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Background Continuing antifungal prophylaxis (AFPx) to prevent invasive mold infections (IMIs) in recipients of allogeneic hematopoietic cell transplantation (alloHCT) after primary hospital discharge from alloHCT admission varies among transplant centers despite recommendations to continue prophylaxis through day +75. Characteristics driving AFPx prescribing at hospital discharge and outcomes are unknown. Methods In this retrospective analysis, we reviewed patients continuing AFPx vs no AFPx at hospital discharge. We included patients with a hospital stay ≥7 days and ≤40 days. We excluded patients with a history of IMI prior to alloHCT, new IMI during admission, or death prior to discharge. Our primary objective was incidence of probable or proven IMI per the European Organization for Research and Treatment of Cancer and the Mycoses Study Group Education and Research Consortium. Our secondary objectives were nonrelapse mortality at day +100, overall survival at day +100, and characteristics driving AFPx discontinuation at hospital discharge. Results Of the 430 patients identified, 387 met inclusion criteria. At discharge, 56% (217/387) continued AFPx, and 44% (170/387) had no AFPx. At day +100, 3 probable IMI cases occurred in the group with continued AFPx vs 1 probable IMI case in the no-AFPx group (no proven IMI). Univariate analysis showed no difference in cumulative incidence of probable IMI (P =.440), nonrelapse mortality (P =.072), and overall survival (P =.855) between groups. Multivariable logistic regression demonstrated that patients were less likely to continue AFPx if they had a diagnosis other than acute myeloid leukemia, a length of stay ≤30 days, acute graft-vs-host disease grade 0 or 1, and corticosteroid use ≤5 days. Conclusions There was no difference in probable IMI at day +100 after alloHCT based on continuing vs discontinuing AFPx at hospital discharge after alloHCT admission supporting a risk-adapted prophylaxis approach. [ABSTRACT FROM AUTHOR]

Background Risk of nonrelapse mortality (NRM) after hematopoietic cell transplantation (HCT) is high. Patient-level clinical prediction models such as the HCT–comorbidity index (HCT-CI) help identify those at increased risk for NRM, but the independent contribution of social determinants of health on HCT outcomes is not well characterized. Methods This study included 1602 patients who underwent allogeneic HCT between 2013 and 2019 at City of Hope. Census tract–level social vulnerability was measured using the social vulnerability index (SVI). Fine-Gray multivariable regression evaluated the association between SVI and 1-year NRM. Subgroup analysis examined risk of NRM across combined SVI and HCT-CI categories and by race and ethnicity. Results Cumulative incidence of 1-year NRM after HCT was 15.3% (95% confidence interval [CI] = 13.6% to 17.1%). In multivariable analysis, patients in the highest SVI tertile (highest social vulnerability) had a 1.4-fold risk (subdistribution hazard ratio [sHR] = 1.36, 95% CI = 1.04 to 1.78) of NRM compared with individuals in the lower tertiles; patients in the highest SVI tertile who also had elevated (≥3) HCT-CI scores had the highest risk (sHR = 1.81, 95% CI = 1.26 to 2.58) of 1-year NRM (reference: lower SVI tertiles and HCT-CI < 3). High social vulnerability was associated with risk of 1-year NRM in Asian (sHR = 2.03, 95% CI = 1.09 to 3.78) and Hispanic (sHR = 1.63, 95% CI = 1.04 to 2.55) but not non-Hispanic White patients. Conclusions High social vulnerability independently associated with 1-year NRM after HCT, specifically among minority populations and those with a high comorbidity burden at HCT. These findings may inform targeted approaches for needs assessment during and after HCT, allowing for timely interventions to improve health outcomes in at-risk patients. [ABSTRACT FROM AUTHOR]

Background: Long-term mortality after hematopoietic cell transplantation (HCT) is conventionally calculated from the time of HCT, ignoring temporal changes in survivors' mortality risks. Conditional survival rates, accounting for time already survived, are relevant for optimal delivery of survivorship care but have not been widely quantified. We estimated conditional survival by elapsed survival time in allogeneic HCT patients and examined cause-specific mortality.Methods: We calculated conditional survival rates and standardized mortality ratio for overall and cause-specific mortality in 4485 patients who underwent HCT for malignant hematologic diseases at a large transplant center during 1976-2014. Statistical tests were two-sided.Results: The 5-year survival rate from HCT was 48.6%. After surviving 1, 2, 5, 10, and 15 years, the subsequent 5-year survival rates were 71.2%, 78.7%, 87.4%, 93.5%, and 86.2%, respectively. The standardized mortality ratio was 30.3 (95% confidence interval [CI] = 29.2 to 35.5). Although the standardized mortality ratio declined in longer surviving patients, it was still elevated by 3.6-fold in survivors of 15 years or more (95% CI = 3.0 to 4.1). Primary disease accounted for 50% of deaths in the overall cohort and only 10% in 15-year survivors; the leading causes of nondisease-related mortality were subsequent malignancy (26.1%) and cardiopulmonary diseases (20.2%). We also identified the risk factors for nondisease-related mortality in 1- and 5-year survivors.Conclusion: Survival probability improves the longer patients survive after HCT. However, HCT recipients surviving 15 years or more remain at elevated mortality risk, largely because of health conditions other than their primary disease. Our study findings help inform preventive and interventional strategies to improve long-term outcomes after allogeneic HCT. [ABSTRACT FROM AUTHOR]

