allo-HSCT Recipients Research Articles

Is cytomegalovirus a risk factor for haemorrhagic cystitis in allogeneic haematopoietic stem cell transplantation recipients?

Haemorrhagic cystitis (HC) is usually a serious complication in allogeneic haematopoietic stem cell transplantation (allo-HSCT) recipients. In this study, our aim was to define risk factors and outcomes for patients with HC in an allo-HSCT setting. We retrospectively evaluated 249 allo-HSCTs performed between 2011 and 2016 in our centre. HC was diagnosed in 98 patients (39%) at a median of 119 days (range 5-580) and 91 (93%) of the patients had late onset disease. In univariate analysis, HC was related to cytomegalovirus (CMV) reactivation (P<0.001) and BK viraemia (P<0.001); in multivariate analysis, the presence of CMV reactivation was determined to be an independent risk factor (odds ratio: 22.1; 95% CI 1.73, 282.44; P=0.017). There was no association detected between acute graft versus host disease and patients diagnosed with HC within 100 days of transplant. HC was significantly increased by the presence of myelo-ablative conditioning (odds ratio: 31.28; 95% CI 3.98, 246.87; P=0.001) and BK viraemia (odds ratio: 3.93; 95% Cl 1.10, 14.05; P=0.035) in patients with HC grade II and beyond. Forced hydration was recommended in all patients with grade I HC. Patients with HC and clots were treated with continuous bladder irrigation, and 14 of 44 patients with BK viraemia received cidofovir ± ribavirin. Eight of these patients (57%) responded to treatment. Refractory HC was detected in 17 patients (17%) and resolved by a variety of procedures. This study suggests that CMV reactivation is associated with increased risk of HC in multivariate analysis, however, this result is not confirmed in patients with HC grade II and beyond.

Functional specific‐T‐cell expansion after first cytomegalovirus reactivation predicts viremia control in allogeneic hematopoietic stem cell transplant recipients

The use of preemptive antiviral therapy to prevent cytomegalovirus (CMV) disease in allogeneic hematopoietic stem cell transplantation (allo-HSCT) recipients might result in over-treatment, inducing drug-related toxicity and viral resistance. A search for predictive markers is needed to determine requirement for antiviral therapy. Clinical follow-up, in combination with the use of streptamers (STs) and cytokine-intracellular staining, could help to identify patients at high risk for CMV reactivations. To study the immune response and reactivation control by CMV-specific CD8+ T-cell (CMV-CTL) populations, we monitored 25 patients who have undergone allo-HSCT by using ST multimer and intracellular cytokine staining. Our study has revealed that the presence of functional CMV-specific T cells, determined by early interferon γ production or by significant T-cell expansion after first CMV reactivation, correlated with short CMV viremia duration and low number of CMV reactivations. By contrast, the absence of functional CMV-CTLs does correlate with CMV recurrence. These results support that behavior of CMV-specific subpopulations after reactivation influences reactivations and can guide preemptive therapy.

Early Antimicrobial De-escalation and Stewardship in Adult Hematopoietic Stem Cell Transplantation Recipients: Retrospective Review.

