Lymphopenia is associated with late onset Pneumocystis jirovecii pneumonia in solid organ transplantation.

BACKGROUND: Pneumocystis jirovecii pneumonia (PJP) affected 5%-15% of solid organ transplant (SOT) recipients prior to universal prophylaxis, classically with trimethoprim-sulfamethoxazole (TMP-SMX). Guidelines generally recommend 6-12 months of prophylaxis post-SOT, yet optimal duration and robust PJP risk stratification have not been established. METHODS: A retrospective, single-center, case-control study of PJP among SOT recipients from January 1998 to December 2013 was conducted. Cases had positive PJ direct fluorescent antibody assay of respiratory specimens. Controls were matched 4:1 by nearest date of SOT. Univariate testing and multivariate logistic regressions were performed. RESULTS: Fifteen cases were identified among 5505 SOT recipients (0.27% rate) and analyzed vs 60 controls. PJP occurred on average 6.1 years (range 0.9-13.8) post-SOT; no case was receiving PJP prophylaxis at diagnosis. Most were treated with reduced immunosuppression and TMP-SMX plus steroids (80%). Six patients (40%) required critical care; 3 (20%) died. There were no significant demographic differences, though cases tended to be older at SOT (54 vs 48 years, P = .1). In univariate analysis, prior viral infection was more common among cases (67% vs 37%, P = .08). Lower absolute lymphocyte count (ALC) at diagnosis date was strongly associated with PJP (400 vs 1230 × 106  cells/µL, P < .001); odds of infection were high with ALC ≤ 500 × 106 cells (OR 18.7, P < .01). CONCLUSION: Pneumocystis jirovecii pneumonia is a rare, late complication of SOT with significant morbidity and mortality. Severe lymphopenia may be useful in identifying SOT recipients who warrant continued or reinstated PJP prophylaxis.

Ganciclovir-resistant cytomegalovirus infection in solid organ transplant recipients: a single-center retrospective cohort study.

BACKGROUND: Ganciclovir-resistant cytomegalovirus (GCV-R CMV) is an emerging challenge among solid organ transplant (SOT) recipients. The literature suggests that about 1% of abdominal transplant recipients develop GCV-R CMV infection. The epidemiology and outcome of GCV-R CMV in SOT recipients who have received alemtuzumab induction is not well described. METHODS: After Institutional Review Board approval, a single-center, retrospective review of 2148 abdominal SOT recipients between January 2006 and July 2011 at our institution (n = 2148) was conducted to identify patients with proven or empirically treated GCV-R CMV. Descriptive statistics on collected demographics, clinical course, and therapeutic outcomes were performed. RESULTS: Of 116 SOT recipient treated for CMV, 14 patients (12.1% of cases; 0.65% of all SOT patients) had proven or suspected GCV-R CMV. Eight (50%) developed GCV-R CMV while receiving valganciclovir (valGCV) prophylaxis. The remainder developed late-onset disease, after having completed an average 212 days (range 83-353) of prophylaxis. Resistance was clinically suspected an average of 103 days (range 10-455) after CMV infection was initially identified; 10 patients had confirmed genotypic resistance. Foscarnet therapy was associated with resolution of CMV in 13. CONCLUSION: Suboptimal dosing of valGCV is associated with development of GCV-R CMV. Our observed rate of GCV-R CMV in alemtuzumab-induced patients is similar to rates seen to historical data for other induction agents.

Current practices for treatment of respiratory syncytial virus and other non-influenza respiratory viruses in high-risk patient populations: a survey of institutions in the Midwestern Respiratory Virus Collaborative.