Background: High intensity treatments such as hematopoietic cell transplantation (HCT) can be curative for patients with hematologic malignancies, but this needs to be balanced by the high risk of nonrelapse mortality (NRM) during the first 2 years after HCT. Sarcopenia (low muscle mass) is associated with physical disability and premature mortality in individuals with nonmalignant diseases and may be a predictor of NRM and poor overall survival in patients undergoing HCT.Methods: This was a retrospective cohort study of 859 patients with acute leukemia or myelodysplastic syndrome who underwent a first HCT as adults (≥18 years) between 2007 and 2014. Sarcopenia was assessed from pre-HCT abdominal computed tomography scans. Two-year cumulative incidence of NRM was calculated, with relapse/progression considered as a competing risk event. Fine-Gray subdistribution hazard ratio estimates and 95% confidence intervals (CI) were obtained and adjusted for relevant covariates. Kaplan-Meier method was used to examine overall survival. All statistical tests were two-sided.Results: Median age at HCT was 51 years (range = 18-74 years); 52.5% had a high [≥3] HCT-comorbidity index; 33.7% had sarcopenia pre-HCT. Sarcopenia was an independent predictor of higher NRM risk (hazard ratio = 1.58, 95% CI = 1.16 to 2.16) compared with patients who were not. The 2-year incidence of NRM approached 30% in patients with sarcopenia and high (≥3) HCT-comorbidity index. Patients with sarcopenia had on average a longer hospitalization (37.2 days vs 31.5 days, P < .001) and inferior overall survival at 2 years (55.2%, 95% CI = 49.5% to 61.0% vs 66.9%, 95% CI = 63.0% to 70.8%, P < .001).Conclusions: Sarcopenia is an important and independent predictor of survival after HCT, with potential additional downstream impacts on health-economic outcomes. This information can be used to facilitate treatment decisions prior to HCT and guide interventions to decrease the risk of treatment-related complications after HCT. [ABSTRACT FROM AUTHOR]

The functional status of cytotoxic T lymphocyte (CTL) populations recognizing cytomegalovirus intermediate-early antigen (IE1) and pp65 polypeptides was investigated in peripheral blood mononuclear cells from hematopoietic stem-cell transplant (HSCT) and solid organ transplant recipients. Combined flow-based CD107a/b degranulation/mobilization and intracellular cytokine (ICC) assays using peptide libraries as antigens indicated that a significantly higher proportion of pp65-specific CTLs were in a more mature functional state, compared with IE1-specific CTLs. Degranulation/multiple cytokine ICC assays also indicated that a significantly higher proportion of pp65-specific than IE1-specific CTLs secreted both interferon-g and tumor necrosis factor- a and possessed greater cytotoxic potential. These results support our earlier findings of functional differences between CTLs recognizing individual epitopes within the IE1 and pp65 antigens in healthy donors and HSCT recipients and extend them to a broader array of human leukocyte antigen-restricted responses to those antigens. We also provide evidence of a relationship between cytotoxic function and the ability of cytomegalovirus-specific CTLs to secrete multiple cytokines. [ABSTRACT FROM AUTHOR]

A panel of 7 human cytomegalovirus (CMV) epitope peptides and corresponding major histocompatibility class 1 tetramers was used to evaluate cellular immunity in healthy seropositive donors and in hematopoietic stem-cell transplant recipients. Broad CMV-specific T cell responses to epitopes were found within several CMV polypeptides and were restricted by multiple human leukocyte antigen alleles. Their cytotoxic functionality was evaluated by use of an assay that measures transient surface levels of lysosomal membrane proteins LAMP-i (CD1O7a) and LAMP-2 (CD1O7b) after peptide stimulation. This assay can be combined with tetramer staining of antigen-specific CD8+ T lymphocytes and has potential as a surrogate marker for cytotoxic function. CD8+ T lymphocytes specific for epitopes within the pp65 or pp50 gene products exhibited significantly higher functionality, compared with populations recognizing CMV major immediate early-i epitopes. These functional differences between T lymphocyte populations within the same individual may have implications for protection against CMV. [ABSTRACT FROM AUTHOR]

Late occurrence of cytomegalovirus (CMV) disease after day 100 after bone marrow transplantation has become an increasing problem; whether a quantitative measurement of CMV DNA in plasma by polymerase chain reaction (P-PCR) could be predictive of such disease was investigated. In a prospective study, 117 subjects undergoing allogeneic marrow transplantation were followed for 120 days with weekly CMV blood cultures, with day 35 bronchoalveolar lavage CMV cultures, with weekly CMV P-PCR, and with clinical follow-up for an additional 1–2 years. Despite preemptive ganciclovir, CMV disease occurred in 9% of subjects, with a median time of onset of 176 days. Quantitative CMV P-PCR was associated with the late development of CMV disease (P =.01). Of 43 subjects with positive P-PCR results, 23% developed CMV disease, but no disease occurred in the 74 subjects with negative P-PCR (P < .001), despite the fact that 22% had CMV isolated from lung lavage fluid and 32% had CMV isolated from blood. [ABSTRACT FROM PUBLISHER]

