IMPORTANCE An understanding of the incidence and outcomes of Clostridium difficile infection (CDI) in the United States can inform investments in prevention and treatment interventions. OBJECTIVE To quantify the incidence of CDI and its associated hospital length of stay (LOS) in the United States using a systematic literature review and meta-analysis. DATA SOURCES MEDLINE via Ovid, Cochrane Library Databases via Wiley, Cumulative Index of Nursing and Allied Health Complete via EBSCO Information Services, Scopus, and Web of Science were searched for studies published in the United States between 2000 and 2019 that evaluated CDI and its associated LOS. STUDY SELECTION Incidence data were collected only from multicenter studies that had at least 5 sites. The LOS studies were included only if they assessed postinfection LOS or used methods accounting for time to infection using a multistate model or compared propensity score-matched patients with CDI with control patients without CDI. Long-term-care facility studies were excluded. Of the 119 full-text articles, 86 studies (72.3%) met the selection criteria. DATA EXTRACTION AND SYNTHESIS Two independent reviewers performed the data abstraction and quality assessment. Incidence data were pooled only when the denominators used the same units (eg, patient-days). These data were pooled by summing the number of hospital-onset CDI incident cases and the denominators across studies. Random-effects models were used to obtain pooled mean differences. Heterogeneity was assessed using the I 2 value. Data analysis was performed in February 2019. MAIN OUTCOMES AND MEASURES Incidence of CDI and CDI-associated hospital LOS in the United States. RESULTS When the 13 studies that evaluated incidence data in patient-days due to hospital-onset CDI were pooled, the CDI incidence rate was 8.3 cases per 10 000 patient-days. Among propensity score-matched studies (16 of 20 studies), the CDI-associated mean difference in LOS (in days) between patients with and without CDI varied from 3.0 days (95% CI, 1.44-4.63 days) to 21.6 days (95% CI, 19.29-23.90 days). CONCLUSIONS AND RELEVANCE Pooled estimates from currently available literature suggest that CDI is associated with a large burden on the health care system. However, these estimates should be interpreted with caution because higher-quality studies should be completed to guide future evaluations of CDI prevention and treatment interventions.

Hematopoietic cell transplantation from HLA-haploidentical related donors is increasingly used to treat hematologic cancers; however, characteristics of the optimal haploidentical donor have not been established. We studied the role of donor HLA mismatching in graft-versus-host disease (GVHD), disease recurrence and survival after haploidentical donor transplantation with post-transplantation cyclophosphamide (PTCy) for 1434 acute leukemia or myelodysplastic syndrome patients reported to the Center for International Blood and Marrow Transplant Research. The impact of mismatching in the graft-versus-host vector for HLA-A, -B, -C, -DRB1, and -DQB1 alleles, the HLA-B leader, and HLA-DPB1 T-cell epitope (TCE) were studied using multivariable regression methods. Outcome was associated with HLA (mis)matches at individual loci rather than the total number of HLA mismatches. HLA-DRB1 mismatches were associated with lower risk of disease recurrence. HLA-DRB1-mismatching with HLA-DQB1-matching correlated with improved disease-free survival. HLA-B leader matching and HLA-DPB1 TCE-non-permissive mismatching were each associated with improved overall survival. HLA-C matching lowered chronic GVHD risk, and the level of HLA-C expression correlated with transplant-related mortality. Matching status at the HLA-B leader and HLA-DRB1, -DQB1 and -DPB1 predicted disease-free survival, as did patient and donor CMV serostatus, patient age and co-morbidity index. A web-based tool was developed to facilitate selection of the best haploidentical related donor by calculating disease-free survival based on these characteristics. In conclusion, HLA factors influence the success of haploidentical transplantation with PTCy. HLA-DRB1 and -DPB1 mismatching and HLA-C, -B leader, and -DQB1 matching are favorable. Consideration of HLA factors may help to optimize the selection of haploidentical related donors.

