Plasma Cell-Free DNA Next-Generation Sequencing to Diagnose and Monitor Infections in Allogeneic Hematopoietic Stem Cell Transplant Patients.
Ontology highlight
ABSTRACT:
SUBMITTER: Fung M
PROVIDER: S-EPMC6297859 | biostudies-literature | 2018 Dec
REPOSITORIES: biostudies-literature
Publications
Plasma Cell-Free DNA Next-Generation Sequencing to Diagnose and Monitor Infections in Allogeneic Hematopoietic Stem Cell Transplant Patients.
Fung Monica M Zompi Simona S Seng Hon H Hollemon Desiree D Parham Adama A Hong David K DK Bercovici Sivan S Dolan Estelle E Lien Kathy K Teraoka Justin J Logan Aaron C AC Chin-Hong Peter P
Open forum infectious diseases 20181116 12
Allogeneic hematopoietic stem cell transplant patients are at risk for common and atypical infections. Superior diagnostics can decrease infection-related morbidity and mortality. A novel plasma cell-free DNA next-generation sequencing test detected an uncommon presentation of <i>Chlamydia trachomatis</i> and recurrent and metastatic complications of <i>Staphylococcus aureus</i> bacteremia before standard microbiology. ...[more]
Similar Datasets
Project description:BackgroundNoninvasive diagnostic options are limited for invasive mold infections (IMIs). We evaluated the performance of a plasma microbial cell-free DNA sequencing (mcfDNA-Seq) test for diagnosing pulmonary IMI after hematopoietic cell transplant (HCT).MethodsWe retrospectively assessed the diagnostic performance of plasma mcfDNA-Seq next-generation sequencing in 114 HCT recipients with pneumonia after HCT who had stored plasma obtained within 14 days of diagnosis of proven/probable Aspergillus IMI (n = 51), proven/probable non-Aspergillus IMI (n = 24), possible IMI (n = 20), and non-IMI controls (n = 19). Sequences were aligned to a database including >400 fungi. Organisms above a fixed significance threshold were reported.ResultsAmong 75 patients with proven/probable pulmonary IMI, mcfDNA-Seq detected ≥1 pathogenic mold in 38 patients (sensitivity, 51% [95% confidence interval {CI}, 39%-62%]). When restricted to samples obtained within 3 days of diagnosis, sensitivity increased to 61%. McfDNA-Seq had higher sensitivity for proven/probable non-Aspergillus IMI (sensitivity, 79% [95% CI, 56%-93%]) compared with Aspergillus IMI (sensitivity, 31% [95% CI, 19%-46%]). McfDNA-Seq also identified non-Aspergillus molds in an additional 7 patients in the Aspergillus subgroup and Aspergillus in 1 patient with possible IMI. Among 19 non-IMI pneumonia controls, mcfDNA-Seq was negative in all samples, suggesting a high specificity (95% CI, 82%-100%) and up to 100% positive predictive value (PPV) with estimated negative predictive values (NPVs) of 81%-99%. The mcfDNA-Seq assay was complementary to serum galactomannan index testing; in combination, they were positive in 84% of individuals with proven/probable pulmonary IMI.ConclusionsNoninvasive mcfDNA-Seq had moderate sensitivity and high specificity, NPV, and PPV for pulmonary IMI after HCT, particularly for non-Aspergillus species.
| S-EPMC8664431 | biostudies-literature
Project description:Acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) are genetically complex and diverse diseases. Such complexity makes challenging the monitoring of response to treatment. Measurable residual disease (MRD) assessment is a powerful tool for monitoring response and guiding therapeutic interventions. This is accomplished through targeted next-generation sequencing (NGS), as well as polymerase chain reaction and multiparameter flow cytometry, to detect genomic aberrations at a previously challenging leukemic cell concentration. A major shortcoming of NGS techniques is the inability to discriminate nonleukemic clonal hematopoiesis. In addition, risk assessment and prognostication become more complicated after hematopoietic stem-cell transplantation (HSCT) due to genotypic drift. To address this, newer sequencing techniques have been developed, leading to more prospective and randomized clinical trials aiming to demonstrate the prognostic utility of single-cell next-generation sequencing in predicting patient outcomes following HSCT. This review discusses the use of single-cell DNA genomics in MRD assessment for AML/MDS, with an emphasis on the HSCT time period, including the challenges with current technologies. We also touch on the potential benefits of single-cell RNA sequencing and analysis of accessible chromatin, which generate high-dimensional data at the cellular resolution for investigational purposes, but not currently used in the clinical setting.