BackgroundAntimicrobial stewardship in allogeneic hematopoietic stem cell transplantation (allo-HSCT) recipients remains underutilized in North America. European guidelines advise de-escalation of broad-spectrum therapy after 72 hours in select patients with neutropenic fever of unknown origin. This is not commonplace in the United States, as current guidelines recommend broad-spectrum therapy until neutrophil engraftment. If de-escalating after at least 5 days of broad-spectrum therapy and defervescence in neutropenic allo-HSCT recipients does not predispose them to recurrent fever or infection, the practice could afford several benefits.MethodsThe primary end point was rate of recurrent fever. Secondary outcomes included Clostridium difficile–associated infections, length of stay, intensive care unit (ICU) admission incidence, in-hospital mortality rate, need for re-escalation of therapy, rate of positive blood cultures for patients who had recurrent fevers, overall antimicrobial utilization from neutropenic fever onset, and pharmacoeconomic impact.ResultsA total of 120 patients were assessed in 2 groups as cohort 1 (n = 46), which received early de-escalation, and cohort 2 (n = 74), which did not. The primary end point met criteria for noninferiority, as 7 patients (15%) in cohort 1 had recurrent fever within the specified time frame compared with 14 (19%) in cohort 2 (90% CI, –0.0878 to 0.1629, P = .026). Patients in cohort 1 received significantly less gram-positive broad-spectrum antimicrobials, with trends toward lower use of broad-spectrum gram-negative agents and lower associated costs and no differences in length of stay, ICU admission incidence, need for re-escalation of therapy, rate of culture-positive bacteremia after de-escalation or discontinuation of broad-spectrum therapy, or in-hospital mortality rate.ConclusionsDe-escalating after at least 5 days of broad-spectrum therapy and defervescence did not appear to affect the rate of recurrent fever. This allowed for significant reductions in gram-positive broad-spectrum antimicrobial utilization, with trends toward lower use of broad-spectrum gram-negative agents and associated costs and no difference in clinical outcomes compared with those continuing such therapy until neutrophil engraftment.

Peripheral nerve injury following allogeneic hematopoietic stem cell transplantation

Background: Allogeneic hematopoietic stem cell transplant (allo-HSCT) recipients may develop peripheral nerve injury mimicking Guillain-Barré syndrome. Although the underlying etiology is obscure, allogeneic immune reaction may play a pivotal causative role.

Pneumococcal polysaccharide vaccination in allogeneic hematopoietic stem cell transplantation recipients: a prospective single-center study

Few studies have evaluated the response of allogeneic hematopoietic stem cell transplantation [allo-HSCT] recipients to pneumococcal polysaccharide vaccine-23 [PPSV23] in the modern transplant era when more elderly patients undergo allo-HSCT. We administered a single dose of PPSV23 to 30 allo-HSCT recipients and evaluated serotype-specific antibody responses using IgG measured by enzyme-linked immunosorbent assay and opsonophagocytic assay [OPA] titers in a multiplexed opsonophagocytic killing assay. The median patient age was 54 years [range, 23–68], and the interval from allo-HSCT to vaccination was 756 days [range, 389–1903]. No severe adverse effects were observed. The median positive response rates at 1 month and 1 year post-vaccination for the 7 serotypes measured by IgG were the same at 43% [range, 33–57], while those for 8 serotypes measured by OPA were 72% [range, 55–86] and 55% [range, 52–62], respectively. Peripheral blood stem cell transplantation improved vaccine response based on OPA titers at 1 month post-vaccination. During the median follow-up period of 1135 days post-vaccination, one patient developed pneumococcal bacteremia at 998 days. Our study suggests that PPSV23 vaccination in allo-HSCT recipients is safe and may result in a serological response.

PD-1 and CTLA-4 up regulation on donor T cells is insufficient to prevent GvHD in allo-HSCT recipients.

The expression of checkpoint blockade molecules PD-1, PD-L1, CTLA-4, and foxp3+CD25+CD4+ T cells (Tregs) regulate donor T cell activation and graft-vs-host disease (GvHD) in allogeneic hematopoietic stem cell transplant (allo-HSCT). Detailed kinetics of PD-1-, CTLA-4-, and PD-L1 expression on donor and host cells in GvHD target organs have not been well studied. Using an established GvHD model of allo-HSCT (B6 → CB6F1), we noted transient increases of PD-1- and CTLA-4-expressing donor CD4+ and CD8+ T cells on day 10 post transplant in spleens of allo-HSCT recipients compared with syngeneic HSCT (syn-HSCT) recipients. In contrast, expression of PD-1- and CTLA-4 on donor T cells was persistently increased in bone marrow (BM) of allo-HSCT recipients compared with syn-HSCT recipients. Similar differential patterns of donor T cell immune response were observed in a minor histocompatibility (miHA) mismatched transplant model of GvHD. Despite higher PD-1 and CTLA-4 expression in BM, numbers of foxp3+ T cells and Tregs were much lower in allo-HSCT recipients compared with syn-HSCT recipients. PD-L1-expressing host cells were markedly decreased concomitant with elimination of residual host hematopoietic elements in spleens of allo-HSCT recipients. Allo-HSCT recipients lacking PD-L1 rapidly developed increased serum inflammatory cytokines and lethal acute GvHD compared with wild-type (WT) B6 allo-HSCT recipients. These data suggest that increased expression of checkpoint blockade molecules PD-1 and CTLA-4 on donor T cells is not sufficient to prevent GvHD, and that cooperation between checkpoint blockade signaling by host cells and donor Tregs is necessary to limit GvHD in allo-HSCT recipients.

