Community acquired respiratory virus infections in adult patients undergoing umbilical cord blood transplantation.
ABSTRACT: 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)?
Project description:Immune reconstitution appears to be delayed following myeloablative conditioning (MAC) and umbilical cord blood transplantation (UCBT) in paediatric recipients. Although reduced toxicity conditioning (RTC) versus MAC prior to allogeneic stem cell transplantation is associated with decreased transplant-related mortality, the effects of RTC versus MAC prior to UCBT on immune reconstitution and risk of graft-versus-host disease (GVHD) are unknown. In 88 consecutive paediatric recipients of UCBT, we assessed immune cell recovery and immunoglobulin reconstitution at days +100, 180 and 365 and analysed risk factors associated with acute and chronic GVHD. Immune cell subset recovery, immunoglobulin reconstitution, and the incidence of opportunistic infections did not differ significantly between MAC versus RTC groups. In a Cox model, MAC versus RTC recipients had significantly higher risk of grade II-IV acute GVHD [Hazard Ratio (HR) 6·1, P = 0·002] as did recipients of 4/6 vs. 5-6/6 HLA-matched UCBT (HR 3·1, P = 0·03), who also had significantly increased risk of chronic GVHD (HR 18·5, P = 0·04). In multivariate analyses, MAC versus RTC was furthermore associated with significantly increased transplant-related (Odds Ratio 26·8, P = 0·008) and overall mortality (HR = 4·1, P = 0·0001). The use of adoptive cellular immunotherapy to accelerate immune reconstitution and prevent and treat opportunistic infections and malignant relapse following UCBT warrants further investigation.
Project description:BACKGROUND:There is a lack of studies comparing clinical outcomes among retrospective versus prospective cohorts of allogeneic stem cell transplant (allo-HCT) recipients with community acquired respiratory virus (CARV) infections. METHODS:We compare outcomes in two consecutive cohorts of allo-HCT recipients with CARV infections. The retrospective cohort included 63 allo-HCT recipients with 108 CARV infections from January 2013 to April 2016 who were screened and managed following standard clinical practice based on influenza and respiratory syncytial virus rapid antigen detection methods. The prospective cohort was comprised of 144 consecutive recipients with 297 CARV episodes included in a prospective interventional clinical surveillance program (ProClinCarvSur-P) based on syndromic multiplex PCR as first-line test from May 2016 to December 2018 at a single transplant center. RESULTS:CARV infections in the retrospective cohort showed more severe clinical features at the time of diagnosis compared to the prospective cohort (fever 83% vs. 57%, hospital admission 69% vs. 28% and lower respiratory tract 58% vs. 31%, respectively, p ? 0.002 for all comparisons). Antiviral therapy was more commonly prescribed in the prospective cohort (69 vs. 43 treated CARV episodes), particularly at the upper respiratory tract disease stage (34 vs. 12 treated CARV episodes). Three-month all-cause mortality was significantly higher in the retrospective cohort (n?=?23, 37% vs. n = 10, 7%, p < 0.0001). Multivariate logistic regression analysis showed that recipients included in ProClinCarvSur-P had lower mortality rate [odds ratio 0.31, 95% confidence interval 0.12-0.7, p?=?0.01]. CONCLUSION:This study report on outcome differences when reporting retrospective vs. prospective CARV infections after allo-HCT. Recipients included in a ProClinCarvSur-P had lower mortality.
