Diagnostic yield of the cytomegalovirus (CMV) antigenemia assay and clinical features in solid organ transplant recipients and hematopoietic stem cell transplant recipients with CMV pneumonia

Data are limited on the value of non-invasive diagnostic methods, such as the cytomegalovirus (CMV) antigenemia assay, and the clinical features of CMV pneumonia in patients who have undergone solid organ transplant (SOT) compared with those who have had hematopoietic stem cell transplant (HSCT). All adult patients with suspected CMV pneumonia, who had received SOT or HSCT in a tertiary hospital during a 5-year period, were retrospectively enrolled. CMV pneumonia was defined as clinical and radiographic evidence of pneumonia in association with the isolation of CMV in viral cultures of bronchoalveolar lavage or lung tissue specimens, or with the identification of CMV in lung tissue. In total, 36 patients with CMV pneumonia were identified. Of these, 29 (80%) had received SOT and 7 (20%) had received HSCT. The incidence of CMV pneumonia in the patients with SOT (3.0 per 1000 person-years [95% confidence interval {CI} 0.6-8.7]) was lower than in those with HSCT (17.0 per 1000 person-years [95% CI 9.9-27.2], P?=?0.003) and CMV-related mortality showed a tendency to have lower mortality in patients with SOT (10% [3/29]) than with HSCT (43% [3/7], P?=?0.07). The overall sensitivity of the CMV assay (≥?1/200,000 leukocytes) in patients with CMV pneumonia was 69% (95% CI 52-84%). The CMV antigenemia test is of limited value in diagnosing CMV pneumonia, given the high cost of false-negative diagnoses of CMV pneumonia.     

Management of CMV infection and disease in transplant patients. 27-29 February 2004

The International Herpes Management Forum (IHMF) has published guidelines for the diagnosis and management of cytomegalovirus (CMV) infection and disease in solid organ (SOT) and haematopoietic stem cell transplant (HSCT) recipients. These recommendations have been updated to include, among others: (1) use of whole blood for the polymerase chain reaction (PCR) diagnosis of CMV infection; (2) CMV load measurements for prognostication and for monitoring response to anti-CMV therapy; (3) valganciclovir prophylaxis in CMV donor-positive/recipientnegative (D+/R-) SOT patients for prevention of CMV disease; (4) oral ganciclovir prophylaxis, in preference to aciclovir, to reduce incidence of CMV disease in SOT patients; (5) pre-emptive therapy with oral ganciclovir to reduce incidence of CMV disease and viraemia in liver transplant patients; (6) valaciclovir prophylaxis, in preference to high-dose oral aciclovir, to prevent CMV infection in allogeneic HSCT patients; and (7) foscarnet as an alternative to intravenous ganciclovir for pre-emptive treatment of CMV infection in allogeneic HSCT patients. New developments in the field requiring further research were highlighted, including: optimal frequency of CMV monitoring in CMV D+/R- SOT patients; optimal duration of prophylaxis for the prevention of late CMV disease; need for an acceptable viral threshold for initiation of pre-emptive therapy; and assessment of the clinical efficacy of valganciclovir for the treatment of CMV disease and as pre-emptive therapy in SOT and HSCT patients. This article presents supporting evidence for these recommendations and statements.     

Comparison of in vitro susceptibility characteristics of Candida species from cases of invasive candidiasis in solid organ and stem cell transplant recipients: Transplant-Associated Infections Surveillance Network (TRANSNET), 2001 to 2006