Predictive implications of albumin and C-reactive protein for progression to pneumonia and poor prognosis in Stenotrophomonas maltophilia bacteremia following allogeneic hematopoietic stem cell transplantation

BackgroundStenotrophomonas maltophilia (S. maltophilia) bacteremia causes significant morbidity and mortality in immunocompromised hosts. However, incidence and risk factors for mortality in S. maltophilia bacteremia following allogeneic hematopoietic stem cell transplantation (allo-HSCT) remain controversial. The primary aim of this study is to clarify factors associated with poor prognosis of allo-HSCT recipients with S. maltophilia bacteremia.MethodsFrom January 2005 to December 2014, patients with hematological diseases and S. maltophilia bacteremia at a single transplantation center in Japan were examined for incidence and 90-day mortality. Prognostic factors associated with 90-day mortality among allo-HSCT recipients were analyzed by log-rank test, and significant variables in the univariate analysis were included in the multivariate Cox proportional-hazards regression model.ResultsA total of 65 patients, including 47 patients undergoing allo-HSCT, developed S. maltophilia bacteremia. The incidence of S. maltophilia bacteremia was significantly higher in allo-HSCT recipients compared to patients not receiving allo-HSCT (6.53 vs. 0.36 per 100 admissions, respectively; p < 0.01). The overall 90-day mortality in allo-HSCT recipients was 43%. Independent risk factors for 90-day mortality were low serum albumin (<3.0 g/dl) (HR = 10.86; 95% CI, 3.27–36.12) and high serum C-reactive protein (CRP) (≥10.0 mg/dl) (HR = 3.28; 95% CI, 1.00–10.72). Among 9 patients with both high CRP and low albumin, 5 had pneumonia at the onset of bacteremia and the remaining 4 patients developed pneumonia in a median of 3 days (range, 1 to 8 days) even under effective treatment. All 9 patients eventually died in a median of 2 days (range, 2 to 32 days). The probabilities of developing pneumonia in patients with or without high CRP and low albumin levels were 100% (9/9) and 10.5% (4/38), respectively (p < 0.01).ConclusionsAllo-HSCT recipients had higher rates of S. maltophilia bacteremia than did patients not receiving allo-HSCT. High serum CRP and low serum albumin at the onset of bacteremia are predictive of disease progression to pneumonia and poor prognosis.

Characteristics and risk of chronic graft-versus-host disease of liver in allogeneic hematopoietic stem cell transplant recipients.

Chronic graft-versus-host-disease (cGvHD) is a serious complication of allogeneic hematopoietic stem cell transplantation (allo-HSCT). Among various organ-specific cGvHD, the cGvHD of liver is less well-characterized. In this study, we applied the National Institutes of Health 2014 scoring criteria of cGvHD to analyze a retrospective cohort of 362 allo-HSCT recipients focusing on cGvHD of liver. The overall incidence of liver cGvHD with a score of 3 by 1.5 years post-transplant was 5.8% (21/362). Poor outcome, in terms of overall survival (OS), were observed in patients with scores of 3 liver cGvHD, comparing to those with scores less than 3 (hazard ratio [HR] 2.037, 95% confidence interval [CI] 1.123–3.696, P = 0.019). In multivariate analysis, male gender (HR 4.004, P = 0.042) and chronic hepatitis C virus (HCV) infection status (HR 19.087, P < 0.001) were statistically significant risk factors for scores of 3 liver cGvHD. Our results indicate that liver cGvHD with scores of 3 has a grave prognosis following allo-HSCT, and that HCV carrier status and male are risk factors. Early recognition of this devastating complication might help in prompt immunosuppressive therapy and reducing late poor outcome.