BACKGROUND: The optimal treatment for respiratory syncytial virus (RSV) infection in adult immunocompromised patients is unknown. We assessed the management of RSV and other non-influenza respiratory viruses in Midwestern transplant centers. METHODS: A survey assessing strategies for RSV and other non-influenza respiratory viral infections was sent to 13 centers. RESULTS: Multiplex polymerase chain reaction assay was used for diagnosis in 11/12 centers. Eight of 12 centers used inhaled ribavirin (RBV) in some patient populations. Barriers included cost, safety, lack of evidence, and inconvenience. Six of 12 used intravenous immunoglobulin (IVIG), mostly in combination with RBV. Inhaled RBV was used more than oral, and in the post-stem cell transplant population, patients with lower respiratory tract infection (LRTI), graft-versus-host disease, and more recent transplantation were treated at higher rates. Ten centers had experience with lung transplant patients; all used either oral or inhaled RBV for LRTI, 6/10 treated upper respiratory tract infection (URTI). No center treated non-lung solid organ transplant (SOT) recipients with URTI; 7/11 would use oral or inhaled RBV in the same group with LRTI. Patients with hematologic malignancy without hematopoietic stem cell transplantation were treated with RBV at a similar frequency to non-lung SOT recipients. Three of 12 centers, in severe cases, treated parainfluenza and metapneumovirus, and 1/12 treated coronavirus. CONCLUSIONS: Treatment of RSV in immunocompromised patients varied greatly. While most centers treat LRTI, treatment of URTI was variable. No consensus was found regarding the use of oral versus inhaled RBV, or the use of IVIG. The presence of such heterogeneity demonstrates the need for further studies defining optimal treatment of RSV in immunocompromised hosts.

Communication gaps associated with donor-derived infections.

The detection and management of potential donor-derived infections is challenging, in part due to the complexity of communications between diverse labs, organ procurement organizations (OPOs), and recipient transplant centers. We sought to determine if communication delays or errors occur in the reporting and management of donor-derived infections and if these are associated with preventable adverse events in recipients. All reported potential donor-derived transmission events reviewed by the Organ Procurement and Transplantation Network Ad Hoc Disease Transmission Advisory Committee from January 2008 to June 2010 were evaluated for communication gaps between the donor center, OPO and transplant centers. The impact on recipient outcomes was then determined. Fifty-six infection events (IEs; involving 168 recipients) were evaluated. Eighteen IEs (48 recipients) were associated with communication gaps, of which 12 resulted in adverse effects in 69% of recipients (20/29), including six deaths. When IEs and test results were reported without delay, appropriate interventions were taken, subsequently minimizing or averting recipient infection (23 IEs, 72 recipients). Communication gaps in reported IEs are frequent, occur at multiple levels in the communication process, and contribute to adverse outcomes among affected transplant recipients. Conversely, effective communication minimized or averted infection in transplant recipients.

Opportunistic infections complicating solid organ transplantation with alemtuzumab induction.

Opportunistic infections remain a common complication of solid organ transplantation. Despite significant changes in immunosuppression and infectious diseases prophylaxis, data are limited on the contemporary epidemiology and outcomes of opportunistic infections. Alemtuzumab, a potent lymphocyte-depleting antibody, has been used with increased frequency in solid organ transplant recipients in the last decade. A literature review was performed to summarize the current understanding of the epidemiology, risk factors, and outcomes of opportunistic infections complicating solid organ transplantation with and without alemtuzumab induction therapy. Areas where data are limited regarding opportunistic infections in solid organ transplantation with alemtuzumab induction are indicated.

Considerations for screening live kidney donors for endemic infections: a viewpoint on the UNOS policy.

In February 2013, the Organ Procurement and Transplantation Network mandated that transplant centers perform screening of living kidney donors prior to transplantation for Strongyloides, Trypanosoma cruzi and West Nile virus (WNV) infection if the donor is from an endemic area. However, specific guidelines for screening were not provided, such as the optimal testing modalities, timing of screening prior to donation and the appropriate selection of donors. In this regard, the American Society of Transplantation Infectious Diseases Community of Practice, together with disease-specific experts, has developed this viewpoint document to provide guidance for the testing of live donors for Strongyloides, T. cruzi and WNV infection, specifically identifying at-risk populations and testing algorithms, including advantages, limitations and interpretation of results.