| S-EPMC10177286 | biostudies-literature
Project description:The need for precision medicine approaches to monitor health and disease makes it important to develop sensitive and accurate assays for proteome profiles in blood. Here, we describe an approach for plasma profiling based on proximity extension assay combined with next generation sequencing. First, we analyze the variability of plasma profiles between and within healthy individuals in a longitudinal wellness study, including the influence of genetic variations on plasma levels. Second, we follow patients newly diagnosed with type 2 diabetes before and during therapeutic intervention using plasma proteome profiling. The studies show that healthy individuals have a unique and stable proteome profile and indicate that a panel of proteins could potentially be used for early diagnosis of diabetes, including stratification of patients with regards to response to metformin treatment. Although validation in larger cohorts is needed, the analysis demonstrates the usefulness of comprehensive plasma profiling for precision medicine efforts.
| S-EPMC8093230 | biostudies-literature
Project description:BackgroundDespite progress in diagnostic, prevention, and treatment strategies, invasive mold infections (IMIs) remain the leading cause of mortality in allogeneic hematopoietic cell transplant (allo-HCT) recipients.MethodsWe describe the incidence, risk factors, and mortality of allo-HCT recipients with proven/probable IMI in a retrospective single-center 10-year (01/01/2010-01/01/2020) cohort study.ResultsAmong 515 allo-HCT recipients, 48 (9.3%) patients developed 51 proven/probable IMI: invasive aspergillosis (IA; 34/51, 67%), mucormycosis (9/51, 18%), and other molds (8/51, 15%). Overall, 35/51 (68.6%) breakthrough IMIs (bIMIs) were identified: 22/35 (62.8%) IA and 13/35 (37.1%) non-IA IMI. One-year IMI cumulative incidence was 7%: 4.9% and 2.1% for IA and non-IA IMI, respectively. Fourteen (29.2 %), 10 (20.8%), and 24 (50.0%) patients were diagnosed during the first 30, 31-180, and >180 days post-HCT, respectively. Risk factors for IMI included prior allo-HCT (sub hazard ratio [SHR], 4.06; P = .004) and grade ≥2 acute graft-vs-host disease (aGvHD; SHR, 3.52; P < .001). All-cause 1-year mortality was 33% (170/515): 48% (23/48) and 31.5% (147/467) for patients with and without IMI (P = .02). Mortality predictors included disease relapse (hazard ratio [HR], 7.47; P < .001), aGvHD (HR, 1.51; P = .001), CMV serology-positive recipients (HR, 1.47; P = .03), and IMI (HR, 3.94; P < .001). All-cause 12-week mortality for patients with IMI was 35.4% (17/48): 31.3% (10/32) for IA and 43.8% (7/16) for non-IA IMI (log-rank P = .47). At 1 year post-IMI diagnosis, 70.8% (34/48) of the patients were dead.ConclusionsIA mortality has remained relatively unchanged during the last 2 decades. More than two-thirds of allo-HCT recipients with IMI die by 1 year post-IMI diagnosis. Dedicated intensified research efforts are required to further improve clinical outcomes.
| S-EPMC8719608 | biostudies-literature
Project description:Metagenomics revealed novel and routinely overlooked viruses, representing sources of unrecognized infections after allogeneic hematopoietic stem cell transplantation (allo-HSCT). We aim to describe DNA and RNA virus prevalence and kinetics in allo-HSCT recipients' plasma for one year post HSCT. We included 109 adult patients with first allo-HSCT from 1 March 2017 to 31 January 2019 in this observational cohort study. Seventeen DNA and three RNA viral species were screened with qualitative and/or quantitative r(RT)-PCR assays using plasma samples collected at 0, 1, 3, 6, and 12 months post HSCT. TTV infected 97% of patients, followed by HPgV-1 (prevalence: 26-36%). TTV (median 3.29 × 105 copies/mL) and HPgV-1 (median 1.18 × 106 copies/mL) viral loads peaked at month 3. At least one Polyomaviridae virus (BKPyV, JCPyV, MCPyV, HPyV6/7) was detected in >10% of patients. HPyV6 and HPyV7 prevalence reached 27% and 12% at month 3; CMV prevalence reached 27%. HSV, VZV, EBV, HHV-7, HAdV and B19V prevalence remained <5%. HPyV9, TSPyV, HBoV, EV and HPg-V2 were never detected. At month 3, 72% of patients had co-infections. TTV and HPgV-1 infections were highly prevalent. BKPyV, MCPyV and HPyV6/7 were frequently detected relative to classical culprits. Further investigation is needed into associations between these viral infections and immune reconstitution or clinical outcomes.