Invasive fungal infections (IFI) are a major cause of morbidity and mortality among both solid organ transplant (SOT) and hematopoietic stem cell transplant (HSCT) recipients. Candida is the most common cause of IFI in SOT recipients and the second most common cause of IFI in HSCT recipients. We determined susceptibilities to fluconazole, voriconazole, itraconazole, posaconazole, amphotericin B, and caspofungin for 383 invasive Candida sp. isolates from SOT and HSCT recipients enrolled in the Transplant-Associated Infection Surveillance Network and correlated these results to clinical data. Fluconazole resistance in C. albicans, C. tropicalis, and C. parapsilosis isolates was low (1%), but the high percentage of C. glabrata and C. krusei isolates within this group of patients increased the overall percentage of fluconazole resistance to 16%. Voriconazole resistance was 3% overall but was 8% among C. glabrata isolates. On multivariable analysis, among HSCT recipients fluconazole nonsusceptibility was independently associated with C. glabrata, non-Hodgkin's lymphoma, cytomegalovirus (CMV) antigenemia, diabetes active at the time of the IFI, and any prior amphotericin B use; among SOT recipients, fluconazole nonsusceptibility was independently associated with any fluconazole use in the 3 months prior to the IFI, C. glabrata, ganciclovir use in the 3 months prior to the IFI, diabetes acquired since the transplant, and gender.     

Immune response to CMV in solid organ transplant recipients: current concepts and future directions

Despite advances in immunosuppression and antiviral therapy, CMV continues to be a significant opportunistic pathogen adversely affecting the outcome of solid organ transplantation (SOT) recipients. While a significant proportion of CMV disease is caused by reactivation of latent virus, the risk is highest among CMV donor+ and recipient- SOT patients. CMV is responsible for both direct (e.g., pneumonitis, colitis) and indirect (e.g., rejection, atherosclerosis) morbidity and mortality. Healthy CMV-seropositive individuals have a high frequency of CMV-specific CD4⁺ and CD8⁺ T cells that provide immune protection by limiting CMV reactivation and replication. Changes to the innate and adaptive immune system from immunosuppressive therapy following SOT contribute to CMV disease pathogenesis. CMV disease after SOT is associated with poorer outcomes, thus novel strategies to prevent it are an area of active research. In this article, we review the current state of knowledge on the immune response to CMV following SOT.     

The impact of human herpesvirus 6B reactivation on early complications following allogeneic hematopoietic stem cell transplantation.

Although human herpesvirus 6 (HHV-6) has been considered an important opportunistic and potentially fatal pathogen for allogeneic hematopoietic stem cell transplantation (HSCT), the clinical significance of HHV-6 reactivation remains controversial. In this study, we monitored HHV-6 DNAemia in 72 consecutive allogeneic HSCT recipients by real-time quantitative polymerase chain reaction. A total of 680 peripheral blood specimens were collected from the recipients before HSCT or at weekly intervals after HSCT. As the predominant variant, HHV-6B was detectable at least once in 47.2% (34/72) of HSCT recipients on the median day 21 (range, 7-84 days); HHV-6A reactivation occurred in only 1 recipient (1.4%). Detectable HHV-6B reactivation was associated with increased probability of skin rash by day 30 after HSCT (hazard ratio [HR], 3.68; 95% confidence interval [CI], 1.24-10.92; P = .019), cytomegalovirus (CMV) antigenemia (HR, 2.35; 95%CI, 1.32-4.19; P = .004), and hemorrhagic cystitis (HC) (HR, 2.59; 95%CI, 0.96-6.98; P = .061) by day 100 after HSCT. Neutrophil and platelet engraftment, mortality for 100 days after HSCT were not affected by HHV-6B reactivation. In conclusion, HHV-6 reactivation is a common event, and this study demonstrates a correlation between HHV-6B infection and CMV reactivation, early rash, and possibly increased incidence of HC after transplantation.     