Diarrhea caused by viruses in transplant recipients.

Diarrhea is a common complication after solid organ transplantation, and viruses are emerging as important but underestimated causative agents. Viral infections in solid organ transplant (SOT) recipients can result in severe and prolonged diarrhea with significant patient morbidity and graft complications. Cytomegalovirus remains the most common of the viruses to cause diarrhea, but other viruses are being increasingly recognized, including norovirus, rotavirus, and adenovirus. This article reviews the epidemiology, clinical presentation, diagnosis, management, and outcomes of these viral causes of diarrhea in SOT patients.

Nosocomial infections within the first month of solid organ transplantation.

Infections remain a common complication of solid organ transplantation. Early postoperative infections remain a significant cause of morbidity and mortality in solid organ transplant (SOT) recipients. Although significant effort has been made to understand the epidemiology and risk factors for early nosocomial infections in other surgical populations, data in SOT recipients are limited. A literature review was performed to summarize the current understanding of pneumonia, urinary tract infection, surgical-site infection, bloodstream infection, and Clostridium difficult colitis, occurring within the first 30 days after transplantation.

Impact of repeat testing of living kidney donors within 14 days of the transplant procedure: a multicenter retrospective survey.

BACKGROUND: A transmission of human immunodeficiency virus (HIV) from a live kidney donor prompted recommendations by the New York State Department of Health and the US Centers for Disease Control and Prevention that all live donors undergo additional screening for HIV, hepatitis B virus (HBV), and hepatitis C virus (HCV) within 7-14 days of the donation procedure. There are concerns that re-screening will result in delays and cancelled transplants. METHODS: We surveyed live-donor transplant centers in New York State to assess their screening protocols and outcomes. Nine live-donor programs (kidney and liver centers) responded. RESULTS: All but 1 program has a formal repeat screening policy. Overall, no cancellations occurred, but 2 centers experienced transplantation delays, generally as the result of technician and laboratory procedural mistakes necessitating repeat phlebotomy. Testing is typically coordinated with pre-surgical visits, additional laboratory tests, and physical examinations. In the initial evaluation, serology was most frequently used (all 9 centers), with few centers utilizing nucleic acid testing (NAT) (HIV NAT, 1; HBV NAT, 2; HCV NAT, 2). Repeat testing modalities varied: HIV antibody (5, 55%), HIV NAT (8, 88%), hepatitis B surface antigen (5, 55%), hepatitis B surface antibody (2, 22%), hepatitis B core antibody (3, 33%), HBV NAT (3, 33%), HCV antibody (3, 33%), and HCV NAT (5, 55%). CONCLUSION: Most respondents have policies to re-test living donors within 14 days of the transplant procedures. Rarely, centers encountered repeat testing-associated delays, but no cancellations occurred.

Education and informed consent about increased risk donor kidneys: a national survey of non-physician transplant providers.

INTRODUCTION: Transplant providers must understand the definition of increased risk donor (IRD) organs to effectively educate transplant candidates and obtain informed consent. This study surveyed non-physician providers from 20 transplant centers about their educational and informed consent practices of IRD kidneys. METHODS: An anonymous, web-based survey about the content and timing of education and informed consent for potential recipients of IRD kidneys, providers' knowledge of IRD kidneys, and provider and center characteristics was completed by most (67%; 90 of 135) of those invited to participate; 87 responses were included in analysis. RESULTS: Most (80%) reported understanding the concept of IRD kidneys. However, few reported sufficient knowledge of the Organ Procurement and Transplantation Network definition of IRDs, risk factors, screening tests, window periods, and infection transmission rates. Most (56%) felt uncomfortable with obtaining specific informed consent for IRD kidneys. Most respondents received informal education about IRD kidneys (78%), and recognized the need for (98%) and were interested in receiving (99%) further education on this topic. CONCLUSION: Non-physician transplant providers need and are interested in better education about IRD kidneys to effectively educate patients and obtain patients' informed consent.

Optimal testing of the live organ donor for blood-borne viral pathogens: the report of a consensus conference.

