumab, after immunosuppression reduction; the patient did not require mechanical ventilation. During the rapid spread of severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) pandemic, transplant clinicians should be readily informed about new cases of COVID‐19 pneumonia in solid organ transplant recipients, with focus on therapeutic strategies employed and their outcome.     

Spotting the owl: surreptitious cytomegalovirus disease in a renal transplant recipient

Abstract:  Cytomegalovirus (CMV) is a known cause of ulcerative oral lesions among HIV-infected patients, but such ulcers have not been previously reported in recipients of solid organ transplants. We describe a case of a renal transplant recipient who developed severe CMV-associated oral lesions despite prophylaxis with valganciclovir, and in the absence of detectable CMV viremia. The diagnosis was made only after multiple biopsies of the lesions. The patient recovered upon reducing immunosuppression. Potential pitfalls in making a prompt diagnosis are reviewed. The differential diagnosis of a large oral ulceration in a transplant recipient is broad, but should include CMV infection.     

Outcomes of Pediatric Kidney Transplantation in Recipients of a Previous Non‐Renal Solid Organ Transplant

Children who receive a non‐renal solid organ transplant may develop secondary renal failure requiring kidney transplantation. We investigated outcomes of 165 pediatric kidney transplant recipients who previously received a heart, lung, or liver transplant using data from 1988 to 2012 reported to the United Network for Organ Sharing. Patient and allograft survival were compared with 330 matched primary kidney transplant (PKT) recipients. Kidney transplantation after solid organ transplant (KASOT) recipients experienced similar allograft survival: 5‐ and 10‐year graft survival was 78% and 60% in KASOT recipients, compared to 80% and 61% in PKT recipients (p = 0.69). However, KASOT recipients demonstrated worse 10‐year patient survival (75% KASOT vs. 97% PKT, p < 0.001). Competing risks analysis indicated that KASOT recipients more often experienced graft loss due to patient death (p < 0.001), whereas allograft failure per se was more common in PKT recipients (p = 0.01). To study more recent outcomes, kidney transplants performed from 2006 to 2012 were separately investigated. Since 2006, KASOT and PKT recipients had similar 5‐year graft survival (82% KASOT vs. 83% PKT, p = 0.48), although 5‐year patient survival of KASOT recipients remained inferior (90% KASOT vs. 98% PKT, p < 0.001). We conclude that despite decreased patient survival, kidney allograft outcomes in pediatric KASOT recipients are comparable to those of PKT recipients.     

Emergence of drug-resistant cytomegalovirus in the era of valganciclovir prophylaxis: therapeutic implications and outcomes

Abstract: Background: Valganciclovir prophylaxis is reportedly associated with a low incidence of ganciclovir‐resistant cytomegalovirus (CMV). We assessed the incidence, clinical features, and outcome of drug‐resistant CMV among solid organ transplant patients who received valganciclovir prophylaxis. Methods: The medical records of all CMV D+/R? kidney, pancreas, liver, and heart recipients were screened for CMV disease, and the clinical course and outcomes of patients with drug‐resistant CMV were reviewed. Results: During a four‐yr‐study period, a total of 225 CMV D+/R? transplant patients received valganciclovir prophylaxis for a median of 92 d. Sixty‐five (29%) of the 225 patients developed delayed‐onset primary CMV disease, including nine (14%) suspected to have drug‐resistant virus. Four (6.2%) had confirmed UL97 or UL54 mutations. All except one patient manifested gastrointestinal tissue‐invasive disease. Together with reduction in immunosuppression, intravenous foscarnet with or without CMV hyperimmunoglobulin was the most common treatment. Drug‐associated nephrotoxicity was commonly observed and resulted in allograft loss in two patients. During the mean follow‐up of 2.2 yr, allograft loss and mortality occurred in two of four patients with proven and in three of five patients with clinically suspected drug‐resistant CMV. Conclusions: Cytomegalovirus disease because of clinically suspected or genotypically confirmed drug‐resistant CMV is not uncommon in CMV D+/R? solid organ transplant patients who received valganciclovir prophylaxis. Because of its significant morbidity and mortality, an optimized strategy of CMV prevention is warranted to reduce the negative impact of drug‐resistant CMV on the successful outcome of organ transplantation.     