A Randomized,Double-Blind,Placebo-Controlled Phase 3 Trial of Oral Brincidofovir for Cytomegalovirus Prophylaxis in Allogeneic Hematopoietic Cell Transplantation

Cytomegalovirus (CMV) infection is a common complication of allogeneic hematopoietic cell transplantation (HCT). In this trial, we randomized adult CMV-seropositive HCT recipients without CMV viremia at screening 2:1 to receive brincidofovir or placebo until week 14 post-HCT. Randomization was stratified by center and risk of CMV infection. Patients were assessed weekly through week 15 and every third week thereafter through week 24 post-HCT. Patients who developed clinically significant CMV infection (CS-CMVi; CMV viremia requiring preemptive therapy or CMV disease) discontinued the study drug and began anti-CMV treatment. The primary endpoint was the proportion of patients with CS-CMVi through week 24 post-HCT; patients who discontinued the trial or with missing data were imputed as primary endpoint events. Between August 2013 and June 2015, 452 patients were randomized at a median of 15 days after HCT and received study drug. The proportion of patients who developed CS-CMVi or were imputed as having a primary endpoint event through week 24 was similar between brincidofovir-treated patients and placebo recipients (155 of 303 [51.2%] versus 78 of 149 [52.3%]; odds ratio, .95 [95% confidence interval, .64 to 1.41]; P = .805); fewer brincidofovir recipients developed CMV viremia through week 14 compared with placebo recipients (41.6%; P < .001). Serious adverse events were more frequent among brincidofovir recipients (57.1% versus 37.6%), driven by acute graft-versus-host disease (32.3% versus 6.0%) and diarrhea (6.9% versus 2.7%). Week 24 all-cause mortality was 15.5% among brincidofovir recipients and 10.1% among placebo recipients. Brincidofovir did not reduce CS-CMVi by week 24 post-HCT and was associated with gastrointestinal toxicity.     

Limited impact of cytomegalovirus infection in the long-term outcome of renal and liver transplant

BackgroundThe strength of the assumed association of CMV and long term deleterious events in solid organ transplant recipients (SOT) is controversial.ObjectivesThe aim of the present study was to evaluate whether viral replication dynamics during CMV infection or CMV disease may correlate not only with graft dysfunction and survival, but also with other potentially related late events in a long-term followed cohort of kidney (KT) and liver (LT) transplant recipients.Study design162 SOT (104 kidney, 58 liver) at our institution (2003–2005) with survival over 180 days and a median follow-up of 71 months (9–86) were analyzed. Using a Cox proportional hazard model, CMV infection (including area under the curve of DNAemia[AUC]) and CMV disease in the first 180 days were evaluated as potential predictors of the following late events (>180 days): mortality, graft dysfunction (GD), graft loss (GL), cardiovascular events (CVE), malignant tumors (MT).ResultsCMV infection occurred in 59% and CMV disease in 8%. Late death occurred in 17%, GD in 45.6%, GL in 14.2%, CVE in 10.5% and MT in 9.9%. We found no significant association between the intensity or duration of CMV viremia (AUC, persistent viremia or untreated CMV viremia) or CMV disease and the development of evaluated late events. According multivariate analysis neither CMV infection (hazard ratio [HR] 2.18 95% CI 0.949–5 p = 0.066) nor CMV disease (HR: 1.72; 95% CI 0.59–5 p = 0.31) were significantly correlated with late mortality.ConclusionsOur data do not support that CMV infection or CMV disease contribute significantly to long-term deleterious events in SOT.     

Comparative Quantitation of Cytomegalovirus (CMV) DNA in Solid Organ Transplant Recipients with CMV Infection by Using Two High-Throughput Automated Systems