Results from registry studies suggest that harnessing Natural Killer (NK) cell reactivity mediated through Killer cell Immunoglobulin-like Receptors (KIR) could reduce the risk of relapse after allogeneic Hematopoietic Cell Transplantation (HCT). Several competing models have been developed to classify donors as KIR-advantageous or disadvantageous. Basically, these models differ by grouping donors based on distinct KIR–KIR–ligand combinations or by haplotype motif assignment. This study aimed to validate different models for unrelated donor selection for patients with Myelodysplatic Syndromes (MDS) or secondary Acute Myeloid Leukemia (sAML). In a joint retrospective study of the European Society for Blood and Marrow Transplantation (EBMT) and the Center for International Blood and Marrow Transplant Research (CIBMTR) registry data from 1704 patients with secondary AML or MDS were analysed. The cohort consisted mainly of older patients (median age 61 years) with high risk disease who had received chemotherapy-based reduced intensity conditioning and anti-thymocyte globulin prior to allogeneic HCT from well-matched unrelated stem cell donors. The impact of the predictors on Overall Survival (OS) and relapse incidence was tested in Cox regression models adjusted for patient age, a modified disease risk index, performance status, donor age, HLA-match, sex-match, CMV-match, conditioning intensity, type of T-cell depletion and graft type. KIR genes were typed using high-resolution amplicon-based next generation sequencing. In univariable and multivariable analyses none of the models predicted OS and the risk of relapse consistently. Our results do not support the hypothesis that optimizing NK-mediated alloreactivity is possible by KIR-genotype informed selection of HLA-matched unrelated donors. However, in the context of allogeneic transplantation, NK-cell biology is complex and only partly understood. KIR-genes are highly diverse and current assignment of haplotype motifs based on the presence or absence of selected KIR genes is over-simplistic. As a consequence, further research is highly warranted and should integrate cutting edge knowledge on KIR genetics, and NK-cell biology into future studies focused on homogeneous groups of patients and treatment modalities.

PURPOSE Ultrahigh resolution (UHR) HLA matching is reported to result in better outcomes following unrelated donor hematopoietic cell transplantation, improving survival and reducing post-transplant complications. However, most studies included relatively small numbers of patients. Here we report the findings from a large, multicenter validation study. METHODS UHR HLA typing was available on 5,140 conventionally 10 out of 10 HLA-matched patients with malignant disease transplanted between 2008 and 2017. RESULTS After UHR HLA typing, 82% of pairs remained 10 out of 10 UHR-matched; 12.3% of patients were 12 out of 12 UHR HLA-matched. Compared with 12 out of 12 UHR-matched patients, probabilities of grade 2-4 acute graft-versus-host disease (aGVHD) were significantly increased with UHR mismatches (overall P = .0019) and in those patients who were HLA-DPB1 T-cell epitope permissively mismatched or nonpermissively mismatched (overall P = .0011). In the T-cell–depleted subset, the degree of UHR HLA mismatch was only associated with increased transplant-related mortality (TRM) (overall P = .0068). In the T-cell–replete subset, UHR HLA matching was associated with a lower probability of aGVHD (overall P = .0020); 12 out of 12 UHR matching was associated with reduced TRM risk when compared with HLA-DPB1 T-cell epitope permissively mismatched patients, whereas nonpermissive mismatching resulted in a greater risk (overall P = .0003). CONCLUSION This study did not confirm that UHR 12 out of 12 HLA matching increases the probability of overall survival but does demonstrate that aGVHD risk, and in certain settings TRM, is lowest in UHR HLA-matched pairs and thus warrants consideration when multiple 10 out of 10 HLA-matched donors of equivalent age are available.

At the onset of the COVID-19 pandemic, the National Marrow Donor Program mandated the cryopreservation of hematopoietic cell grafts from volunteer unrelated donors due to numerous patient and donor safety concerns and logistical hurdles. Using the Center for International Blood and Marrow Transplant Research (CIBMTR) outcomes database, we report the impact of cryopreservation on overall survival (OS) and other outcomes within one year following hematopoietic cell transplantation (HCT). We analyzed 1,543 recipients of cryopreserved allografts receiving HCT at US centers during the first 6-months of the pandemic and compared them to 2,499 recipients of fresh allografts during the same 6-month period in 2019. On multivariable regression analysis, we observed no difference in OS (HR, 1.12; 95% CI: 0.98-1.28; P=0.09), non-relapse mortality (HR, 1.01; 95% CI: 0.84-1.22; P=0.89), graft-versus-host disease (GVHD), or GVHD-free, relapse-free survival (HR 1.03; 95% CI 0.93-1.14; P=0.58) in recipients of cryopreserved versus fresh allografts. Disease-free survival (DFS) was lower in the cryopreserved group (HR, 1.18; 95% CI: 1.05-1.33; P=0.006) due to a higher risk of relapse (HR, 1.21; 95% CI: 1.04-1.41; P=0.01). Primary graft failure was higher with cryopreservation (OR 1.48; 95% CI: 1.10-2.00; P=0.01) and the risk of chronic GVHD was lower (HR, 0.65; 95% CI: 0.50-0.84; P=0.001). In conclusion, while there was no negative impact of cryopreservation on OS, relapse was higher and DFS was lower. Fresh grafts are recommended as the pandemic related logistical hurdles resolve. Cryopreservation should be considered an option for patients when fresh grafts are not feasible.