In 2011, live donor transmission events involving Human Immunodeficiency Virus (HIV) and Hepatitis C virus (HCV) prompted consideration of changing the process of live donor testing and evaluation in the United States. Following CDC recommendations for screening all live donors with nucleic acid testing for HIV, HCV and Hepatitis B (HBV), a consensus conference was convened to evaluate this recommendation. Workgroups focused on determining whether there was an evidence based rationale for identifying live donors at increased risk for HIV, HBV and HCV, testing options and timing for diagnosing these infections in potential donors and consent issues specific to potential increased risk donor utilization. Strategies for donor assessment were proposed. Based on review of the limited available evidence as well as guidance documents and policies currently in place in the United States and other countries, the conference participants recommended that HIV, HBV and HCV NAT should not be required for live donor evaluation; the optimal timing of live donor testing for these blood borne pathogens has not been determined.

Deceased organ donor screening for HIV, hepatitis B, and hepatitis C viruses: a survey of organ procurement organization practices.

Although Organ Procurement and Transplantation Network (OPTN) policy requires that all potential deceased organ donors are screened for human immunodeficiency (HIV), hepatitis B (HBV) and hepatitis C (HCV) viruses by serology, no current policy requires the use of nucleic acid testing (NAT) for organ donor screening. An electronic survey was sent to 58 organ procurement organizations (OPO) in the United States to assess current screening practices of potential deceased organ donors. Fifty-seven responses were collected for data analysis; not all respondents answered all questions. All OPOs performed required HIV, HBV and HCV serology screening and 48 (84%) performed confirmatory testing for seropositive donors. Ninety-eight percent, 75% and 97% of OPOs performed prospective HIV, HBV and HCV NAT, respectively. Fifty-two percent and 47% used a transcription-mediated amplification assay for HIV and HCV NAT, respectively. Of the 56 respondents that performed HIV NAT and 55 respondents that performed HCV NAT, 39 tested all donors. Seventeen (32%) OPOs performed confirmatory testing for all HIV-positive NAT results, and 15 (27%) OPOs performed confirmatory testing for all HCV-positive NAT results. Since 2008, the number of OPOs performing NAT has increased and more OPOs are testing all donors.

BK virus replication and nephropathy after alemtuzumab-induced kidney transplantation.

BK virus nephropathy (BKVN) is a recognized cause of graft failure in kidney transplant recipients. There are limited data on the epidemiology of BK virus (BKV) infection after alemtuzumab induction. By clinical protocol, the kidney transplant recipients at our center were screened with BKV plasma PCR monthly for the first 4 months posttransplant then every 2-3 months for 2 years. A single center retrospective cohort study of all kidney transplant recipients from January 2008 to August 2010 was conducted to determine incidence and outcomes of BKV infection. Descriptive statistics and Kaplan-Meier analysis was performed. Of 666 recipients, 250 (37.5%) developed viruria, 80 (12%) developed viremia and 31 (4.7%) developed BKVN at a median of 17, 21 and 30 weeks, respectively. Induction with alemtuzumab did not significantly affect incidence of BKVN. Increased recipient age, African American race, acute graft rejection and CMV infection were significantly associated with the development of BKVN in multivariate analysis. The incidence of BK viruria, viremia and nephropathy was not significantly different among kidney transplant recipients who received alemtuzumab induction compared to patients receiving less potent induction.

Opportunities for shared decision making in kidney transplantation.

Health researchers and policy-makers increasingly urge both patient and clinician engagement in shared decision making (SDM) to promote patient-centered care. Although SDM has been examined in numerous clinical settings, it has received little attention in solid organ transplantation. This paper describes the application of SDM to the kidney transplantation context. Several distinctive features of kidney transplantation present challenges to SDM including fragmented patient-provider relationships, the time-sensitive and unpredictable nature of deceased organ offers, decision-making processes by transplant providers serving as both organ guardians (given the organ scarcity) versus advocates for specific patients seeking transplantation, variable clinical practices and policies among transplant centers, and patients' potentially compromised cognitive status and literacy levels. We describe potential barriers to and opportunities for SDM, and posit that SDM is feasible, warranting encouragement in kidney transplantation. We propose strategies to promote and overcome obstacles to SDM in kidney transplantation. We contend that engagement in SDM can be facilitated by re-organization of clinical care, communication and education of providers and patients.