Impact of oral gut decontamination on Staphylococcus aureus colonisation in patients undergoing allogeneic haematopoietic stem cell transplantation

Recipients of allogeneic haematopoietic stem cell transplantation (allo-HSCT) are severely immunocompromised and are at increased risk of infection. In this prospective, observational, single-centre study including 110 allo-HSCT recipients, the rate of Staphylococcus aureus colonisation was reduced from 11.8% to 0% (P < 0.001) following peritransplant oral gut decontamination. No invasive S. aureus infections were observed.

Upper respiratory viral infections in patients with haematological malignancies after allogeneic haematopoietic stem cell transplantation: a retrospective study.

Community respiratory viruses (CRVs) are associated with upper respiratory viral infections (URI), pneumonia or life-threatening respiratory disease in patients with allogeneic haematopoietic stem cell transplantation (allo-HSCT). Our aim is to demonstrate our URI experience related to CRVs after allo-HSCT. From January 2013 to November 2015, 39 post allo-HSCT patients with acute URI symptoms were included in the study. We evaluated CRVs by multiplex PCR from nasopharyngeal wash and throat swabs. The median age of the patients was 39 (range 20-67 years). A total of 25 patients (64%) had viral panel positivity at a median 140 days post-transplant (range 3-617 days). The most common agents detected were respiratory syncytial virus (32%) and parainfluenza (32%). The patients with viral panel positivity had significantly lower lymphocyte count (1.05×109/l versus 3.09×109/l; P=0.013). During follow-up, 20 patients (80%) were diagnosed with pneumonia. Patients with concurrent bacterial or fungal infections were more likely to have pneumonia (100% versus 68%; P=0.023). 10 patients (40%) died due to pneumonia and related complications. Lower lymphocyte counts and higher C-reactive protein levels at the time of viral panel positivity were risk factors for mortality (1.5×109/l versus 0.39×109/l, P=0.007; 74.2 versus 199.7, P=0.006). The viral panel was positive in 64% of patients with acute URI symptoms. Lower lymphocyte count was detected in CRV-positive patients. The onset of concomitant bacterial or fungal infections increased the risk of lower respiratory infection disease. Indeed, prospective studies should be designed for risks and outcomes of CRVs in allo-HSCT recipients.

Clinical impact of pre-transplant gut microbial diversity on outcomes of allogeneic hematopoietic stem cell transplantation

Post-transplant microbial diversity in the gastrointestinal tract is closely associated with clinical outcomes following allogeneic hematopoietic stem cell transplantation (allo-HSCT). However, little is known about the impact of the fecal microbiota before allo-HSCT. We analyzed fecal samples approximately 2weeks before conditioning among 107 allo-HSCT recipients between 2013 and 2015. Microbial analysis was performed using 16S rRNA gene sequencing. Operational taxonomic unit-based microbial diversity was estimated by calculating the Shannon index. Patients were classified into three groups based on the diversity index: low (<2), intermediate (2, 3), and high (>3) diversity (18 (16.8%), 48 (44.9%), and 41 (38.3%) patients, respectively). There were no significant differences in the 20-month overall survival, cumulative incidence of relapse, and non-relapse mortality among three groups. The cumulative incidence of grade II to IV acute graft-versus-host disease (aGVHD) was similar among the three groups (low 55.6%; intermediate 35.4%; high 48.8%, p=0.339, at day 100). Furthermore, we found no differences in the cumulative incidence of grade II to IV acute gastrointestinal GVHD among the three groups (low 38.9%; intermediate 21.3%; high 24.4%, p=0.778, at day 100). Regarding the composition of microbiota before allo-HSCT, aGVHD patients showed a significantly higher abundance of phylum Firmicutes (p<0.01) and a lower tendency for Bacteroidetes (p=0.106) than non-aGVHD patients. Maintenance of Bacteroidetes throughout allo-HSCT may be a strategy to prevent aGVHD.

