An investigation of the potential association between gastrointestinal viral and bacterial infection and development of intestinal acute graft versus host disease following allogeneic hematopoietic stem cell transplantation.

It is uncertain whether gastrointestinal (GI) infection caused by viral and bacterial pathogens may predispose to gastrointestinal acute Graft-versus-host disease (aGvHD-GI) in allogeneic hematopoietic stem cell transplant recipients (allo-HSCT). We investigated the potential association between detection of enteropathogenic viruses or bacteria in stools and subsequent occurrence of aGvHD-GI in a cohort of 121 allo-HSCT patients. Eighty-six out of 121 patients (71%) had acute diarrhea and underwent screening for primary GI pathogens by molecular diagnostic methods. One or more GI pathogens were detected in 27 out of the 86 patients with diarrhea (31.3%). Specifically, Clostridioides difficile was found in 16 patients (18.6%), enteropathogenic viruses in 11 patients (12.7%) (Astrovirus, n = 4; Norovirus, n = 2; Sapovirus, n = 2; Adenovirus, n = 2; and Rotavirus, n = 1), and Campylobacter spp. in two patients (2.3%). Thirty patients were diagnosed with all grade aGvHD-GI by histopathology. Detection of primary GI pathogens was achieved in 12 out of 30 patients (Clostridium difficile, n = 5; enteric viruses, n = 8; Campylobacter spp., n = 1) who either subsequently developed (n = 9) or previously had (n = 3) grade I-IV IaGvHD (n = 9). Neither the detection of these microorganisms (all combined), enteric viruses, nor C. difficile was significantly associated with subsequent aGvHD-GI development in Cox models (hazard ratio [HR] = 1.11, p = .80; HR = 1.64, p = .62; HR = 0.75, p = .64, respectively). Analogous results were obtained when grade II-IV aGvHD-GI was selected as the clinical outcome. In summary, data in the current study did not support an association between GI infection and subsequent occurrence of aGvHD-GI in an unselected cohort of allo-HSCT recipients.

Community acquired respiratory virus infections in adult patients undergoing umbilical cord blood transplantation.

Characteristics and risk factors (RFs) of community-acquired respiratory virus (CARV) infections after umbilical cord blood transplantation (UCBT) are lacking. We retrospectively analyzed CARV infections in 216 single-unit myeloablative UCBT recipients. One-hundred and fourteen episodes of CARV infections were diagnosed in 62 (29%) patients. Upper respiratory tract disease (URTD) occurred in 61 (54%) whereas lower respiratory tract disease (LRTD) in 53 (46%). The 5-year cumulative incidence of CARV infection was 29%. RFs for developing CARV infections were: prednisone-based graft-versus-host disease (GVHD) prophylaxis and grade II-IV acute GVHD. RFs analysis of CARV progression to LRTD identified 2007-2009 period and absolute lymphocyte count (ALC) < 0.5 × 109/L. ALC < 0.5 × 109/L had a negative impact on day 60 mortality in both overall CARV and those with LRTD, whereas proven LRTD was associated with higher day 60 mortality. CARV infections had a negative effect on non-relapse mortality. Overall survival at day 60 after CARV detection was significantly lower in recipients with LRTD compared with URTD (74% vs. 93%, respectively). In conclusion, CARV infections after UCBT are frequent and may have a negative effect in the outcomes, in particular in the context of lymphocytopenia.

High Heterogeneity of Multidrug-Resistant Enterobacteriaceae Fecal Levels in Hospitalized Patients Is Partially Driven by Intravenous ß-Lactams.

Multidrug-resistant Enterobacteriaceae (MRE) colonize the intestine asymptomatically from where they can breach into the bloodstream and cause life-threatening infections, especially in heavily colonized patients. Despite the clinical relevance of MRE colonization levels, we know little about how they vary in hospitalized patients and the clinical factors that determine those levels. Here, we conducted one of the largest studies of MRE fecal levels by tracking longitudinally 133 acute leukemia patients and monitoring their MRE levels over time through extensive culturing. MRE were defined as Enterobacteriaceae species that acquired nonsusceptibility to ≥1 agent in ≥3 antimicrobial categories. In addition, due to the selective media used, the MRE had to be resistant to third-generation cephalosporins. MRE were detected in 60% of the patients, but their fecal levels varied considerably among patients and within the same patient (>6 and 4 orders of magnitude, respectively). Multivariate analysis of clinical metadata revealed an impact of intravenous beta-lactams (i.e., meropenem and piperacillin-tazobactam), which significantly diminished the fecal MRE levels in hospitalized patients. Consistent with a direct action of beta-lactams, we found an effect only when the patient was colonized with strains sensitive to the administered beta-lactam (P < 0.001) but not with nonsusceptible strains. We report previously unobserved inter- and intraindividual heterogeneity in MRE fecal levels, suggesting that quantitative surveillance is more informative than qualitative surveillance of hospitalized patients. In addition, our study highlights the relevance of incorporating antibiotic treatment and susceptibility data of gut-colonizing pathogens for future clinical studies and in clinical decision-making.