Cytomegalovirus (CMV) DNA quantitation in clinical specimens is progressively becoming a cornerstone in the diagnosis and management of CMV infection in the immunocompromised host. We evaluated two automated and reproducible PCR tests, the LightCycler (Roche Molecular Biochemicals, Indianapolis, Ind.) and the COBAS AMPLICOR CMV Monitor (Roche Diagnostics, Pleasanton, Calif.), for the detection of CMV DNA in blood samples from transplant recipients with CMV infection as determined by shell vial culture. Following a log transformation analysis, the mean CMV DNA in plasma (PL), whole blood (WB), peripheral blood leukocytes (PBL), and peripheral blood mononuclear cells (PBMC) using the LightCycler was 6.79 copies per ml, 7.23 copies per ml, 6.38 copies per 2 x 10(6) cells, and 6.27 copies per 2 x 10(6) cells, respectively. This compares to 7.86 copies per ml, 8.37 copies per ml, 7.59 copies per 2 x 10(6) cells, and 7.44 copies per 2 x 10(6) cells, respectively, using COBAS AMPLICOR CMV Monitor. While higher CMV DNA levels were observed for the various blood compartments analyzed using COBAS AMPLICOR CMV Monitor, a high degree of correlation was evident between the two automated systems (jackknife correlation r = PL 0.77 [95% confidence interval (CI); 0.64, 0.90], WB 0.77 [95% CI; 0.62, 0.92], PBL 0.77 [95% CI; 0.67, 0.88], and PBMC 0.81 [95% CI; 0.72, 0.89], all P < 0.001). Therefore, we conclude that either automated diagnostic system is accurate for CMV DNA quantitation.     

Impact of Cytomegalovirus Replication and Cytomegalovirus Serostatus on the Outcome of Patients with B Cell Lymphoma after Allogeneic Stem Cell Transplantation

Cytomegalovirus (CMV) replication after allogeneic hematopoietic stem cell transplantation (HSCT) was historically associated with increased nonrelapse mortality (NRM). More recently, different groups have reported an association between CMV replication and reduced risk of acute myeloid leukemia (AML) relapse. Given the conflicting results, we evaluated the impact of CMV replication and other covariates on the outcome of a retrospective cohort of 265 adults with B cell lymphoma receiving allogeneic HSCT from HLA-identical siblings or alternative donors. In time-dependent multivariate analysis, CMV replication, evaluated by pp65 antigenemia, had no independent effect on the risk of relapse (hazard ratio [HR], 1.0; 95% confidence interval [CI], .6 to 1.6; P = .9), although it was associated with a reduced overall survival (HR, 2.0; 95% CI, 1.3 to 3.2; P = .001) and an increased NRM (HR, 2.5; 95% CI, 1.1 to 5.3; P = .01). Consistently, donor and/or recipient CMV seropositivity were not associated with a different outcome relative to CMV double-negative serostatus. In multivariate models, a diagnosis of follicular lymphoma (P < .0001) and pretransplantation complete remission status (P < .0001) were the main independent predictors for improved relapse-free survival. In summary, contrary to what is observed in patients with AML, this report identifies no independent role for CMV replication or serostatus on the relapse of patients with B cell lymphomas undergoing allogeneic HSCT.     

Risk of infectious diseases among first-degree relatives of transplant recipients who develop CMV infection: is the infectious phenotype inheritable?

Transplant recipients are at high risk of cytomegalovirus (CMV) infection. Mechanisms explaining the variation in risk of infections are far from fully elucidated. We hypothesised that host genetics explains part of the variation in risk of infection and examined if relatives of recipients with CMV infection have higher rates of severe infections compared to relatives of recipients without this infectious phenotype. In a register-based study, we included first-degree relatives of transplant recipients and examined the risk of hospitalisation due to overall infection or viral infection and risk of death among relatives of recipients who developed CMV infection within the first year of transplantation compared to relatives of recipients without CMV. Analyses were adjusted for sex, age and calendar year. We included 4470 relatives who were followed for 103,786 person-years, median follow-up 24 years [interquartile range (IQR) 12–36]. There were a total of 1360 infection-related hospitalisations in the follow-up period, incidence rate (IR) 13.1/1000 person-years [95% confidence interval (CI), 12.4; 13.8]. 206 relatives were hospitalised with viral infection, IR 1.8/1000 person-years (95% CI, 1.6; 2.0). There was no increased risk of hospitalisation due to infections, IR ratio (IRR) 0.99 (95% CI, 0.88; 1.12), nor specifically viral infections, IRR 0.87 (95% CI, 0.63; 1.19), in relatives of recipients with CMV compared to relatives of recipients without CMV. Also, no difference was seen in analyses stratified by transplant type, family relation and CMV serostatus. The risk of hospitalisation due to infection is not increased among first-degree relatives of transplant recipients with CMV infection compared to relatives of recipients without CMV.     