A risk-adapted approach to treating respiratory syncytial virus and human parainfluenza virus in allogeneic stem cell transplantation recipients with oral ribavirin therapy: A pilot study.

Here we report the applicability of a protocol based on clinical conditions and risk factors (RFs) for managing 35 allogeneic hematopoietic stem cell transplantation (allo-HSCT) recipients who developed a total of 52 episodes of respiratory viral infections (RVIs) caused by respiratory syncytial virus (RSV; n=19), human parainfluenza virus (HPIV; n=29), or both (n=4) over a 2-year study period. Risk categories were classified as high risk (cat-1) when the immunodeficiency scoring index was ≥3 and/or ≥3 RFs and/or ≥1 co-infective virus(es) were present; the remaining cases were classified as low risk (cat-0). The presence of two or more signs or symptoms including fever (T>38°C), sinusitis, otitis, sore throat, tonsillitis, or baseline C-reactive protein increased by >2-fold at the time of the RVI, was considered a clinically-intense episode (CIE). Overall, 34 out of 52 episodes (65%) were limited to upper respiratory tract infections (URTIs). Overall, 26 (50%) received oral ribavirin. Twenty-four of 40 (60%) cat-1 episodes were treated, compared to 2 of 12 (17%) cat-0 RVIs (P=.01), while 17 of the 25 (68%) CIEs were treated compared to 9 of the remaining 27 (33%) episodes (P=.02). Regardless of antiviral therapy, the overall resolution rate was 100% for URTI and 95% for lower respiratory tract infection; the virus-related mortality was low (4%). In conclusion, the use of a risk-adapted protocol to guide therapeutic decisions for allo-HSCT recipients with RSV or HPIV RVIs is feasible and may limit unnecessary antiviral therapy.

Dynamics of Torque Teno virus viremia could predict risk of complications after allogeneic hematopoietic stem cell transplantation.

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is an established treatment option for several hematological diseases. However, the first year post-transplantation is often complicated by infections and graft-versus-host disease (GVHD). Improvements in immunological monitoring could reduce such post-transplant complications. Torque Teno virus (TTV), a chronically persisting DNA virus, is reported to be a marker for immune function in immunocompromised patients. In the present study, the TTV kinetics were analyzed to investigate the potential role of TTV viremia as immune-competence read-out after allo-HSCT. Twenty-three monocentric allo-HSCT recipients were retrospectively tested for TTV-DNA in whole blood at given day post-transplant. Dynamics of TTV viremia was analyzed with respect to episodes of non-TTV viral reactivations (CMV, EBV, and BKPyV), acute GVHD, and recovery of immune cells. Recipients affected by persisting viral infections and/or GVHD during the first 100days after allo-HSCT showed a significantly higher median TTV load at day +30 than patients with a less complicated clinical course (p=0.005). This was also associated with a total lymphocyte count <5.5E+08 cells/L in this high-risk group (p=0.039). These findings suggest that TTV could represent an additional parameter to identify patients at higher risk for complications in the first 100days following allo-HSCT. Prospective studies, including the monitoring of lymphocyte subsets, are required to define the potential use of TTV in immunological monitoring after allo-HSCT.

