Razonable, Raymund R.

Abstract Background The impact of cytomegalovirus (CMV) infection on the risk of relapse after Hematopoietic Cell Transplantation (HCT) remains controversial, with some studies demonstrating lower risk (Green et al, Blood 2013), while others demonstrating no impact (Schmidt-Hieber et al, Blood 2013), or lower relapse risk only in myeloablative (MA) (Manjappa et al, BBMT, 2014) or in reduced intensity conditioning (RIC) (Cichocki et al, ASH 2014) HCT. Furthermore, the majority of studies have used antigenemia for CMV monitoring, while there is limited data with the use of Quantitative Nucleic Acid Testing (QNAT). Aim To determine the impact of CMV infection, as detected by QNAT, on transplant-related outcomes for patients with acute myeloid leukemia (AML), stratified by MA or RIC HCT. Methods After IRB approval, consecutive adults with AML who underwent allogenic HCT from HLA-matched peripheral blood (PB) grafts at our institution between 2006 and 2014 were retrospectively reviewed. All grafts were T-cell replete. Early CMV infection was defined as any positive CMV result by PCR assay during the first 100 days post HCT. Relapse incidence (RI), non-relapse mortality (NRM), disease-free survival (DFS), and overall survival (OS) were compared between patients with and without CMV infection, and stratified according to MA or RIC. DFS and OS were estimated using the Kaplan-Meier method, and compared with log-rank test. Cumulative incidence of relapse and NRM were analyzed as competing events, using Gray's test. Multivariable analyses adjusting for patient's age, disease status at transplant, cytogenetic risk, and ABO incompatibility were performed using Cox's proportional hazards regression, and the Fine and Gray approach. Results A total of 190 consecutive patients, including 94 (49%) MA and 96 (51%) RIC HCT were analyzed. Patients, disease, and transplant characteristics are shown in table 1. Of the 94 MA HCT (median age 45 y, 50% male), 66 (70%) received total body irradiation. After a median follow up of 18 m, 36 (38%) CMV infection, 16 (17%) relapses, 22 (23%) NRM and 35 (37%) deaths occurred in the MA group. Median time to CMV infection and to relapse in this group was 38 (range 8-241) and 140 (29-1690) days, respectively. Among the recipients of MA HCT, patients with early CMV infection showed no difference in the RI (figure 1), but had a significant trend towards higher NRM and significantly lower DFS and OS in both univariate and multivariable analysis (figure 2) (P values shown in table 2). Among 96 RIC HCT (median age 59 y, 56% male), fludarabine plus melphalan was used in 62 (65%) and fludarabine plus busulfan in 34 (35%) patients. In this group, early CMV infection occurred in 33 (34%), relapse in 25 (26%), NRM in 25 (26%), and deaths in 46 (48%) patients after a median follow up of 21 m (1-91 m). Among the recipients of RIC HCT, median time to CMV infection and to relapse was 40 (17-175) and 291 (19-1971) days, respectively. In the RIC group, early CMV infection was associated with a significant trend towards lower RI (figure 1) and higher NRM in both univariable and multivariable analysis, but no difference in DFS and OS (figure 2). Conclusion Our study of a large homogenous group of AML patients who underwent a uniform HLA-matched PB HCT demonstrates a significantly lower risk of relapse associated with early CMV infection detected by QNAT following RIC, but not MA HCT. Early CMV infection in MA HCT is associated with higher NRM and therefore inferior survival, whereas in the RIC HCT, there is no impact on survival as the benefit of lower relapse is offset by the higher NRM. Table 1. Patients, disease and transplant characteristics according to CMV infection All Patients Patients with CMV Viremia Patients without CMV Viremia P value Patients, no (%) 190 (100) 69 (36) 121 (64) - Median age, y (range) 54 (18-72) 54 (26-70) 54 (18-72) 0.75 Male Patients, no (%) 104 (55) 30 (43) 74 (61) 0.02 D/R CMV Serostatus, no (%) <0.0001 -/- 29 (15) 1 (1) 28 (23) +/+ 64 (34) 35 (51) 29 (24) +/- 13 (7) 1 (1) 12 (10) -/+ 84 (44) 32 (47) 52 (43) Conditioning 0.65 MA 96 (51) 33 (48) 63 (52) RIC 94 (49) 36 (52) 58 (48) Disease status at Transplant 0.96 CR1 129 (68) 46 (67) 83 (69) CR2 34 (18) 13 (19) 21 (17) Other 27 (14) 10 (14) 17 (14) Cytogenetic 0.65 Favorable 8 (4) 2 (3) 6 (5) Intermediate 130 (68) 46 (67) 84 (69) Unfavorable 52 (28) 21 (30) 31 (26) Disclosures Al-Kali: Novartis: Research Funding.