Interactions between anti‐infective agents and immunosuppressants—Guidelines from the American Society of Transplantation Infectious Diseases Community of Practice

These updated guidelines from the Infectious Diseases Community of Practice of the American Society of Transplantation provide an update on potential drug‐drug interactions between anti‐infectives and immunosuppressants, which are most notable with calcineurin and mTOR inhibitors. Drug‐drug interactions may occur through pharmacokinetic mechanisms leading to altered drug concentrations of either the anti‐infective or immunosuppressive drug, or by pharmacodynamic interactions increasing or decreasing the efficacy or toxicity of the medications. Many of the significant pharmacokinetic interactions occur through inhibition or induction of the cytochrome 3A4 system by anti‐infective agents leading to increased or decreased immunosuppressive agent levels, respectively. The membrane transporter P‐glycoprotein is also often involved in drug interactions. Since the last iteration of these guidelines, multiple new hepatitis C virus direct‐acting antivirals have become available for use in SOT recipients. Of these agents, some are substrates of cytochrome and drug transporter systems, while others inhibit these systems and may affect immunosuppressive agents. Due to the high risk for drug‐drug interactions in the solid organ transplant population, practitioners must be aware of potential interactions and be vigilant in monitoring and adjusting drug dosing when appropriate.     

Combination of caspofungin and low‐dose trimethoprim/sulfamethoxazole for the treatment of severe Pneumocystis jirovecii pneumonia in renal transplant recipients

Pneumocystis jirovecii pneumonia (PJP) is a severe and life‐threatening complication in immunocompromised patients. Trimethoprim/sulfamethoxazole (TMP‐SMZ) is well known for its effectiveness as prophylaxis of PJP. However, the use of TMP‐SMZ is associated with various adverse effects that may not be tolerated by critically ill patients. Caspofungin is recommended for invasive fungal infections, but the treatment of PJP after solid organ transplantation (SOT) is an off‐label use of this drug. In this study, three cases of severe PJP in renal transplant recipients treated with a combination of caspofungin and low‐dose TMP‐SMZ were presented. Initial findings indicated that the combined treatment may be beneficial for the treatment of PJP and decrease the incidence of TMP‐SMZ‐related adverse effects.     

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.     

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.     

Utilization of direct-acting oral anticoagulation in solid organ transplant patients: A national survey of institutional practices

The safety and efficacy of direct-acting oral anticoagulants (DOACs) and reversal strategies are not well established in the solid organ transplant population. This was a survey of pharmacists to assess DOAC and urgent reversal practices among adult transplant programs in the United States. A 27-question survey was distributed to members of transplant pharmacy organization listservs between 5/28/19 and 6/30/19. A total of 115 responses were received from kidney (43.5%), heart (20.0%), lung (18.3%), liver (13.9%), and pancreas (4.4%) transplant programs. DOAC use prior to transplant was mostly prohibited in thoracic programs (77.3%) but more permissive in kidney transplant programs (64.0%). If permitted, apixaban (57.8%) was most preferred. At transplant surgery, reversal of DOAC was performed “as needed” (20.9%) or was not routine (18.3%). DOAC use post-transplant was more permissive (94.3%). A majority of responders follow FDA recommended dosing in the setting of drug-drug interactions (51.1%). Major factors influencing DOAC prescribing decisions included renal function, drug-drug interactions, and insurance. High clinical practice variability exists regarding DOAC utilization and urgent reversal strategies in pre-, peri-, and post-transplant stages. While more research is needed to refine the clinical landscape, many institutions are using DOAC therapy under the perception that they pose a similar risk of bleeding compared to a non-transplant population.     

Transplantation of solid organ recipients shedding Epstein‐Barr virus DNA pre‐transplant: A prospective study

Epstein‐Barr virus (EBV) poses a significant threat to patient and graft survival post‐transplant. We hypothesized that recipients who shed EBV at transplant had less immunologic control of the virus and hence were more likely to have active EBV infection and disease post‐transplant. To test this hypothesis, we conducted a 5‐year prospective study in primary solid organ transplant recipients. We measured EBV DNA in oral washes and blood samples by quantitative PCR before transplant and periodically thereafter for up to 4 years. Pre‐transplant samples were available from 98 subjects. EBV DNA was detected pre‐transplant in 32 of 95 (34%) and 5 of 93 subjects (5%) in oral wash and blood, respectively. Recipients with and without detectable pre‐transplant EBV DNA were not significantly different demographically and had no significant difference in patient and graft survival (P = .6 for both comparisons) or post‐transplant EBV viremia‐free survival (P = .8). There were no cases of EBV‐related disease or post‐transplant lymphoproliferative disorder (PTLD) in any of the patients with detectable EBV DNA pre‐transplant. In conclusion, detectable EBV DNA pre‐transplant was not associated with differences in patient/graft survival, post‐transplant EBV viremia, or EBV‐related diseases including PTLD.     