Epidemiology and Risk Factors for Invasive Fungal Diseases among Allogeneic Hematopoietic Stem Cell Transplant Recipients in Korea: Results of “RISK” Study

Incidence, epidemiology, and risk factors of invasive fungal diseases (IFDs) in allogeneic hematopoietic stem cell transplant (allo-HSCT) recipients can vary from different cohorts and countries. Therefore, we performed a nationwide study to establish a proper antifungal prophylaxis strategies based on risk stratifications of IFDs after all-HSCT in Korea (RISK study). This was a multicenter, retrospective, and observational study in Korea. All consecutive adult patients who received allo-HSCT in 2013 were included. The 12-month cumulative incidence of proven/probable IFDs (PP-IFDs) was calculated during the early (days 0 to 40), late (days 41 to 100), and very late (days 101 to 365) phases after allo-HSCT. Cox proportional hazard regression analysis was performed to identify risk factors for PP-IFDs at each phase. A total 521 allo-HSCT cases in 518 patients were analyzed. Overall cumulative incidence of PP-IFDs were 4.09% (95% confidence interval [CI], 2.38 to 5.81), 7.38% (95% CI, 5.09 to 9.67), and 15.36% (95% CI, 12.04 to 18.68) at the early, late and very phases, respectively. In multiple Cox regression analysis, variables were associated with PP-IFDs in each period were identified. Variables associated with early phase include underlying pulmonary diseases, underlying nonmalignant stable or chronic disease at allo-HSCT, unrelated or family mismatched donor, and prolonged neutropenia. Variables associated with the late phase include high ferritin level at the time point of allo-HSCT, use of secondary immunosuppressive agents due to refractory graft-versus-host disease (GVHD), and cytomegalovirus reactivation. For the very late phase, variables were secondary neutropenia, severe chronic GVHD, and use of TNF-alpha inhibitor for refractory GVHD. This study revealed the high cumulative incidence of IFDs in Korean allo-HSCT recipients, which have distinct risk factors in each phase after allo-HSCT. Our findings indicate that tailored antifungal prophylaxis is necessary for high-risk patients. Clinicians should consider using mold-active antifungal prophylaxis in allo-HSCT recipients who have high risks at different treatment period.

Dynamics of BKPyV reactivation and risk of hemorrhagic cystitis after allogeneic hematopoietic stem cell transplantation.

Aim of this retrospective study was to analyze the dynamics of BKPyV reactivation in allogeneic hematopoietic stem cell transplant recipients in order to identify patients with higher risk to develop BKPyV-associated hemorrhagic cystitis (BKPyV-associated HC). The study included 58 allo-HSCT recipients from the University Hospital of Cologne detected BKPyV positive by real-time PCR between 2009 and 2015. For correlative analysis, the first detected BKPyV-DNA load in urine and in plasma as well as the onset and severity of HC following the first day of conditioning regimen was considered. Phylogenetic analysis of BKPyV isolates was performed. In 25 of 58 patients, BKPyV-DNA was detected in urine only (group U), whereas 33 patients developed additional viremia (group P). A chronologic sequence viruria-viremia-HC was identified. Viral load of >106 copies/mL at first viruria and evidence of viremia after 45days from the start of conditioning represented risk factors for the onset of HC. Molecular characterization revealed a non-stereotypic distribution of viral subtypes across groups U and P. Monitoring of BKPyV-DNA by real-time PCR after initiation of conditioning, regularly performed in clinical practice, can be a crucial tool for the early identification of patients with higher risk of BKPyV-associated HC.

Humoral Immune Reconstitution Kinetics after Allogeneic Hematopoietic Stem Cell Transplantation in Children: A Maturation Block of IgM Memory B Cells May Lead to Impaired Antibody Immune Reconstitution