Immune-based monitoring for cytomegalovirus infection in solid organ transplantation: is it ready for clinical primetime?

The impact of CMV infection and disease in solid organ transplant (SOT) recipients continues despite remarkable improvements in its prevention and management with antiviral drugs. Studies that have investigated the host immune response to CMV have paved way for the development of novel immune-based assays that are anticipated to complement the current antiviral-based strategies for CMV management after transplantation. In this article, we review the emerging data on the clinical application of innovative CMV-specific T-cell assays, including their role in risk-stratification, prognostication, prevention and treatment of CMV infection and disease in SOT recipients.     

Prevalence and Premature Mortality Statistics of Autism Spectrum Disorder Among Children in Korea: A Nationwide Population-Based Birth Cohort Study

BackgroundThe aim of this study was to estimate the 8-year prevalence and mortality statistics of autism spectrum disorder (ASD) according to birth year (2002–2012).MethodsWe used the National Health Insurance Service database with 4,989,351 children born from 2002 to 2012 including 35,529 children diagnosed with ASD until 8 years of age. The 8-year cumulative prevalence of ASD was calculated annually (2010–2020) with 8 years of follow-up. The 8-year mortality was estimated using Cox models adjusted for sex, household income, area of residence, and year of birth.ResultsOf the 473,494 children born in 2002, 2,467 (5.2 per 1,000 births) were diagnosed with ASD until 2010. The ASD prevalence was 2.6 times higher among boys (1,839; 7.4 per 1,000 boy births) than girls (628; 2.8 per 1,000 girl births). Of the 467,360 children born in 2012, 4,378 (9.4 per 1,000 births) were diagnosed with ASD until 2020. The ASD prevalence was 2.7 times higher among boys (3,246; 13.5 per 1,000 boy births) than girls (1,132; 5.0 per 1,000 girl births). The risk of all-cause mortality was higher among children with ASD than those without (hazard ratio [HR], 2.340; 95% confidence interval [CI], 2.063–2.654), which is substantially higher among girls (HR, 4.223; 95% CI, 3.472–5.135) than boys (HR, 1.774; 95% CI, 1.505–2.090).ConclusionThe present study demonstrated that national-level prevalence and mortality statistics of ASD can be estimated effectively using claims data comprising newborns born each year and followed up for to the age of interest. Because this information is essential to establish evidence-based policies, health authorities need to consider producing epidemiological information of ASD continuously using the same methodology.     

Clinical significance of human cytomegalovirus viruria and the effect of antiviral therapy in hematopoietic stem cell transplant recipients

BackgroundCytomegalovirus (CMV) causes life-threatening infections in immunocompromised host. The clinical significance of asymptomatic CMV viruria in patients receiving hematopoietic stem cell transplantation (HSCT) remains unclear. This study aims to clarify whether antiviral therapy is associated with a favorable clinical outcome.MethodsHSCT recipients whose urine was culture-positive for CMV were retrospectively reviewed and followed. Viruria episodes were divided according to whether or not antiviral therapy was used. Mortality and the estimated glomerular filtration rate (eGFR) in 2 years following CMV viruria were compared between patients with and without antiviral therapy.ResultsSixty-two episodes of culture-proven asymptomatic CMV viruria were identified in 28 HSCT recipients. Antiviral therapy was used in 35 (56.5%) and spared in 27 (43.5%) viruric episodes. Compared with the baselines, there were no significant difference in the decrements of eGFR between the two groups at the end the 1st year (4.78 vs 5.02 mL/min/1.73 m², p = 0.968) and the 2nd year (1.13 vs 7.66 mL/min/1.73 m², p = 0.276). Antiviral therapy for asymptomatic CMV viruria was also not associated with a favorable survival (p = 0.288). On the other hand, presence of CMV viremia correlated with a poorer survival (2-year mortality rate 60% vs 13.33%, p < 0.001).ConclusionAntiviral therapy for asymptomatic CMV viruria is not associated with a clear clinical benefit in HSCT recipients. Further studies may be needed to identify if specific patient populations may benefit from antiviral therapy in CMV viruria.     