Screening recipients of increased-risk donor organs: a survey of transplant infectious diseases physician practices.

BACKGROUND: In 1994, the Public Health Service published guidelines to minimize the risk of human immunodeficiency virus (HIV) transmission and to monitor recipients following the transplantation of organs from increased-risk donors. A 2007 survey revealed the post-transplant surveillance of recipients of organs from increased-risk donors (ROIRD) is variable. METHODS: An electronic survey was sent to transplant infectious diseases physicians at US solid organ transplant centers. RESULTS: A total of 126 surveys were sent to infectious diseases physicians, and we received 51 (40%) responses. We found that 22% of respondents obtain only verbal, 69% verbal and written, and 8% do not obtain any special consent from ROIRD, despite an Organ Procurement and Transplantation Network policy requiring such consent. Post-solid organ transplantation serologies for HIV, hepatitis B virus (HBV), and hepatitis C virus (HCV) are performed by 6-8% of respondents in all recipients, by 69% of respondents in ROIRD only, and 25% of respondents do not perform them at all. Post-transplant nucleic acid testing is carried out by 55-64% of respondents in ROIRD, by 0-2% in all recipients, and not performed by 35-43% of respondents. CONCLUSION: Screening RIORD for HIV, HBV, and HCV has increased since 2007, but remains less than optimal and is incomplete when screening for disease transmission at many centers.

Preventable errors in organ transplantation: an emerging patient safety issue?

Several widely publicized errors in transplantation including a death due to ABO incompatibility, two HIV transmissions and two hepatitis C virus (HCV) transmissions have raised concerns about medical errors in organ transplantation. The root cause analysis of each of these events revealed preventable failures in the systems and processes of care as the underlying causes. In each event, no standardized system or redundant process was in place to mitigate the failures that led to the error. Additional system and process vulnerabilities such as poor clinician communication, erroneous data transcription and transmission were also identified. Organ transplantation, because it is highly complex, often stresses the systems and processes of care and, therefore, offers a unique opportunity to proactively identify vulnerabilities and potential failures. Initial steps have been taken to understand such issues through the OPTN/UNOS Operations and Safety Committee, the OPTN/UNOS Disease Transmission Advisory Committee (DTAC) and the current A2ALL ancillary Safety Study. However, to effectively improve patient safety in organ transplantation, the development of a process for reporting of preventable errors that affords protection and the support of empiric research is critical. Further, the transplant community needs to embrace the implementation of evidence-based system and process improvements that will mitigate existing safety vulnerabilities.

Diagnosis and management of tuberculosis in transplant donors: a donor-derived infections consensus conference report.

Mycobacterium tuberculosis is a ubiquitous organism that infects one-third of the world's population. In previous decades, access to organ transplantation was restricted to academic medical centers in more developed, low tuberculosis (TB) incidence countries. Globalization, changing immigration patterns, and the expansion of sophisticated medical procedures to medium and high TB incidence countries have made tuberculosis an increasingly important posttransplant infectious disease. Tuberculosis is now one of the most common bacterial causes of solid-organ transplant donor-derived infection reported in transplant recipients in the United States. Recognition of latent or undiagnosed active TB in the potential organ donor is critical to prevent emergence of disease in the recipient posttransplant. Donor-derived tuberculosis after transplantation is associated with significant morbidity and mortality, which can best be prevented through careful screening and targeted treatment. To address this growing challenge and provide recommendations, an expert international working group was assembled including specialists in transplant infectious diseases, transplant surgery, organ procurement and TB epidemiology, diagnostics and management. This working group reviewed the currently available data to formulate consensus recommendations for screening and management of TB in organ donors.

