Adverse events associated with patient isolation: a systematic literature review and meta-analysis.

BACKGROUND: Patient isolation is widely recommended and used in healthcare institutions to prevent transmission of multidrug-resistant organisms (MDROs). However, its risk: benefit ratio is debated. AIM: To assess, based on newly published studies, whether or not there are physical and psychological adverse events associated with patient isolation. METHODS: Systematic literature review and meta-analysis were performed in accordance with the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines. Studies were systematically searched from PubMed, from May 1st, 2009 to January 31st, 2020. The concepts of the research questions were defined as: 'Adverse events', 'patient isolation or cohorting', and 'multi-drug resistant organisms colonized or infection patients'. Three reviewers independently screened studies and extracted data. All statistical analysis was performed with Stata Software and R. FINDINGS: After screening titles of 15,921 articles and abstracts of 196, and reviewing full texts of 50 studies, 19 studies were included. Studies were divided into three groups: four qualitative studies, seven observational studies suitable for meta-analysis, and eight other observational studies. Meta-analysis shows no adverse events related to clinical care or patients' experience associated with patient isolation. CONCLUSION: More studies with correct methodology, including a control group and standardized inclusion criteria, must be conducted to confirm our results.

Risk factors for the environmental spread of different multidrug-resistant organisms: a prospective cohort study.

BACKGROUND: Substantial scientific evidence shows that contamination of environmental surfaces in hospitals plays an important role in the transmission of multidrug-resistant organisms (MDROs). To date, studies have failed to identify the risk factors associated with environmental contamination. AIM: To evaluate, compare, and identify factors associated with environmental contamination around carriers of different MDROs. METHODS: This was a prospective cohort study from May 2018 to February 2020. A total of 125 patients were included, having been admitted to Avicenne Hospital and Hotel Dieu de France de Beyrouth Hospital who were faecal carriers of MDROs (extended-spectrum ß-lactamase-producing Enterobacterales (ESBL-PE), carbapenemase-producing Enterobacterales (CPE), vancomycin-resistant enterococci (VRE)). For each patient, quantification of MDRO in stool was undertaken, plus a qualitative evaluation of the presence of MDRO in six different environmental sites; and clinical data were collected. FINDINGS: MDROs comprised ESBL-PE (34%), CPE (45%), and VRE (21%). The most frequent MDRO species was Escherichia coli. Contamination of at least one environmental site was observed for 22 (18%) patients. Only carriage of VanA was associated with a significantly higher risk of dissemination. Having a urinary catheter, carriage of OXA48 and E. coli were protective factors against environmental contamination. There were no significant differences in environmental contamination between E. coli and other Enterobacterales or between ESBL-PE and CPE. CONCLUSIONS: Hospital environmental contamination rates are substantially higher for patients with VRE, compared to the low environment dissemination rates around ESBL-PE and CPE. Further studies on a larger scale are needed to confirm the validity of our findings.

Evaluation of polymerase chain reaction assays for direct screening of carbapenemase-producing Enterobacteriaceae from rectal swabs: a diagnostic meta-analysis.

Recently, molecular assays have been demonstrated to be reliable for rapid detection of carbapenemase-producing Enterobacteriaceae (CPE) directly from positive blood cultures, reducing significantly the time for identification. Few studies have tested their performance on rectal swabs and no comprehensive conclusions have been reached regarding their utility for infection control management. Our aim was to review and assess the overall diagnostic test accuracy of polymerase chain reaction for the detection of CPE in rectal swabs. The electronic database PubMed was searched, up to October 1st, 2019, without language restriction or publication date restrictions. First, the concepts of the research questions were defined: 'carbapenemase-producing Enterobacteriaceae', 'molecular testing', 'test detection', and 'rectal screening'. Two reviewers independently screened studies, extracted data, and assessed quality using the QUADAS-2 instrument. Statistical analyses were carried out in Stata software using the bivariate model. In all, 143 articles were screened and 16 studies were included. Five (31%) of the studies were conducted in the context of a CPE outbreak; one study (6%) included patients pre-identified with CPE in clinical samples (blood or tracheal secretions), whereas the rest (63%) collected rectal swabs from patients considered at high risk of colonization. The molecular assays evaluated had a relatively good sensitivity of 0.95 (95% confidence interval (CI): 0.902-0.989), and an excellent specificity of 0.994 (95% CI: 0.965-1). Molecular techniques seem to be a useful, accurate diagnostic tool in screening for carriage of CPE in contact patients around a fortuitous discovery of a non-isolated hospitalized carrier patient.