Monitoring human cytomegalovirus infection in transplant recipients.

Human cytomegalovirus (HCMV) infection remains one of the most challenging infectious complications in both solid organ transplant (SOT) and hemopoietic stem cell transplant (HSCT) recipients. In the last two decades advances have been made in the diagnosis and monitoring of HCMV infection in SOT and HSCT recipients following introduction of quantitative assays such as rapid virus isolation in blood (viremia), quantitation of pp65 in peripheral blood leukocytes (antigenemia), and quantitation of viral genome in blood (DNAemia). The availability of these rapid diagnostic assays has allowed treatment administration during the presymptomatic phase of HCMV infection (preemptive treatment) and greatly reduced HCMV-related morbidity and mortality, particularly among HSCT recipients. Definition of clinically validated thresholds for initiating preemptive treatment in SOT and HSCT recipients is a major goal in the transplantation setting. With respect to universal prophylaxis of HCMV infection in transplant recipients, the preemptive treatment approach shows advantages in (i) treating a lower number of patients for shorter periods of time and (ii) avoiding the reported emergence of HCMV disease after interruption of anti-HCMV prophylaxis. To understand the mechanism behind long-term control of HCMV infection in transplant recipients, the HCMV-specific T-cell response must be evaluated.     

Immune response to CMV in solid organ transplant recipients: current concepts and future directions

Despite advances in immunosuppression and antiviral therapy, CMV continues to be a significant opportunistic pathogen adversely affecting the outcome of solid organ transplantation (SOT) recipients. While a significant proportion of CMV disease is caused by reactivation of latent virus, the risk is highest among CMV donor+ and recipient- SOT patients. CMV is responsible for both direct (e.g., pneumonitis, colitis) and indirect (e.g., rejection, atherosclerosis) morbidity and mortality. Healthy CMV-seropositive individuals have a high frequency of CMV-specific CD4(+) and CD8(+) T cells that provide immune protection by limiting CMV reactivation and replication. Changes to the innate and adaptive immune system from immunosuppressive therapy following SOT contribute to CMV disease pathogenesis. CMV disease after SOT is associated with poorer outcomes, thus novel strategies to prevent it are an area of active research. In this article, we review the current state of knowledge on the immune response to CMV following SOT.     

CMV antigenemia and quantitative viral load assessments in hematopoietic stem cell transplant recipients

BackgroundSensitive and reliable diagnostic tests are essential for the prevention of cytomegalovirus (CMV) disease after hematopoietic stem cell transplantation (HSCT). pp65 antigenemia and polymerase chain reaction (PCR) assays are commonly used to monitor CMV in HSCT recipients. However, there is considerable intra- and inter-laboratory variability in the results, which impact comparability and clinical practice.Objectives/study designUsing 380 samples from 135 HSCT recipients, we compared the new FDA approved quantitative PCR assay, COBAS^® AmpliPrep/COBAS^® TaqMan^® CMV test (CAP/CTM CMV test) developed and standardized using the 1st WHO International Standard for CMV with pp65 antigenemia and COBAS^® AMPLICOR MONITOR CMV tests.ResultsThe median time between transplantation and testing samples was 57 days (range, 0–207 days). The median CMV load (log₁₀) was 3.17 IU/mL (3.21 copies/mL). Among samples with detectable CMV load, 52% were negative by pp65 antigenemia. CMV loads were higher in pp65 antigenemia-positive than in negative samples. One pp65-antigenemia-positive cell per 100,000 leukocytes corresponded to a median CMV load of 1200 IU/mL. CMV loads determined by the CAP/CTM CMV test were slightly lower than the ones by the AMPLICOR MONITOR CMV test (?0.15 [95% CI, ?0.18 to ?0.13] copies/mL), but slope differences indicated only limited co-linearity.ConclusionsThe CAP/CTM CMV test is more sensitive than pp65 antigenemia and the AMPLICOR MONITOR CMV test in HSCT recipients. The lower limit of quantification and co-linearity with the international WHO standard renders the CAP/CTM CMV test suitable for future clinical trials defining viral load thresholds of CMV therapy.     