Although T cell immune reconstitution after allogeneic hematopoietic stem cell transplantation (allo-HSCT) has been well studied, long-term B cell immune reconstitution remains less characterized. We evaluated humoral immune reconstitution among 71 pediatric allo-HSCT recipients. Although tetanus toxoid antibody levels were normal at 1 year after allo-HSCT, antipolysaccharide carbohydrate antibodies remained persistently low for up to 5 years. While naive B cell counts normalized by 6 months, IgM memory B cell deficiency persisted for up to 2 years (P = .01); switched memory B cell deficiency normalized by 1 year after allo-HSCT. CD4+ T cell immune reconstitution correlated with that of switched memory B cells as early as 6 months after allo-HSCT (r = .55, P = .002) but did not correlate with IgM memory B cells at any time point after allo-HSCT. Taken together, this suggests that allo-HSCT recipients have impaired antibody immune reconstitution, mainly due to IgM memory B cell maturation block, compared with more prompt T cell–dependent switched memory cell immune reconstitution. We further explored other factors that might affect humoral immune reconstitution. The use of total body irradiation was associated with lower naive B cells counts at 6 months after HSCT (P = .04) and lower IgM (P = .008) and switched (P = .003) memory B cells up to 2 years. Allo-HSCT recipients with extensive chronic graft-versus-host disease had lower IgM memory B cell counts (P = .03) up to 2 years after allo-HSCT. The use of cord blood was associated with better naive (P = .01), IgM (P = .0005), and switched memory (P = .006) B cells immune reconstitution. These findings may inform future prophylaxis and treatment strategies regarding risk of overwhelming infection, graft-versus-host disease, and post-allogeneic HSCT revaccination.

Respiratory virus infection after allogeneic hematopoietic stem cell transplant in a tropical center: Predictive value of the immunodeficiency scoring index

BackgroundRespiratory virus infection (RVI) is a prevalent infection in patients after allogeneic hematopoietic stem cell transplant (allo‐HSCT) and can result in significant morbidity and mortality. Ability to assess the potential severity of RVI is important in the management of such patients.MethodsWe reviewed the cases of RVI in allo‐HSCT recipients and explored the predictive value of the immunodeficiency scoring index (ISI) established for respiratory syncytial virus (RSV) and its applicability for RVI caused by other respiratory viruses.ResultsRVI occurred year‐round in our tropical transplant center, with peaks in the middle and end of the year. Ninety‐five of the 195 recipients developed a total of 191 episodes of RVI, giving a cumulative incidence of 28% by 6 months and 52% by 24 months for the first episode of RVI. RSV, influenza, rhinovirus, and parainfluenza were the most common viruses. Pneumonia occurred in 63.64%, 42.31%, and 32.42% of adenovirus, influenza, and RSV RVI episodes, respectively, but was also non‐negligible in the more benign viruses, such as coronavirus (31.58%) and rhinovirus (23.68%). Nineteen of the 63 episodes of viral pneumonia required mechanical ventilation and 14 deaths occurred within 6 weeks of the RVI. Receiver operating characteristic analysis showed that an ISI of ≥8 predicted pneumonia with a positive predictive value of >80% for RVI caused by RSV, influenza, adenovirus, and parainfluenza, while it was not predictive for coronavirus and rhinovirus.ConclusionsThe ISI is a useful aid for decision‐making during clinic consultation for patients presenting with symptoms suggestive of an RVI.

Physical and psychosocial aspects of adolescent and young adults after allogeneic hematopoietic stem-cell transplantation: results from a prospective multicenter trial.

Allogeneic hematopoietic stem-cell transplantation (alloHSCT) is physically and psychosocially demanding. Among transplant recipients, adolescent and young adults (AYA) represent a special group, as disease occurs early in life, resulting in the prospect of long survival time and high burden of alloHSCT sequelae. However, data focusing on AYA undergoing alloHSCT are rare. Data resulting from a prospective multicenter trial initially focusing on graft-versus-host disease (GvHD) after alloHSCT were reused to analyse the differences between AYA and elderly patients. In total, data of 205 alloHSCT recipients were evaluated. Patients completed the FACT-BMT, HAP, SF-36, 24-AM, LOT-R, BSSS, HADS, and GvHD questionnaires. Median age of AYA and non-AYA patients was 29 and 52years. Using 24-AM-Test, evaluating personality traits, non-AYA reported to be more conscientious (p=0.033). However, AYA described higher quality of life regarding physical role functioning (p=0.001), physical functioning (p=0.002), bodily pain (p=0.023), and emotional role function (p=0.027) in the SF-36. General health perception, vitality, social role functioning, and mental health were comparable among both groups. On HAP scale, AYA reported higher maximum (p=0.003) and adjusted activity scores (p=0.002), but showed similar restrictions regarding activity, self-supply, and self-determination. AYA represent a particular group characterized by higher physical well-being and activity scores, and significantly vary from non-AYA patients in psychosocial aspects. Studies covering distinctive features of AYA undergoing alloHSCT are warranted to improve awareness of the special needs of this group.