Cytomegalovirus in solid organ transplant recipients—Guidelines of the American Society of Transplantation Infectious Diseases Community of Practice

Cytomegalovirus (CMV) is one of the most common opportunistic infections that affect the outcome of solid organ transplantation. This updated guideline from the American Society of Transplantation Infectious Diseases Community of Practice provides evidence‐based and expert recommendations for screening, diagnosis, prevention, and treatment of CMV in solid organ transplant recipients. CMV serology to detect immunoglobulin G remains as the standard method for pretransplant screening of donors and transplant candidates. Antiviral prophylaxis and preemptive therapy are the mainstays of CMV prevention. The lack of a widely applicable viral load threshold for diagnosis and preemptive therapy is highlighted, as a result of variability of CMV nucleic acid testing, even in the contemporary era when calibrators are standardized. Valganciclovir and intravenous ganciclovir remain as drugs of choice for CMV management. Strategies for managing drug‐resistant CMV infection are presented. There is an increasing use of CMV‐specific cell‐mediated immune assays to stratify the risk of CMV infection after solid organ transplantation, but their role in optimizing CMV prevention and treatment efforts has yet to be demonstrated. Specific issues related to pediatric transplant recipients are discussed.     

Outcome of kidney transplant in primary,repeat, and kidney‐after‐nonrenal solid‐organ transplantation: 15‐year analysis of recent UNOS database

The number of nonrenal solid‐organ transplants increased substantially in the last few decades. Many of these patients develop renal failure and receive kidney transplantation. The aim of this study was to evaluate patient and kidney allograft survival in primary, repeat, and kidney‐after‐nonrenal organ transplantation using national data reported to United Network for Organ Sharing (UNOS) from January 2000 through December 2014. Survival time for each patient was stratified into the following: Group A (comparison group)—recipients of primary kidney transplant (178 947 patients), Group B—recipients of repeat kidney transplant (17 819 patients), and Group C—recipients of kidney transplant performed after either a liver, heart, or lung transplant (2365 patients). We compared survivals using log‐rank test. Compared to primary or repeat kidney transplant, patient and renal allograft survival was significantly lower in those with previous nonrenal organ transplant. Renal allograft and patient survival after liver, heart, or lung transplants are comparable. Death was the main cause of graft loss in patients who had prior nonrenal organ transplant.     

Chemotherapy,targeted therapy and immunotherapy: Which drugs can be safely used in the solid organ transplant recipients?

In solid organ transplant recipients, cancer is associated with worse prognosis than in the general population. Among the causes of increased cancer-associated mortality, are the limitations in selecting the optimal anticancer regimen in solid organ transplant recipients, because of the associated risks of graft toxicity and rejection, drug-to-drug interactions, reduced kidney or liver function, and patient frailty and comorbid conditions. The advent of immunotherapy has generated further challenges, mainly because checkpoint inhibitors increase the risk of rejection, which may have life-threatening consequences in recipients of life-saving organs. In general, there are no safe or unsafe anticancer drugs. Rather, the optimal choice of the anticancer regimen results from a careful risk/benefit assessment, from the awareness of potential pharmacokinetic and pharmacodynamic drug-to-drug interactions, and of the risk of drug overexposure in patients with kidney or liver dysfunction. In this review, we summarize general principles that may help the oncologists and transplant physicians in the multidisciplinary management of recipients of solid organ transplantation with cancer who are candidates for chemotherapy, targeted therapy, or immunotherapy.     

Travel medicine,transplant tourism,and the solid organ transplant recipient—Guidelines from the American Society of Transplantation Infectious Diseases Community of Practice

These updated guidelines from the Infectious Diseases Community of Practice of the American Society of Transplantation review recommendations for prevention and management of travel‐related infection in solid organ transplant (SOT) recipients as well as risks associated with transplant tourism. Counseling regarding travel post‐transplant should be included during the pre‐transplant evaluation, and all SOT recipients should be seen by a travel medicine specialist prior to traveling to destinations with higher rates of infection. Patients should be advised on vaccine‐preventable illnesses as well as any need for prophylaxis (ie, malaria) based on their individual travel itineraries. Information with regards to specific recommendations for vaccines and prophylactic medications, along with drug‐drug interactions, is summarized. Counseling should be provided for modifiable risks and exposures (ie, food and water safety, and insect bite prevention) as well as non‐infectious travel topics. These guidelines also briefly address risks associated with transplant tourism and specific infections to consider if patients seek care for transplants done in foreign countries.     