| S-EPMC10142697 | biostudies-literature
Project description:BackgroundAllogeneic hematopoietic cell transplant recipients (allo-HCTRs) with positive cytomegalovirus (CMV) serology may have false-positive results due to blood product transfusion-associated passive immunity.MethodsThis single-center cohort study included allo-HCTRs with negative baseline (at malignancy diagnosis) CMV serology and indeterminate/low-positive (CMV IgG titer, ≥0.6-<50 U/mL) pretransplant CMV serology with negative pretransplant plasma CMV DNAemia. The CMV status of those patients was reclassified from R+ to R- (CMVR- reclassification group). We compared those patients to allo-HCTRs with negative (CMV IgG titer <0.6 U/mL) pretransplant CMV IgG (CMVR- group). We describe the number and type of patients whose pretransplant CMV status was reclassified from indeterminate/positive to negative. We reviewed all plasma CMV DNAemia tests performed during the first 6 months posttransplant in both groups to assess the safety of this approach.ResultsAmong 246 (84.5%) of 291 transplanted patients identified as CMVR+ pretransplant, 60 (24.4%) were reclassified from CMV serology indeterminate (N:10)/low-positive (N:50) to R-. Only 1 of 60 patients (1.67%) in the CMVR- reclassification group versus 3 of 44 (6.8%; P = .30) in the CMVR- group developed CMV DNAemia during the follow-up period. There were no significant differences in the number of CMV DNAemia tests performed, CMV DNAemia range, and time posttransplant between the 2 groups.ConclusionsOne of 4 allo-HCT CMVR+ may be falsely flagged as R+, with significant impact on donor selection and prophylaxis administration. A 2-step approach including CMV serology testing at hematologic malignancy diagnosis in allo-HCT candidates and careful review of pretransplant CMV IgG titers may help correctly classify CMV serology status.
| S-EPMC10874258 | biostudies-literature
Project description:Importance:Studies demonstrating improved survival after allogeneic hematopoietic cell transplant generally exclude infants. Objective:To analyze overall survival trends and other outcomes among infants who undergo allogeneic hematopoietic cell transplant. Design, Setting, and Participants:In this cohort study, we used time-trend analysis to evaluate 3 periods: 2000 through 2004, 2005 through 2009, and 2010 through 2014. The study was conducted in a multicenter setting through the Center for International Blood and Marrow Transplant Research, which is made up of a voluntary working group of more than 450 transplant centers worldwide. Two groups of infants aged 1 year or younger in 2 cohorts were included: those with malignant conditions, such as leukemia, and those with nonmalignant disorders, including immunodeficiencies. Data analysis was conducted from July 2017 to December 2018. Exposures:Allogeneic hematopoietic cell transplant. Main Outcomes and Measures:Survival trends, disease relapse, and toxicity. Results:A total of 2498 infants with a median age of 7 months (range, <1-12 months) were included. In the nonmalignant cohort (n = 472), survival rates improved from the first to the second period (hazard ratio, 0.77 [95% CI, 0.63-0.93]; P = .007) but did not change after 2004. Compared with infants with nonmalignant diseases (n = 2026; 3-year overall survival: 2000-2004, 375/577 [65.0%]; 2005-2009, 503/699 [72.0%]; and 2010-2014, 555/750 [74.0%]), those with malignant conditions had poorer survival rates, without improvement over time (3-year overall survival: 2000-2004, 109/199 [54.8%]; 2005-2009, 104/161 [64.6%]; and 2010-2014, 66/112 [58.9%]). From 2000 through 2014, relapse rates increased in infants with malignant conditions (3-year relapse rate: 2000-2004, 19% [95% CI, 14%-25%]; 2005-2009, 23% [95% CI, 17%-30%]; 2010-2014, 36% [95% CI, 27%-46%]; P = .01). Sinusoidal obstruction syndrome was frequent, occurring with a cumulative incidence of 13% (95% CI, 11%-16%) of infants with nonmalignant diseases and 32% (95% CI, 22%-42%) of those with malignant diseases. Generally, recipients of human leukocyte antigen-identical sibling bone marrow grafts had the best outcomes. Conclusions and Relevance:Survival rates have not improved for infants with malignant diseases over the 15-year study period. Infants with nonmalignant diseases had improved survival rates in the earlier but not the later study period. Higher relapses for the malignant cohort and toxicities for all infants remain significant challenges. Strategies to reduce relapse and toxicity and optimize donor and graft selection may improve outcomes in the future.