Can real-time polymerase chain reaction allow a faster recovery of hospital activity in cases of an incidental discovery of carbapenemase-producing Enterobacteriaceae and vancomycin-resistant Enterococci carriers?

BACKGROUND: Detection of faecal carriers of carbapenemase-producing Enterobacteriaceae (CPE) and vancomycin-resistant Enterococci (VRE) has become a routine medical practice in many countries. In an outbreak setting, several public health organizations recommend three-weekly rectal screenings to rule-out acquisition in contact patients. This strategy, associated with bed closures and reduction of medical activity for a relatively long time, seems costly. AIM: The objective of this study was to test the positive and negative predictive values of reverse transcription polymerase chain reaction (RT-PCR; GeneXpert®) carried-out at Day 0, compared with conventional three-weekly culture-based rectal screenings, in identifying, among contact patients, those who acquired CPE/VRE. METHODS: A multicentre retrospective study was conducted from January2015 to October2018. All contact patients (CPs) were included identified from index patients (IPs) colonized or infected with CPE/VRE, incidentally discovered. Each CP was investigated at Day 0 by PCR (GeneXpert®), and by the recommended three-weekly screenings. FINDINGS: Twenty-two IPs and 159 CPs were included. An average of 0.77 secondary cases per patient was noted, with a mean duration of contact of 10 days (range 1-64). Among the 159 CPs, 16 (10%) had a CPE/VRE-positive culture during the monitoring period. Rectal screenings were positive at Day 0 (10 patients), Day 7 (two patients), Day 14 (four patients). Thirteen of 16 patients with positive culture had a positive PCR at Day 0. Overall, a concordance of 97.5% (155/159) was observed between the three-weekly screenings and Day 0 PCR results. When performed on CPs at Day 0 of the identification of an IP, PCR (GeneXpert®) allowed the reduction in turnaround time by five to 27 days, compared to three-weekly screenings. Positive predictive value and negative predictive value were 100% and 98%, respectively. CONCLUSIONS: The use of RT-PCR (GeneXpert®) can avoid the three-weekly rectal samplings needed to rule-out acquisition of CPE/VRE.

B-cell activating factor (BAFF) plasma level at the time of chronic GvHD diagnosis is a potential predictor of non-relapse mortality.

Biological markers for risk stratification of chronic GvHD (cGvHD) could improve the care of patients undergoing allogeneic hematopoietic stem cell transplantation. Increased plasma levels of B-cell activating factor (BAFF), chemokine (C-X-C motif) ligand 9 (CXCL9) and elafin have been associated with the diagnosis, but not with outcome in patients with cGvHD. We evaluated the association between levels of these soluble proteins, measured by ELISA at the time of cGvHD diagnosis and before the initiation of therapy, with non-relapse-mortality (NRM). Based on the log-transformed values, factor levels were divided into tertiles defined respectively as low, intermediate, and high levels. On univariable analysis, BAFF levels were significantly associated with NRM, whereas CXCL9 and elafin levels were not. Both low (⩽2.3 ng/mL, hazard ratio (HR)=5.8, P=0.03) and high (>5.7 ng/mL, HR=5.4, P=0.03) BAFF levels were associated with a significantly higher NRM compared with intermediate BAFF level. The significant effect of high or low BAFF levels persisted in multivariable analysis. A subset of cGvHD patients had persistently low BAFF levels. In conclusion, our data show that BAFF levels at the time of cGvHD diagnosis are associated with NRM, and also are potentially useful for risk stratification. These results warrant confirmation in larger studies.

Multi-center analysis of the effect of T-cell acute lymphoblastic leukemia subtype and minimal residual disease on allogeneic stem cell transplantation outcomes.