Murine cytomegalovirus (MCMV) infection in the lungs of T cell-deficient athymic BALB/c (Nu/Nu) mice and their immunocompetent heterozygous (Nu/+) littermates was examined. Following intranasal inoculation, MCMV replicated in the lungs of both Nu/Nu and Nu/+ mice, but virus titers were significantly higher in T cell-deficient mice. After subcutaneous inoculation, virus disseminated to lung tissue of athymic mice, leading to progressive MCMV replication in lungs that was not seen in the immunocompetent mice. Athymic mice failed to develop an antibody response to MCMV. Histologically, athymic mice uniformly developed focal interstitial cellular aggregates adjacent to blood vessels or airways, which progressively enlarged and coalesced. Pneumonitis was not seen in the lungs of any Nu/+ mice. Thus, MCMV can replicate in the lungs without pneumonitis in immunocompetent mice, but MCMV produces a progressive focal pneumonitis during deficiency of T cell-mediated immunity. [ABSTRACT FROM PUBLISHER]

The role of tumor necrosis factor-α (TNFα) in acute lethal and sublethal murine cytomegalovirus (MCMV) infection in BALB/c mice was examined. During the course of acute infection, TNFα was not detectable in the serum or bronchoalveolar lavage (BAL) fluids, while TNFα was uniformly detected in both serum and BAL following intravenous administration of lipopolysaccharide (LPS). Administration of recombinant murine (rMu) TNFα did not consistently alter the virus content of tissues during acute infection. Passive transfer of purified polyclonal immunoglobulin containing neutralizing antibody to TNFα did not alter mortality or MCMV replication in tissues during acute infection but did block the TNFα response when LPS was administered to BALB/c mice. Thus, TNFα appears to play little role in the course and outcome ofacute MCMV infection. [ABSTRACT FROM PUBLISHER]

Events were examined that might contribute to mortality in acute murine cytomegalovirus (MCMV) infection after intraperitoneal inoculation. Specifically, viral replication in the liver, spleen, and pancreas and the concomitant biochemical abnormalities induced by MCMV during lethal and nonlethal acute viral infection were compared. Mortality was limited to susceptible strains of mice infected bythe intraperitoneal (ip) route. In addition, the virus content of the lung, liver, spleen, and pancreas was 100- to 1000-fold greater with lethal infection in the ip-infected group than in those with nonlethal infection. Serum transaminase and lipase levels were markedly elevated in susceptible mice inoculated with MCMV ip, Histopathologic and immunocytochemical changes in the liver, coupled with elevated serum transaminase levelsindicating severe hepatitis, appear sufficient to explain the early mortality seen with the ip route of infection. [ABSTRACT FROM PUBLISHER]

DNA-DNA hybridization was compared with culture for virus and histopathology for the detection and quantitation of human cytomegalovirus (HCMV) in lungs from bone marrow transplant recipients. The hybridization assay detected 100 pg of HCMV DNA or >520 plaque-forming unit equivalents. Compared with culture for virus, the hybridization assay had a sensitivity of 90.6% and a speci ficity of 77.8%. The quantitiy of HCMV DNA and the infectivity titer were directly correlated. Quantitation of HCMV DNA by hybridization was more reproducible than were infectivity titers for frozen specimens. Histopathologic examination of lung specimens detected HCMV inclusions in 60% (15 of 25) of patients with HCMV-associated interstitial pneumonia, whereas hybridization results were positive for 96% (24 of 25) of these patients. A significant inverse correlation was demonstrated between quantitative values for HCMV DNA and the duration of pneumonia. [ABSTRACT FROM PUBLISHER]

Human cytomegalovirus (HCMV) infection continues to be the most important infection occurring after allogeneic bone marrow transplantation (BMT). Although T cell—specific antiviral immunity appears to be necessary for control of the infection, the humoral immune reaction also contributes to a complete immune response. In this paper we report our findings concerning the anitbody response to the individual polypeptides of HCMV in patients who had undergone BMT and subsequently had displayed evidence ofHCMV infection. Sera obtained from the subjects during and after HCMV viremia were studied by using both a radioimmunoprecipitation assay and an immunoblot assay, and the results were compared with the pattern of antibody response in normal individuals. The results show that the BMT patient can make antibodies to individual proteins of HCMV in a pattern similar to that displayed by persons with natural infection. The polypeptide-specific antibody response present most frequently was directed to proteins of 64 kDa, 50 kDa, and 36 kDa. Some BMT recipients also produced antibody to a wide range of HCMV proteins: 183 kDa, 155 kDa, 130 kDa, 110 kDa, 92 kDa, 86 kDa, 74 kDa, 71 kDa, 69 kDa, 39–44 kDa, 33 kDa, and 29 kDa. [ABSTRACT FROM PUBLISHER]