| S-EPMC6503511 | biostudies-literature
Project description:This retrospective study aimed to determine the characteristics of infection and diagnostic efficacy of next-generation sequencing (NGS) in patients with fever after allogeneic hematopoietic stem cell transplantation (allo-HSCT). A total of 71 patients with fever after HSCT were enrolled in this study. Compared with conventional microbiological test (CMT), we found that the sensitivity of NGS versus CMT in peripheral blood samples was 91.2% vs. 41.2%, and that NGS required significantly less time to identify the pathogens in both monomicrobial infections (P=0.0185) and polymicrobial infections (P= 0.0027). The diagnostic performance of NGS was not affected by immunosuppressant use. Viruses are the most common pathogens associated with infections. These results indicated that the sensitivity, timeliness, and clinical significance of NGS are superior for the detection of infections. Although NGS has the advantage of identifying a wide range of potential pathogens, the positive rate is related closely to the sample type. Therefore, we recommend that, in the clinical application of NGS to detect pathogens in patients after allo-HSCT, an appropriate sample type and time should be selected and submitted to improve the positive rate and accuracy of NGS. NGS holds promise as a powerful technology for the diagnosis of fever after HSCT.
| S-EPMC9239075 | biostudies-literature
Project description:Allogeneic hematopoietic cell transplantation (alloHCT) is a potentially curative treatment for myelodysplastic syndromes (MDS), but patients who relapse after transplant have poor outcomes. In order to understand the contribution of tumor clonal evolution to disease progression,we applied exome and error-corrected targeted sequencing coupled with copy number analysis to comprehensively define changes in the clonal architecture of MDS in response to therapy using 51 serially acquired tumor samples from 9 patients who progressed after an alloHCT. We show that small subclones before alloHCT can drive progression after alloHCT. Notably, at least one subclone expanded or emerged at progression in all patients. Newly acquired structural variants (SVs) were present in an emergent/expanding subclone in 8 of 9 patients at progression, implicating the acquisition of SVs as important late subclonal progression events. In addition, pretransplant therapy with azacitidine likely influenced the mutation spectrum and evolution of emergent subclones after alloHCT. Although subclone evolution is common, founding clone mutations are always present at progression and could be detected in the bone marrow as early as 30 and/or 100 days after alloHCT in 6 of 8 (75%) patients, often prior to clinical progression. In conclusion, MDS progression after alloHCT is characterized by subclonal expansion and evolution, which can be influenced by pretransplant therapy.
| S-EPMC5922277 | biostudies-literature
Project description:As survival rates in allogeneic hematopoietic stem cell transplantation (HSCT) continue to improve, attention to long-term complications, including cardiovascular disease, becomes a major concern. Cardiovascular disease and dyslipidemia are a common, yet often overlooked occurrence post-HSCT that results in significant morbidity and mortality. Also, increasing evidence shows that several anti-hyperlipidemia medications, the 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors in particular, may have a role in modulating graft-versus-host disease (GVHD). However, factors such as drug-drug interactions, adverse effect profiles, and the relative efficacy in lowering cholesterol and triglyceride levels must be taken into account when choosing safe and effective lipid-lowering therapy in this setting. This review seeks to provide guidance to the clinician in the management of dyslipidemia in the allogeneic HSCT population, taking into account the recently published American College of Cardiology/American Heart Association guidelines on hyperlipidemia management, special considerations in this challenging population, and the evidence for each agent's potential role in modulating GVHD.
| S-EPMC4408224 | biostudies-literature