This study aims to provide a detailed analysis of allogeneic stem cell transplantation (allo-SCT) outcomes in a large T-cell acute lymphoblastic leukemia (T-ALL) cohort with a specific emphasis on the effects of pre-transplant minimal residual disease (MRD) and disease subtype, including the aggressive early-thymic precursor (ETP) subtype. Data from 102 allo-SCT patients with a diagnosis of T-ALL from three centers were retrospectively analyzed. Patients were grouped into four T-ALL subtypes: ETP, early, cortical and mature. At 3 years, overall survival (OS), PFS, non-relapse mortality and cumulative incidence (CI) progression were 35, 33, 11 and 55%, respectively. Patients transplanted in first complete remission (CR1) had a 3-year OS of 62% versus those transplanted in CR2 or greater (24%) (hazards ratio 1.6, P=0.2). Patients with MRD positivity at the time of transplant had significantly higher rates of progression compared with those with MRD negativity (76 vs 34%, hazards ratio 2.8, P=0.006). There was no difference in OS, PFS or cumulative incidence (CI) progression between disease subtypes, including ETP (n=16). ETP patients transplanted in CR1 (n=10) had OS of 47%, comparable to other disease subtypes, suggesting that allo-SCT can overcome the poor prognosis associated with ETP. MRD status at transplant was highly predictive of disease relapse, suggesting novel therapies are necessary to improve transplant outcomes.

Fate of the fecal indicator Escherichia coli in irrigation with partially treated wastewater.

Treated wastewater reuse is increasing in semi-arid regions as a response to the effects of climate change and increased competition for natural water resources. Investigating the fate of bacterial indicators is relevant to assess their persistence in the environment and possible transfer to groundwater or to the food chain. A long-term field-scale experimental campaign and a soil column test were carried out to evaluate the fate of the fecal indicator Escherichia coli (E. coli) in a cultivated soil when contaminated water resources are used for irrigation. For field experiments, fecal contamination was simulated by dosing the indicator to the effluent of a membrane bioreactor, thus simulating a filtration system's failure, and irrigating a test field where grass was grown. The presence of E. coli on grass and topsoil samples was monitored under different scenarios. For evaluating the fate of the same indicator in the subsoil, a set of soil columns was installed next to the field, operated, and monitored for E. coli concentration over time and along depth. Real municipal wastewater was used in this case as source of fecal contamination. Results showed that short- and medium-term effects on topsoil were strongly dependent on the concentration of E. coli in the irrigation water. Limited persistence and no relevant accumulation of the indicator on the grass and in the topsoil were observed. Watering events performed after fecal contamination did not influence significantly the decay in the topsoil, which followed a log-linear model. The trend of the E. coli concentrations in the leaching of the soil columns followed a log-linear model as well, suggesting bacterial decay as the dominant mechanism affecting the underground indicator's concentration.

Long-term outcome of reduced-intensity allogeneic hematopoietic SCT in patients with AML in CR.

A total of 36 consecutive patients with AML in CR underwent reduced-intensity allogeneic hematopoietic SCT (RISCT) with fludarabine and melphalan conditioning. All patients were ineligible for myeloablative transplantation because of age or comorbidity. In total, 30 patients were in first CR and six patients were in second CR. Donors were siblings in 21 (58%) patients and were unrelated in 15 (42%) patients. Hematopoietic cell transplant specific comorbidity scores ≥3 were present in 26 (72%) patients. With a median follow-up of 52 months (range, 34-103 months), OS and PFS rates at 4 years were 71% (s.e., 8%) and 68% (s.e., 8%), respectively. At 4 years, the cumulative incidence of non-relapse mortality was 20% (s.e., 7%) and of relapse mortality was 8% (s.e., 5%). Neither OS nor PFS was affected by older age (>60 years), unrelated donor, melphalan dose, or comorbidity score. At last follow up, of the 24 surviving patients, 21 (88%) had performance status (ECOG) of 0 without any active chronic GVHD requiring steroids. Hence, RISCT with fludarabine and melphalan conditioning produces durable long-term remission in older patients with AML.

Prognostic value of response after upfront therapy for acute GVHD.

