No abstract

No abstract

BACKGROUND. Understanding outcomes and immunologic characteristics of cellular therapy recipients with SARS-CoV-2 is critical to performing these potentially life-saving therapies in the COVID-19 era. In this study of recipients of allogeneic (Allo) and autologous (Auto) hematopoietic cell transplant and CD19-directed chimeric antigen receptor T cell (CAR T) therapy at Memorial Sloan Kettering Cancer Center, we aimed to identify clinical variables associated with COVID-19 severity and assess lymphocyte populations. METHODS. We retrospectively investigated patients diagnosed between March 15, 2020, and May 7, 2020. In a subset of patients, lymphocyte immunophenotyping, quantitative real-time PCR from nasopharyngeal swabs, and SARS-CoV-2 antibody status were available. RESULTS. We identified 77 patients with SARS-CoV-2 who were recipients of cellular therapy (Allo, 35; Auto, 37; CAR T, 5; median time from cellular therapy, 782 days; IQR, 354-1611 days). Overall survival at 30 days was 78%. Clinical variables significantly associated with the composite endpoint of nonrebreather or higher oxygen requirement and death (n events = 25 of 77) included number of comorbidities (HR 5.41, P = 0.004), infiltrates (HR 3.08, P = 0.032), and neutropenia (HR 1.15, P = 0.04). Worsening graft-versus-host disease was not identified among Allo recipients. Immune profiling revealed reductions and rapid recovery in lymphocyte populations across lymphocyte subsets. Antibody responses were seen in a subset of patients. CONCLUSION. In this series of Allo, Auto, and CAR T recipients, we report overall favorable clinical outcomes for patients with COVID-19 without active malignancy and provide preliminary insights into the lymphocyte populations that are key for the antiviral response and immune reconstitution.

Background ADV (adenovirus) is an important cause of viral mortality in hematopoietic stem cell transplantation (HSCT). T-cell depleted (TCD) HSCT are at increased risk of viral infections. We compared the rates and outcomes of ADV viremia and disease between TCD and conventional (CONV) HSCT at our institution. Methods This was an observational study of 624 adult and pediatric recipients of myeloablative HSCT at Memorial Sloan-Kettering Cancer Center from January 1, 2006, through March 11, 2011. Viral cultures and ADV polymerase chain reaction (PCR) were ordered as clinically indicated. ADV viremia by a quantitative PCR assay was defined as ≥1 positive value ≥1,000 copies/mL or ≥2 consecutive values at any value. Competing risk regression analyses were used to identify predictors for ADV viremia. Results Eight percent TCD and 4.0% CONV were noted to have ADV viremia at 1 year after HSCT (P=.041). Among TCD, 15% of children compared with 5% of adults developed ADV viremia (P=.008). Young age (Hazard Ratio [HR] 3.0; P<.001) and acute graft-versus-host-disease (GVHD) (HR 3.2; P=.001) were risk factors for ADV viremia. ADV viremia was a predictor of mortality (HR 6.0; P<.001). ADV disease developed in 3.5% TCD and 0.4% CONV HSCT (P=.022) with attributable mortality of 27%. Among TCD, grade 2–4 GVHD was a risk factor for ADV disease (HR 13; P<.001); age was not significant. More than 90% ADV disease cases had a viral load of ≥ 10,000 copies/mL. Conclusions Rates of ADV disease were 10-fold higher in TCD compared with CONV HSCT, predominantly in patients who developed acute GVHD. The benefit of preemptive therapy for ADV viral load ≥ 10,000 copies/mL for prevention of ADV disease in recipients of TCD grafts should be evaluated in prospective clinical trials.

Clostridium difficile infection (CDI) is frequently diagnosed in recipients of allogeneic hematopoietic stem cell transplantation (allo-HSCT). We characterized early-transplant CDI and its associations, and analyzed serially-collected feces to determine intestinal carriage of toxigenic C. difficile. Fecal specimens were collected longitudinally from 94 patients during allo-HSCT hospitalization, from the start of pre-transplant conditioning until up to 35 days after stem cell infusion. Presence of C. difficile 16S rRNA and tcdB genes was determined. Clinical variables and specimen data were analyzed for association with development of CDI. Historical data from an additional 1144 allo-HSCT patients was also used. Fecal specimens from 37 patients (39%) were found to harbor C. difficile. Early-transplant CDI was diagnosed in 16 of 94 (17%) patients undergoing allo-HSCT; cases were generally mild and resembled non-CDI diarrhea associated with transplant conditioning. CDI was associated with preceding colonization with tcdB-positive C. difficile and conditioning regimen intensity. We found no associations between early-transplant CDI and graft-versus-host disease or CDI later in transplant. CDI occurs with high frequency during the early phase of allo-HSCT, where recipients are pre-colonized with toxigenic C. difficile. During this time, CDI incidence peaks during pre-transplant conditioning, and is correlated to intensity of the treatment. In this unique setting, high rates of CDI may be explained by prior colonization and chemotherapy; however, cases were generally mild and resembled non-infectious diarrhea due to conditioning, raising concerns of misdiagnosis. Further study of this unique population with more discriminating CDI diagnostic tests are warranted.