Project description:BACKGROUND:Immunocompromised children might be predisposed to serious infections from human coronaviruses (HCoVs), including strains OC43, NL63, HKU1, and 229E; however, the virologic and clinical features of HCoV infection in immunocompromised children have not been compared to those in nonimmunocompromised children. METHODS:We retrospectively analyzed a cohort of children who presented to Seattle Children's Hospital and in whom HCoV was detected by a multiplex respiratory polymerase chain reaction assay of a nasal sample between October 2012 and March 2016. Lower respiratory tract disease (LRTD) was defined as possible or definite infiltrate seen in chest imaging, need for oxygen, or abnormal lung examination in conjunction with a physician diagnosis of LRTD. We used logistic regression modeling to evaluate risk factors for LRTD and LRTD that necessitated oxygen use (severe LRTD), including an immunocompromised state, in children with HCoV infection. RESULTS:The median ages of 85 immunocompromised and 1152 nonimmunocompromised children with HCoV infection were 6.3 and 1.6 years, respectively. The prevalence of LRTD and of severe LRTD did not differ greatly between the immunocompromised and nonimmunocompromised patients (22% vs 26% [LRTD] and 15% vs 11% [severe LRTD], respectively); however, in a multivariable model, an immunocompromised state was associated with an increased likelihood of severe LRTD (adjusted odds ratio, 2.5 [95% confidence interval, 1.2-4.9]; P = .01). Younger age, having an underlying pulmonary disorder, and the presence of respiratory syncytial virus were also associated with LRTD or severe LRTD in multivariable models. The risks of LRTD or severe LRTD did not differ among the children with different HCoV strains. CONCLUSIONS:The presence of a copathogen and host factors, including an immunocompromised state, were associated with increased risk for severe LRTD. Recognizing risk factors for severe respiratory illness might assist in risk stratification.
Project description:Using the Center for International Blood and Marrow Transplant Research (CIBMTR) registry, we analyzed 1404 umbilical cord blood transplantation (UCBT) patients (single (<18 years)=810, double (?18 years)=594) with acute leukemia to define the incidence of acute GvHD (aGvHD) and chronic GvHD (cGvHD), analyze clinical risk factors and investigate outcomes. After single UCBT, 100-day incidence of grade II-IV aGvHD was 39% (95% confidence interval (CI), 36-43%), grade III-IV aGvHD was 18% (95% CI, 15-20%) and 1-year cGvHD was 27% (95% CI, 24-30%). After double UCBT, 100-day incidence of grade II-IV aGvHD was 45% (95% CI, 41-49%), grade III-IV aGvHD was 22% (95% CI, 19-26%) and 1-year cGvHD was 26% (95% CI, 22-29%). For single UCBT, multivariate analysis showed that absence of antithymocyte globulin (ATG) was associated with aGvHD, whereas prior aGvHD was associated with cGvHD. For double UCBT, absence of ATG and myeloablative conditioning were associated with aGvHD, whereas prior aGvHD predicted for cGvHD. Grade III-IV aGvHD led to worse survival, whereas cGvHD had no significant effect on disease-free or overall survival. GvHD is prevalent after UCBT with severe aGvHD leading to higher mortality. Future research in UCBT should prioritize prevention of GvHD.
Project description:Dosing regimens for antithymocyte globulin (ATG) and anti-CD52 antibody (alemtuzumab) for graft vs. host disease prophylaxis (GVHD) are empiric or weight-based, and do not account for individual patient factors. Recently, it has been shown that recipient peripheral blood absolute lymphocyte count (ALC) on the day of ATG administration interacts with the dose of ATG administered to predict transplantation outcome. Similarly, we wanted to analyze if the recipient ALC interacts with alemtuzumab dosing to predict outcomes. We retrospectively compared 364 patients, 124 patients receiving ATG (anti-thymocyte globulin) for GVHD prophylaxis, and undergoing unrelated first allogeneic transplant for myeloid and lymphoid malignancies (group 1) to 240 patients receiving alemtuzumab (group 2), in similar time period. There was no difference in survival or acute and chronic GVHD between 60 and 100 mg of alemtuzumab dosing. Unlike ATG (where the pre-transplant recipient ALC interacted with ATG dose on day of its administration (day 1) to predict OS and DFS (p = 0.05), within alemtuzumab group, the recipient ALC on second day of alemtuzumab administration (day 2) and its interaction with alemtuzumab dose strongly predicted OS, DFS and relapse (p = 0.05, HR-1.81, 1.1-3.3; p = 0.002, HR-2.41, CI, 1.3-4.2; and p = 0.003, HR-2.78, CI, 1.4-5.2), respectively. ALC (day 2) of 0.08 × 109/lit or higher, had a specificity of 96% in predicting inferior DFS. Like ATG, there is definite but differential interaction between the recipient peripheral blood ALC and alemtuzumab dose to predict OS, DFS, and relapses.