One challenge in designing clinical trials for treatment of acute GVHD (aGVHD) is the lack of an established standardized end point to measure the success of therapies. To facilitate assessment of end points in clinical trials for treatment of aGVHD in the current allo-SCT era, a national workshop was recently organized. In this study, which was presented at the workshop, we evaluated the prognostic value of response to upfront therapy in a cohort of 83 patients who had been enrolled on two clinical trials testing novel therapies for aGVHD at our institution. Our results indicate that patients whose aGVHD has a CR or PR by day 28 after initiation of systemic therapy have a significantly lower 6-month cumulative incidence of non-relapse mortality (NRM) (16%) than patients whose aGVHD did not respond to therapy by day 28 (48%, P=0.005). Multivariate analysis based on the Cox proportional hazards regression analysis showed that the impact of response on NRM is independent of patient and aGVHD characteristics. Our data confirm the validity of using day-28 response as a primary end point in clinical trials for upfront therapy for aGVHD.

Phase II trial of high-dose topotecan, melphalan and CY with autologous stem cell support for multiple myeloma.

In spite of high-dose chemotherapy followed by autologous hematopoietic SCT multiple myeloma (MM) eventually recurs, highlighting the need for more effective treatment approaches. Patients received topotecan 3.5 mg/m(2) intravenously on days -6 to -2, melphalan 70 mg/m(2) intravenously on days -3 and -2 and CY 1 g/m(2) intravenously on days -6, -5 and -4. Overall response rate (ORR) consisting of complete response and partial response (CR+PR, PFS, OS and toxicity are reported. Between August 2002 to March 2004, 60 patients (34 men and 26 women) with a median age of 61 years (range 45-72) were enrolled. Forty-one patients were treated for consolidation of first remission, while 19 patients had relapsed/refractory disease. ORR was 85% (CR 12%, very good PR 43% and PR 30%). Median time to neutrophil (ANC>0.5 × 10(9)/L) and plt engraftment (>20 × 10(9)/L) was 10 (range 7-12 days) and 9 days (range 6-79 days), respectively. A majority of the common adverse events were grade 1-3 mucositis/stomatitis (65%), grade 1 or 2 nausea (59%) and grade 1 or 2 diarrhea (41%). Median PFS was 18.5 months and median OS has yet not been reached. In conclusion, topotecan, melphalan and CY is a safe and active conditioning regimen for auto hematopoietic SCT in MM. The ORR and PFS were comparable to high-dose melphalan.

Reduced-intensity conditioning using fludarabine, melphalan and thiotepa for adult patients undergoing haploidentical SCT.

Haploidentical SCT (HaploSCT) has been most commonly performed using a myeloablative, TBI-based preparative regimen; however, the toxicity with this approach remains very high. We studied the feasibility of a reduced-intensity conditioning regimen in a phase II clinical trial using fludarabine, melphalan and thiotepa and antithymocyte globulin (ATG) for patients with advanced hematological malignancies undergoing T-cell depleted HaploSCT. Twenty-eight patients were entered in the study. Engraftment with donor-derived hematopoiesis was achieved in 78% of patients after a median of 13 days. Six patients experienced primary graft failure, three out of four tested patients had donor-specific anti-HLA antibodies (DSA) (P=0.001). Toxicity included mostly infections. A total of 21 out of 22 patients with AML/myelodysplastic syndrome (MDS) achieved remission after transplant (16 with relapsed/refractory AML). Five out of the 12 patients (42%) with AML/MDS with <15% BM blasts survived long term as compared with none with more advanced disease (P=0.03). HaploSCT with this fludarabine, melphalan and thiotepa and ATG RIC is an effective, well-tolerated conditioning regimen for patients with AML/MDS with low disease burden at the time of transplant and allowed a high rate of engraftment in patients without DSA. Patients with overt relapse fared poorly and require novel treatment strategies.

Leukemia burden delays lymphocyte and platelet recovery after allo-SCT for AML.