Colonization with these 3 bacterial groups is associated with a lower risk of CDI. These groups have been shown to be vital components of the intestinal microbiota. Targeted efforts to maintain them may help minimize the risk of CDI in this at-risk population.

Isavuconazole is a broad-spectrum triazole approved for treatment of invasive fungal infections (IFIs). In this open-label, single-arm study, we evaluated isavuconazole for antifungal prophylaxis after allogeneic hematopoietic cell transplantation (HCT). Adult patients admitted for first HCT received micafungin 150 mg i.v. daily from admission through day +7 (D+7) post-transplantation ( §2 days) followed by isavuconazole prophylaxis (i.v./p.o. 372 mg every 8 hours for 6 doses and then 372 mg daily) through maximum D+98 post-HCT. Patients were followed through D+182. The primary endpoint was prophylaxis failure, defined as discontinuation of prophylaxis for proven/probable IFI; systemic antifungal therapy for >14 days for suspected IFI; toxicity leading to discontinuation; or an adverse event. Between June 2017 and October 2018, 99 patients were enrolled in the study, of whom 95 were included in our analysis. The median patient age was 57 years (interquartile range [IQR], 50 to 66 years). Sixty-four (67%) patients received peripheral blood, 17(18%) received bone marrow, and 14 (15%) received a cord blood allograft for acute leukemia (55%), lymphoma (17%), myelodysplastic syndrome (16%), or another hematologic disease (14%). One-third (n = 31; 33%) of patients underwent CD34 + -selected HCT. Isavuconazole prophylaxis was given for a median of 90 days (IQR, 87 to 91 days). Ten patients (10.7%) met the primary endpoint. Candidemia occurred in 3 patients (3.1%), 1 of whom had grade III skin acute graft-versus-host disease (GVHD). Toxicity leading to discontinuation occurred in 7 patients (7.4%). The most common toxicity was liver function abnormalities in 5 patients, including grade 1 transaminitis in 2 patients and grade 3 hyperbilirubinemia in 3 patients. Four patients (4.2%) had early discontinuation of isavuconazole for reasons not meeting the primary study endpoint. Six patients died during the study period, including 3 during prophylaxis and 3 during follow-up. No deaths were attributed to isavuconazole. The majority (85%) of allogeneic HCT recipients completed isavuconazole prophylaxis according to protocol. The rate of breakthrough candidemia was 3.1%, and there were no invasive mold infections. Our data support the utility of isavuconazole for antifungal prophylaxis after HCT.

Non-typhoidal Salmonella (NTS) is an important commensal microorganism. The purpose of this study was to determine the epidemiological relation between NTS isolates from livestock and NTS isolates from human by analyzing antimicrobial susceptibilities and performing molecular typing. We determined the serotypes of 36 human clinical isolates and 64 livestock isolates, performed antimicrobial susceptibility testing against 8 antibiotics, and determined the molecular types of isolated NTS spp. by pulsed field gel electrophoresis (PFGE). In human isolates, S. enteritidis was the most common serotype (17 isolates; 47.2%) and S. typhimurium the second most (8 isolates; 22.2%). In livestock isolates, S. typhimurium was the most common serotype (15 isolates; 23.44%), and S. enteritidis was the second most (14 isolates; 21.88%). Ampicillin and tetracycline resistance were 50% (32/64 isolates) each among broiler-chicken NTS isolates. No human or livestock NTS isolates showed resistance to ciprofloxacin, TMP-SMX, or ceftriaxone. However, 19.4% (7/36) and 46.8% (30/64) of the human and livestock NTS isolates were resistant to nalidixic acid (MIC ≥16 mg/mL), respectively. The presence of the three identical PFGE molecular types from human and broiler-chicken NTS isolates suggests the possibility of transmission from livestock to humans.