Project description:Infections and graft-versus-host disease (GVHD) have historically resulted in high mortality among children undergoing umbilical cord blood transplantation (UCBT). However, recent advances in clinical practice have likely improved outcomes of these patients. We conducted a retrospective cohort study of children (<18years of age) undergoing UCBT at Duke University between January 1, 1995 and December 31, 2014. We compared 2-year all-cause and cause-specific mortality during 3 time periods based on year of transplantation (1995 to 2001, 2002 to 2007, and 2008 to 2014). We used multivariable Cox regression to identify demographic and UCBT characteristics that were associated with all-cause mortality, transplantation-related mortality, and death from invasive aspergillosis after adjustment for time period. During the 20-year study period 824 children underwent UCBT. Two-year all-cause mortality declined from 48% in 1995 to 2001 to 30% in 2008 to 2014 (P?=?.0002). White race and nonmalignant UCBT indications were associated with lower mortality. Black children tended to have a higher risk of death for which GVHD (18% versus 11%; P?=?.06) or graft failure (9% versus 3%; P?=?.01) were contributory than white children. Comparing 2008 to 2014 with 1995 to 2001, more than half (59%) of the reduced mortality was attributable to a reduction in infectious mortality, with 45% specifically related to reduced mortality from invasive aspergillosis. Antifungal prophylaxis with voriconazole was associated with lower mortality from invasive aspergillosis than low-dose amphotericin B lipid complex (hazard ratio, .09; 95% confidence interval, .01 to .76). With the decline in mortality from invasive aspergillosis, adenovirus and cytomegalovirus have become the most frequentinfectious causes of death in children after UCBT. Advances in clinical practice over the past 20years improved survival of children after UCBT. Reduced mortality from infections, particularly invasive aspergillosis, accounted for the largest improvement in survival and was associated with use of voriconazole for antifungal prophylaxis.
Project description:Community-acquired respiratory virus (CARV) infections have been recognized as a significant cause of morbidity and mortality in patients with leukemia and those undergoing hematopoietic stem cell transplantation (HSCT). Progression to lower respiratory tract infection with clinical and radiological signs of pneumonia and respiratory failure appears to depend on the intrinsic virulence of the specific CARV as well as factors specific to the patient, the underlying disease, and its treatment. To better define the current state of knowledge of CARVs in leukemia and HSCT patients, and to improve CARV diagnosis and management, a working group of the Fourth European Conference on Infections in Leukaemia (ECIL-4) 2011 reviewed the literature on CARVs, graded the available quality of evidence, and made recommendations according to the Infectious Diseases Society of America grading system. Owing to differences in screening, clinical presentation, and therapy for influenza and adenovirus, ECIL-4 recommendations are summarized for CARVs other than influenza and adenovirus.