Abstract Background Mycobacterium tuberculosis disease may occur after treatment of latent TB infection (LTBI). Prompted by a case of reactivation TB disease in a solid organ transplant (SOT) recipient who received LTBI treatment, we reviewed the literature to examine outcomes, adverse effects, resistance, and treatment choices of tuberculosis after LTBI therapy. Methods MEDLINE and Web of Science from inception to 5/2019 were reviewed using key words “latent tuberculosis infection” and “SOT” or “transplantation.” The search yielded nine cases, 41 cohort studies and six randomized controlled trials (RCT). Results Cohort and RCT demonstrated significant reduction in TB disease among transplanted patients who received LTBI therapy; only 56/2651 (2.1%) SOT patients developed TB after LTBI therapy. Adverse drug reactions occurred in 149/1148 (12.9%) and 73/641 (11.4%) of cohort and RCT patients, respectively. Among liver recipients, 56/266 (21%) developed side effects, of which half (29/56, 51.8%) was INH‐related. There was no reported INH resistance. Conclusions Latent TB infection treatment is efficacious in SOT recipients at risk of TB disease. However, tuberculosis may still occur despite LTBI treatment. Hepatotoxicity associated with LTBI therapy is infrequent, although more commonly observed among liver recipients.

AbstractCytomegalovirus (CMV) viral loads overall were 0.29 log IU/mL higher with cobas CMV for use on the cobas 6800/8800 System (cobas CMV) compared with Cobas AmpliPrep/Cobas TaqMan CMV Test (CAP/CTM CMV). Cytomegalovirus DNAemia was detected 11.5 days earlier by cobas CMV, whereas clearance was delayed by 12.8 days. Cytomegalovirus remained detectable by cobas CMV in 44.2% of patients at the time of viral clearance as determined by CAP/CTM CMV. Undetectable viral load by cobas CMV at end of treatment was associated with reduced risk for retreatment (odds ratio, 0.26; 95% confidence interval, 0.04–0.99; P = .05).The use of different quantitative cytomegalovirus nucleic acid tests may affect direct patient care as a result of significant differences in reporting the degree of CMV DNAemia and the time to first detection and clearance of CMV DNAemia.

Microsporidiosis is an emerging opportunistic infection in immunocompromised patients. We report a case of fatal disseminated Anncaliia algerae infection in a profoundly immunosuppressed pancreas and kidney transplant recipient.

AbstractBackgroundAntifungal prophylaxis strategies for lung transplant recipients vary without consensus or standard of care. Our current study aims to identify antifungal prophylaxis practices in the United States.MethodsFrom November 29, 2018, to February 15, 2019, we emailed surveys to medical directors of adult lung transplant centers. An alternate physician representative was approached if continued non‐response after three survey attempts. Descriptive statistics were used to report findings.ResultsForty‐four of 62 (71.0%) eligible centers responded. All Organ Procurement and Transplantation Networks were represented. Only four (9.1%) centers used pre‐transplant prophylaxis for prevention of tracheobronchitis (3 of 4) and invasive fungal disease (4 of 4). Thirty‐nine of forty (97.5%) centers used post‐transplant prophylaxis: 36 (90.0%) universal and 3 (7.5%) pre‐emptive/selective prophylaxis. Most centers used nebulized amphotericin with a systemic agent (26 of 36, 72.2%). Thirty‐two of thirty‐six (88.9%) centers continued universal prophylaxis beyond the hospital setting. Duration of prophylaxis ranged from the post‐transplant hospitalization to lifelong with most centers (25 of 36, 69.4%) discontinuing prophylaxis 6 months or less post‐transplant.ConclusionMost United States' lung transplant centers utilize a universal prophylaxis with nebulized amphotericin and a systemic triazole for 6 months or less post‐transplant. Very few centers use pre‐transplant antifungal prophylaxis.

Abstract Human herpesviruses 6 (HHV-6) A and B cause encephalitis in patients with hematologic malignancies, especially those undergoing allogeneic hematopoietic stem cell transplantation. In this cohort of 10 patients, persistent neurologic deficits associated with moderate to severe bilateral hippocampal atrophy were characteristic long-term findings, despite prolonged antiviral treatment.

AbstractBackgroundLung transplant recipients are prone to invasive fungal infections prompting many transplant centers to use prolonged triazole antifungal prophylaxis. From a practical standpoint, it is unclear if lung transplant recipients are able to continue prolonged or lifelong prophylaxis without premature discontinuation from side effects, drug interactions, development of fungal disease, or medication cost. We examined the number of patients that are able to reach a prophylactic endpoint and understand the reasons for early termination.MethodsWe conducted a retrospective chart review of all lung and heart‐lung transplant patients at Mayo Clinic Rochester from May 1, 2002 to December 31, 2017. Type, duration, and reason for discontinuation of triazole prophylaxis were examined.ResultsDuring the study period, 193 patients underwent lung or heart‐lung transplantation. Itraconazole, voriconazole, and posaconazole were given to 180, 73, and 60 post‐transplant patients, respectively. Providers switched itraconazole to another prophylactic antifungal medication for reasons other than prophylactic completion in 61.8% (126 out of 204) of exposure episodes; this was similar with voriconazole (68.8%, 53 out of 77, P = 0.41). Posaconazole was actively discontinued significantly less often (18.3%, 11 out of 60, P < 0.05). The most common reasons for discontinuing itraconazole were malabsorption (15.5% of exposure episodes) and concern for breakthrough fungal infection (10.2%). In comparison, the most common reason for voriconazole discontinuation was side effect or intolerance (54.5% of VR exposure episodes vs 9.8% of IT exposure episodes, P < 0.05).ConclusionsItraconazole and posaconazole appeared to have fewer side effects prompting discontinuation than voriconazole, but itraconazole was discontinued more often because of malabsorption and clinical suspicion of fungal infections.

AbstractCytomegalovirus (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.