Lymphocyte and platelet recovery may influence outcomes of allo-SCT for treatment of AML. It is not clear, however, if this impact is independent of patient and transplant characteristics. To investigate this question, we evaluated the influence of pre- or post transplant factors on day +30 absolute lymphocyte count (ALC) and the speed of platelet engraftment. We studied 106 AML patients treated with fludarabine and melphalan reduced-intensity conditioning and allo-SCT. Twenty nine percent of patients were in CR at the initiation of the conditioning, 39% had active disease with circulating blasts and 32% had active disease without circulating blasts. The graft source was peripheral blood from a matched sibling donor in 55% and BM from a matched unrelated donor in 45%. Our data showed that the presence of circulating blasts before transplantation is significantly correlated with low post-SCT day +30 ALC and slow platelet engraftment. This finding suggests that the impact of early ALC and platelet recovery on transplant outcome may not be independent of disease status at transplantation.

High-dose chemotherapy and autologous hematopoietic progenitor cell transplantation for non-Hodgkin's lymphoma in patients >65 years of age.

PATIENTS AND METHODS: We present a retrospective analysis of 99 consecutive patients with relapsed non-Hodgkin's lymphomas who were older than 65 years at the time of high-dose chemotherapy and autologous progenitor cell transplantation. RESULTS: Median age at transplant was 68 years (range 65-82). Thirty-six percent of patients had a hematopoietic cell transplantation comorbidity index of >2 at the time of transplantation. The cumulative nonrelapse mortality was 8% [95% confidence interval (CI) 4-17] at 26 months and the 3-year overall survival (OS) was 61% (95% CI 49-71). On multivariate analysis, disease status at transplant and lactate dehydrogenase (LDH) > normal were significant predictors for OS (P = 0.002). Comorbidity index of >2 did not impact OS but did predict for higher risk of developing grade 3-5 toxicity (P = 0.006). Eight patients developed secondary myelodysplastic syndrome/acute myelogenous leukemia after transplantation (cumulative incidence 16%). CONCLUSIONS: Patients with relapsed lymphomas who are >65 years of age should be considered transplant candidates, particularly if they have chemosensitive disease and normal LDH levels at the time of transplantation. Patients with comorbidity index of >2 can also undergo transplantation with acceptable outcomes but may be at higher risk for developing toxicity.

Efficacy of prophylactic transfusions using single donor apheresis platelets versus pooled platelet concentrates in AML/MDS patients receiving allogeneic hematopoietic stem cell transplantation.

Superiority of single-donor apheresis platelets (SDAP) over pooled platelet concentrates (PPC) transfusions is largely assumed, but unproven. We hypothesized that prophylactic SDAP and PPC transfusions are clinically equivalent after allogeneic hematopoietic stem cell transplants (HSCT). We studied all transfusions administered to 33 patients with AML/MDS during the first 100 days after busulfan-based, myeloablative HSCT. All donor-recipient pairs were ABO identical. Transfusion threshold was a platelet count < or =15 x 10(9)/l. The corrected increment (CCI) was used for all comparisons. Median time to platelet engraftment was 13 days (n=30). PPC transfusions (n=105) were ABO compatible, while 10% of 41 SDAP were not (P=0.006). Median post-transfusion platelet count was 51K/microl (5-118K) after SDAP and 36K/microl (3-115K) after PPC (P=0.0004). Median CCI was 14.178 (SDAP) versus 7.793 (PPC) (P=0.0001). Median time to another transfusion was 3 days (SDAP) and 2 days (PPC; P=0.3). In the week following any given transfusion, the median number of new transfusions was similar (n=2), as well as the need of further transfusion (16 versus 24%, P=0.2). A total of 17% of SDAP and 30% of PPC transfusions were labeled 'ineffective' (P=0.1). There were two non-lethal hemorrhage episodes (6%). SDAP transfusions produced better platelet counts, but SDAP and PPC were equally effective in preventing hemorrhage.

Risk factors associated with late cytomegalovirus reactivation after allogeneic stem cell transplantation for hematological malignancies.