Detection of plasmid-mediated colistin resistance, mcr-1 gene, in Escherichia coli isolated from high-risk patients with acute leukemia in Spain.

BACKGROUND: Bacterial infections in immunocompromised patients are associated with a high mortality and morbidity rate. In this high-risk group, the presence of multidrug-resistant (MDR) bacteria, particularly bacteria that harbor a transferable antibiotic resistance gene, complicates the management of bacterial infections. In this study, we investigated the presence of the transferable colistin resistance mcr genes in patients with leukemia in Spain. METHODS: 217 fecal samples collected in 2013-2015 from 56 patients with acute leukemia and colonized with MDR Enterobacteriaceae strains, were screened on September 2017 for the presence of the colistin resistance mcr genes (mcr-1 to -5) by multiplex PCR. mcr positive strains selected on LBJMR and MacConkey supplemented with colistin (2 µg/ml) media were phenotypically and molecularly characterized by antimicrobial susceptibility testing, minimum inhibitory concentration, multilocus sequence typing and plasmid characterization. RESULTS: Among 217 fecal samples, 5 samples collected from 3 patients were positive for the presence of the mcr-1 colistin-resistance gene. Four Escherichia coli strains were isolated and exhibited resistance to colistin with MIC = 4 µg/ml. Other genes conferring the resistance to ß-lactam antibiotics have also been identified in mcr-1 positive strains, including blaTEM-206 and blaTEM-98. Three different sequence types were identified, including ST1196, ST140 and ST10. Plasmid characterization allowed us to detect the mcr-1 colistin resistance gene on conjugative IncP plasmid type. CONCLUSION: To the best of our knowledge, we have identified the mcr-1 gene for the first time in leukemia patients in Spain. In light of these results, strict measures have been implemented to prevent its dissemination.

Challenges in Clinical Metaproteomics Highlighted by the Analysis of Acute Leukemia Patients with Gut Colonization by Multidrug-Resistant Enterobacteriaceae.

The microbiome has a strong impact on human health and disease and is, therefore, increasingly studied in a clinical context. Metaproteomics is also attracting considerable attention, and such data can be efficiently generated today owing to improvements in mass spectrometry-based proteomics. As we will discuss in this study, there are still major challenges notably in data analysis that need to be overcome. Here, we analyzed 212 fecal samples from 56 hospitalized acute leukemia patients with multidrug-resistant Enterobactericeae (MRE) gut colonization using metagenomics and metaproteomics. This is one of the largest clinical metaproteomic studies to date, and the first metaproteomic study addressing the gut microbiome in MRE colonized acute leukemia patients. Based on this substantial data set, we discuss major current limitations in clinical metaproteomic data analysis to provide guidance to researchers in the field. Notably, the results show that public metagenome databases are incomplete and that sample-specific metagenomes improve results. Furthermore, biological variation is tremendous which challenges clinical study designs and argues that longitudinal measurements of individual patients are a valuable future addition to the analysis of patient cohorts.

Bloodstream infections in adult patients undergoing cord blood transplantation from unrelated donors after myeloablative conditioning regimen.

The incidence, epidemiology, and risk factors of bloodstream infection (BSI) and their impact on transplant outcomes after umbilical cord blood transplantation (UCBT) are not well defined. Between May 1997 and December 2012, 202 isolates in 189 episodes of BSI were registered in 134 of 241 patients who underwent single-unit myeloablative UCBT. Cumulative incidence (CI) of developing at least 1 episode of BSI was 21%, 29%, 34%, 42%, and 52% at days +7, +14, +30, +100, and +365, respectively. The median time of onset for the first BSI episode was day +10 (range, day -7 to +1217). Early BSI before day 7 was associated with increased nonrelapse mortality (relative risk [RR], 1.5; 95% confidence interval [CI], 1.1 to 2.3; P = .04), whereas BSI before day 14 was an independent adverse risk factor for neutrophil recovery (RR, .6; 95% CI, .5 to .9; P = .002). A higher CD8(+) cell dose of the graft was the only variable independently associated with reduced risk of BSI (RR, .1; 95% CI, .02 to .7; P = .02). The gram-negative rod (GNR) to gram-positive bacteria ratio was .9 before day +30 and 1.6 thereafter (P = .03). Escherichia coli (31%) and Pseudomonas sp. (28%) were the most frequently isolated among GNR. The overall crude mortality rate was 12% at day 7 and was higher for GNR (18%) compared with gram-positive bacteria (7%) (P = .03). These findings emphasize the importance of preventing bacterial infections during conditioning and the very early post-UCBT period.