Clinical characteristics and immunosuppressant management of coronavirus disease 2019 in solid organ transplant recipients

Over 1 000 000 cases of coronavirus disease 2019 (COVID‐19) have been confirmed since the worldwide outbreak began. Not enough data on infected solid organ transplant (SOT) recipients are available, especially data about the management of immunosuppressants. We report two cases of COVID‐19 in two transplant recipients, with different treatments and prognoses. The first patient received liver transplantation due to hepatitis B virus–related hepatocellular carcinoma and was confirmed to have COVID‐19 9 days later. Following a treatment regimen consisting of discontinued immunosuppressant use and low‐dose methylprednisolone‐based therapy, the patient developed acute rejection but eventually recovered. The other patient had undergone a renal transplant from a living‐related donor 17 years ago, and was admitted to the hospital because of persistent fever. This patient was also diagnosed with COVID‐19. His treatment regimen consisted of reduced immunosuppressant use. No signs of rejection were observed during the regimen. In the end, the patient successfully recovered from COVID‐19. These effectively treated cases can provide a basis for immunosuppressant management of COVID‐19‐positive SOT recipients.     

Urinary tract infections in solid organ transplant recipients: Guidelines from the American Society of Transplantation Infectious Diseases Community of Practice

These updated guidelines from the Infectious Diseases Community of Practice of the American Society of Transplantation review the diagnosis, prevention, and management of urinary tract infections (UTI) in solid organ transplantation, focusing on kidney transplant (KT) recipients. KT recipients have unique risk factors for UTI, including indwelling stents and surgical manipulation of the genitourinary tract. KT recipients experience multi‐drug antibiotic‐resistant infections—UTI prevention and management strategies must consider risks of antimicrobial resistance. Non‐antimicrobial prevention strategies for UTI in KT recipients are reviewed. It is important to recognize that some renal transplant recipients with UTI may primarily present with fever, malaise, leukocytosis, or a non‐specific sepsis syndrome without symptoms localized to the urinary tract. However, asymptomatic bacteriuria (AB) must be distinguished from UTI because AB is not necessarily a disease state. Accumulating data indicate that there are no benefits of antibiotics for treatment of AB in KT recipients more than 2 months after post‐transplant. Further research is needed on management of AB in the early (<2 months) post‐transplant period, prophylaxis for UTI in this era of antibiotic resistance, recurrent UTI, non‐antimicrobial prevention of UTI, and uropathogens identified in donor urine and/or preservative fluid cultures.     

The Use of Non–Vitamin K Antagonist Oral Anticoagulants in Post-Kidney Transplantation,Single-Center Experience

BackgroundNovel oral anticoagulants (NOACs) are widely used alternatives to warfarin, because they do not require routine monitoring and have better safety profile. There is limited experience for NOACs in organ transplant recipients.MethodsThis study assessed NOAC safety and efficacy among renal transplant recipients in a single center. A retrospective matched cohort study was conducted among the adult renal transplant recipients concomitantly administered calcineurin inhibitors (tacrolimus or cyclosporin) and NOACs between November 2015 and December 2019.ResultsThe study included 16 patients divided into 2 equal groups on NOACs and warfarin. Male patients constitute 50% and 75% of the NOAC group and warfarin group, respectively, and 75% and 87.5% of cases are post living donor transplants in the NOAC group and warfarin group, respectively. In the NOAC group, the most common indication for anticoagulation was atrial fibrillation (62.5%), followed by deep vein thrombosis (37.5%), whereas in the warfarin group, the most common indication was atrial fibrillation (50%), followed by valve replacement (25%). In the NOAC group, 6 patients (75%) received rivaroxaban, 1 patient (12.5%) received dabigatran, and 1 patient (12.5%) received apixaban; 68.75% of patients were on a tacrolimus-based regimen. There were no thromboembolic events, rejection episodes, bleeding, or admissions due to NOAC adverse events. There were 3 cases of bleeding in the warfarin group. Calcineurin inhibitor levels and estimated glomerular filtration rate did not change significantly in the NOAC group (P = .34 and .96, respectively).ConclusionsCompared to warfarin, NOACs are well tolerated and effective for preventing and treating thromboembolic events in renal transplant recipients. A larger randomized controlled study is required.     

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.