We analyzed the clinical factors associated with late cytomegalovirus (CMV) reactivation in a group of 269 consecutive recipients of allogeneic stem cell transplant (SCT) for hematological malignancies. Eighty-four subjects (31%) experienced late CMV reactivation, including 64 with prior early reactivation and 20 with isolated late reactivation. Multivariate analyses were conducted in patients with early CMV reactivation to identify factors associated with late recurrence. Important risk factors included lymphoid diagnosis, occurrence of graft-versus-host disease (GVHD), greater number of episodes of early reactivation, persistent day 100 lymphopenia and the use of a CMV-seronegative donor graft. We combined these risk factors in a predictive model to identify those at relatively low, intermediate and high risk. The low-risk group (15% cumulative incidence, CI) encompassed patients without early CMV reactivation, and subjects transplanted for a myeloid malignancy from a matched-related (MR) donor without subsequent acute GVHD. The high-risk patients (73% CI) met all of the following criteria: (1) received an MR graft but developed GVHD, or received a non-MR graft irrespective of GVHD; (2) had more than two episodes of early reactivation; and (3) received a CMV-seronegative graft and/or remained persistently lymphopenic at day 100 after SCT. The remaining patients had an intermediate incidence of 32%.

Autologous stem cell transplantation is safe and feasible in elderly patients with multiple myeloma.

Several clinical trials have shown the superiority of autologous stem cell transplantation over conventional dose therapy for patients with multiple myeloma. This treatment, however, is limited to younger patients (<65 years) owing to concerns about toxicity and treatment-related mortality (TRM) in older patients. We treated 26 elderly myeloma patients (>70 years), who received a preparative regimen of melphalan 200 mg/m2 (19 patients), melphalan 180 mg/m2 (six patients) or melphalan 140 mg/m2 (one patient). Twenty-two of the 26 patients were alive after a median follow-up of 25 months (range=8-74). Responses (complete+partial response) were seen in 20 patients (77%), five (19%) of which were complete responses. Median PFS was 24 months, whereas median OS has not been reached. Cumulative incidence of 100-day TRM was 0%. Three-year PFS and OS were 39% (range=16-61) and 65% (range=35-83), respectively. A low serum albumin (<3.5 g/dl) was associated with a shorter PFS (P=0.02). Patients with relapsed disease at transplant, and an interval of >12 months between diagnosis and autotransplant, had a shorter OS (P=0.0004 and 0.04). HDT and autologous transplant is safe and feasible in elderly myeloma patients.

Hyperthyroidism: a rare cause of reversible pulmonary hypertension.

We describe a case of pulmonary hypertension and high-output heart failure in a 61-year-old woman suffering from relapsing Graves disease. The patient experienced prompt hemodynamic and symptomatic recovery after normal thyroid function was restored. Possible mechanisms for the development of pulmonary arterial hypertension due to hyperthyroidism include damage to pulmonary vascular endothelium due to high cardiac output or an autoimmune process or increased metabolism of intrinsic pulmonary vasodilators. Another possible mechanism is vascular vasoconstriction due to decreased cholinergic output.

Steroid myopathy in patients with acute graft-versus-host disease treated with high-dose steroid therapy.

High-dose steroids are the first line of treatment for acute graft-versus-host disease (aGVHD). Steroid myopathy is a debilitating steroid-induced complication that significantly impairs a patient's performance status. To determine the frequency and severity of steroid myopathy and other steroid related complications in patients with acute myeloid leukemia (AML)/myelodysplastic syndrome (MDS) who developed grade >or=2 aGVHD after allogeneic hematopoietic stem cell transplantation (HSCT), we performed a retrospective analysis. Patients were included in the analysis if they had a diagnosis of AML/MDS, underwent an allogeneic HSCT between January 1996 and December 2001 and developed grade >or=2 aGVHD that was treated with 2 mg/kg of methylprednisolone and survived at least 100 days post transplant. A total of 70 patients fulfilled our inclusion criteria. Steroid myopathy was identified in 29 (41%) patients. Steroid myopathy was generally of moderate severity with severe debilitating steroid myopathy seen in only 3% of patients. We concluded that steroid myopathy is a common complication of high-dose steroid therapy after allogeneic HSCT in AML/MDS. Interventions aimed at preventing and treating this complication are warranted and need to be explored in prospective clinical trials.