Project description:BACKGROUND:Parainfluenza virus (PIV) commonly infects patients following hematopoietic cell transplantation (HCT), frequently causing lower respiratory tract disease (LRTD). The definition of LRTD significantly differs among studies evaluating the impact of PIV after HCT. METHODS:We retrospectively evaluated 544 HCT recipients with laboratory-confirmed PIV and classified LRTD into 3 groups: possible (PIV detection in upper respiratory tract with new pulmonary infiltrates with/without LRTD symptoms), probable (PIV detection in lung with LRTD symptoms without new pulmonary infiltrates), and proven (PIV detection in lung with new pulmonary infiltrates with/without LRTD symptoms). RESULTS:Probabilities of 90-day survival after LRTD were 87%, 58%, and 45% in possible, probable, and proven cases, respectively. Patients with probable and proven LRTD had significantly worse survival than those with upper respiratory tract infection (probable: hazard ratio [HR], 5.87 [P < .001]; proven: HR, 9.23 [P < .001]), whereas possible LRTD did not (HR, 1.49 [P = .27]). Among proven/probable cases, oxygen requirement at diagnosis, low monocyte counts, and high-dose steroid use (>2 mg/kg/day) were associated with high mortality in multivariable analysis. CONCLUSIONS:PIV LRTD with viral detection in lungs (proven/probable LRTD) was associated with worse outcomes than was PIV LRTD with viral detection in upper respiratory samples alone (possible LRTD). This new classification should impact clinical trial design and permit comparability of results among centers.
Project description:Acute graft-versus-host disease (GVHD) occurs less frequently after umbilical cord blood transplantation (UCBT). More recent investigations include the use of 2 partially human leukocyte antigen (HLA)-matched UCB units, or double UCB graft, to meet the minimum cell-dose requirement. The purpose of this analysis was to assess the relative risk of acute GVHD in 265 consecutive patients receiving transplants with UCB graft composed of 1 (n = 80) or 2 (n = 185) units. The incidence of grade III-IV acute GVHD was similar between cohorts. However, the incidence of grade II-IV acute GVHD was higher among double UCBT recipients (58 vs 39%, P < .01). Three risk factors for grade II-IV acute GVHD were identified in multiple regression analysis: use of 2 UCB units, use of nonmyeloablative conditioning, and absence of antithymocyte globulin in the conditioning regimen. Transplantation-related mortality (TRM) at 1 year, however, was significantly lower after double UCBT (24 vs 39%, P = .02) even if recipients had grade II-IV acute GVHD (20 vs 39%, P = .05). These data suggest that, despite a higher incidence of grade II acute GVHD in recipients of 2 partially HLA-matched UCB units, there is no adverse effect on TRM. This study is registered at (http://www.clinicaltrials.gov) under the identifiers NCT00305682 and NCT00309842.
Project description:Recent publications note an association between antibiotic exposure and respiratory viral infections (RVIs). Antibiotics affect microbiota and impair immune response against RVIs in mice, and low microbiome diversity is associated with pulmonary complications including viral lower respiratory tract disease (LRTD) in hematopoietic cell transplantation (HCT) recipients. In this study, we examined whether antibiotic exposure was associated with increased risk of disease progression in RVIs post-transplantation. We analyzed patients who underwent allogeneic HCT (June 2008 to February 2016) and had their first RVI due to parainfluenza virus (PIV), respiratory syncytial virus (RSV), or human metapneumovirus (MPV) during the initial 100 days post-transplantation. Antibiotic exposure in the 3 weeks before RVI onset was defined as (1) use of specific antibiotics versus none of these antibiotics and (2) number of antibiotic-days. Cox proportional hazards models were used to examine associations between antibiotic exposures and risk of viral disease progression to proven/probable/possible LRTD. Ninety HCT recipients (84 adults, 6 children) fulfilled study criteria; 33 progressed to LRTD. The number of antibiotic-days was associated with progression to LRTD after adjusting for neutropenia, steroid use, and either lymphopenia (hazard ratio, 1.41 [95% confidence interval, 1.04 to 1.92], P?=?.027) or monocytopenia (hazard ratio, 1.46 [95% confidence interval, 1.11 to 1.91], P?=?.006). Specific antibiotic classes was not associated with the outcome. Cumulative antibiotic exposure immediately before RVI onset is a risk factor for disease progression following PIV, RSV, and MPV infections post-transplantation. Larger cohort studies are needed to determine the impact of specific antibiotics or antibiotic classes on disease severity.