A Time-to-Event Model for Acute Kidney Injury after Reduced-Intensity Conditioning Stem Cell Transplantation Using a Tacrolimus- and Sirolimus-based Graft-versus-Host Disease Prophylaxis

There is a paucity of data evaluating acute kidney injury (AKI) incidence and its relationship with the tacrolimus–sirolimus (Tac-Sir) concentrations in the setting of reduced-intensity conditioning (RIC) after allogeneic stem cell transplantation (allo-HSCT). This multicenter retrospective study evaluated risk factors of AKI defined by 2 classification systems, Kidney Disease Improving Global Outcome (KDIGO) score and “Grade 0-3 staging,” in 186 consecutive RIC allo-HSCT recipients with Tac-Sir as graft-versus-host disease prophylaxis. Conditioning regimens consisted of fludarabine and busulfan (n = 53); melphalan (n = 83); or a combination of thiotepa, fludarabine, and busulfan (n = 50). A parametric model, with detailed Tac-Sir consecutive blood levels, describing time to AKI was developed using the NONMEM software version 7.4. Overall, 81 of 186 (44%) RIC allo-HSCT recipients developed AKI with a cumulative incidence of 42% at a median follow-up of 25 months. Time to AKI was best described using a piecewise function. AKI-predicting factors were melphalan-based conditioning regimen (HR, 1.96; P < .01), unrelated donor (HR, 1.79; P = .04), and tacrolimus concentration: The risk of AKI increased 2.3% per each 1-ng/mL increase in tacrolimus whole blood concentration (P < .01). In multivariate analysis, AKI grades 2 and 3 according to KDIGO staging were independent risk factors for 2-year nonrelapse mortality (HR, 2.8; P = .05; and HR, 6.6; P < .0001, respectively). According to the KDIGO score, overall survival decreased with the increase in severity of AKI: 78% for patients without AKI versus 68%, 50%, and 30% for grades 1, 2, and 3, respectively (P < .0001). In conclusion, AKI is frequent after Tac-Sir–based RIC allo-HSCT and has a negative impact on outcome. This study presents the first predictive model describing time to AKI as a function of tacrolimus drug concentration.

Protective Factors in the Intestinal Microbiome Against Clostridium difficile Infection in Recipients of Allogeneic Hematopoietic Stem Cell Transplantation.

Clostridium difficile infection (CDI) is a frequent complication in recipients of allogeneic hematopoietic stem cell transplantation (allo-HSCT), who receive intensive treatments that significantly disrupt the intestinal microbiota. In this study, we examined the microbiota composition of allo-HSCT recipients to identify bacterial colonizers that confer protection against CDI after engraftment. Feces collected from adult recipients allo-HSCT at engraftment were analyzed; 16S ribosomal RNA genes were sequenced and analyzed from each sample. Bacterial taxa with protective effects against development of CDI were identified by means of linear discriminant analysis effect size analysis and then further assessed with clinical predictors of CDI using survival analysis. A total of 234 allo-HSCT recipients were studied; postengraftment CDI developed in 53 (22.6%). Within the composition of the microbiota, the presence of 3 distinct bacterial taxa was correlated with protection against CDI: Bacteroidetes, Lachnospiraceae, and Ruminococcaceae. Colonization with these groups at engraftment was associated with a 60% lower risk of CDI, independent of clinical factors. Colonization with these 3 bacterial groups is associated with a lower risk of CDI. These groups have been shown to be vital components of the intestinal microbiota. Targeted efforts to maintain them may help minimize the risk of CDI in this at-risk population.