Current practices and evaluation of screening solid organ donors for West Nile virus.

The first cases of West Nile virus (WNV) transmitted through solid organ transplantation (SOT) were identified in 2002. Subsequently, 5 additional clusters have been reported to public health officials in the United States. Based upon a limited number of known cases, patients who acquire WNV from infected donor organs might be at higher risk for severe neurologic disease and death, compared with patients infected through mosquito bites. In response, some organ procurement organizations (OPOs) have instituted pre-transplant screening of organ donors for WNV infection. We evaluated the current practices, concerns, and challenges related to screening organ donors for WNV in the United States by reviewing the relevant medical literature and interviewing key stakeholders. Screening organ donors for WNV is not required by national policy. In 2008, 11 (19%) of 58 OPOs performed WNV screening using nucleic acid amplification testing (NAT). These OPOs differ in their screening strategies, NAT performed, and logistical challenges. Concerns of delays in receiving NAT results before transplant and potential false-positive results leading to organ wasting are limitations to more widespread screening. Furthermore, it is unknown if WNV screening practices decrease SOT-related morbidity and mortality, or if screening is cost-effective. Additional data are needed to assess and improve transplant outcomes related to WNV.

Use of the QuantiFERON-TB Gold interferon-gamma release assay for screening transplant candidates: a single-center retrospective study.

BACKGROUND: Tuberculosis (TB) reactivation is a rare but significant complication of organ transplantation, and screening of all transplant candidates for latent infection is recommended with either an interferon-γ release assay (IGRA) or tuberculin skin test (TST). METHODS: After institutional review board approval, we retrospectively collected data to describe the yield of transplant candidate screening using the QuantiFERON-TB Gold (QFT) and QuantiFERON-TB Gold In-Tube (QFT-IT) assays since the institution of TB screening in 2008 and the epidemiology of all cases of post-transplant TB in our institution since 2004. RESULTS: A total of 2392 patients were screened with either the QFT or QFT-IT assay through October 2009; 245 (10.2%) tested positive and 206 (8.6%) were indeterminate. Of those with positive results, 107 (43.7%) were foreign born and most of the remainder had prior TB exposures. Of the tests performed at a reference lab, 29% were indeterminate, whereas 14% were indeterminate using our in-house lab. The majority of indeterminate results were seen in liver transplant candidates (40.6% vs. 11.8% in non-liver candidates). Three of 694 (0.43%) screened patients who underwent transplantation developed TB post transplant. CONCLUSIONS: Post-transplant TB occurs at a low rate with universal IGRA-based candidate screening, which is comparable to studies using TST screening.

Organ donor screening using parallel nucleic acid testing allows assessment of transmission risk and assay results in real time.

Expansion of the donor pool may lead to utilization of donors with risk factors for viral infections. Donor laboratory screening relies on serological and nucleic acid testing (NAT). The increased sensitivity of NAT in low prevalence populations may result in false-positive results (FPR) and may cause unnecessary discard of organs.We developed a screening algorithm to deal, in real time, with potential FPR. Three NAT assays: COBAS AmpliScreen assay (CAS), AmpliPrep Total Nucleic Acid Isolation/CAS, and AmpliPrep/TaqMan assays, were validated and used in parallel for prospective screening of increased-risk donors (IRD), and the probability of FPR was calculated. The lower limit of detection of this algorithm was 9.79, 21.02, and 4.31 IU/mL for human immunodeficiency virus-1, hepatitis C virus, and hepatitis B virus, respectively, with an average turn-around-time of 7.67 h from sample receipt to result reporting. The probability that a donor is potentially infectious with two NAT concordant results was >90%. NAT screening of 35 IRD within 18 months resulted in transplantation of 102 additional organs that without screening would either not be used or used with restrictions in Australia. Using a parallel testing algorithm, real-time confirmation of seropositive donors allows use of organs from IRD and safer expansion of the donor pool.