Risk factors for death in adults with severe asthma

BACKGROUND: Mortality risk in adult asthma is poorly understood, especially the interplay among race, disease severity, and health care access. OBJECTIVE: To examine mortality risk factors in adult asthma. METHODS: In a prospective cohort study of 865 adults with severe asthma in a closed-panel managed care organization, we used structured interviews to evaluate baseline sociodemographics, asthma history, and health status. Patients were followed up until death or the end of the study (mean, 2 years). We used Cox proportional hazards regression to evaluate the impact of sociodemographics, cigarette smoking, and validated measures of perceived asthma control, physical health status, and severity of asthma on the risk of death. RESULTS: We confirmed 123 deaths (mortality rate, 6.7 per 100 person-years). In an analysis adjusted for sociodemographics and tobacco history, higher severity-of-asthma scores (hazard ratio [HR], 1.11 per 0.5-SD increase in severity-of-asthma score; 95% confidence interval [CI], 1.01-1.23) and lower perceived asthma control scores (HR, 0.91 per 0.5-SD increase in perceived asthma control score; 95% CI, 0.83-0.99) were each associated with risk of all-cause mortality. In the same adjusted analysis, African American race was not associated with increased mortality risk relative to white race (HR, 0.64; 95% CI, 0.36-1.14). CONCLUSIONS: In a large managed care organization in which access to care is unlikely to vary widely, greater severity-of-asthma scores and poorer perceived asthma control scores are each associated with increased mortality risk in adults with severe asthma, but African American patients are not at increased risk for death relative to white patients.     

Adenovirus Viremia and Disease: Comparison of T Cell–Depleted and Conventional Hematopoietic Stem Cell Transplantation Recipients from a Single Institution

Adenovirus (ADV) is an important cause of viral mortality in hematopoietic stem cell transplantation (HSCT). Recipients of T cell–depleted (TCD) HSCT are at increased risk for viral infections. We compared the rates and outcomes of ADV viremia and disease between TCD and conventional (CONV) HSCT at our institution. This was an observational study of 624 adult and pediatric recipients of myeloablative HSCT at Memorial Sloan-Kettering Cancer Center between January 1, 2006, and March 11, 2011. Viral cultures and ADV PCR were ordered as clinically indicated. ADV viremia by quantitative PCR assay was defined as 1 or more positive values ≥1,000 copies/mL or 2 or more consecutive positive values. Competing-risk regression analyses were used to identify predictors for ADV viremia. ADV viremia at 1 year after HSCT occurred in 8% of TCD HSCT recipients and in 4.0% of CONV HSCT recipients (P = .041). Among the TCD recipients, ADV viremia was seen in 15% of children, compared with 5% of adults (P = .008). Young age (hazard ratio [HR], 3.0; P < .001) and acute graft-versus-host disease (GVHD) (HR, 3.2; P = .001) were identified as risk factors for ADV viremia. ADV viremia was predictive of mortality (HR, 6.0; P < .001). ADV disease developed in 3.5% of TCD HSCT recipients and in 0.4% of CONV HSCT recipients (P = .022), with an attributable mortality of 27%. Among TCD HSCY recipients, grade II to IV GVHD was a risk factor for ADV disease (HR, 13; P < .001), but age was not. More than 90% of the cases of ADV disease involved a viral load of ≥10,000 copies/mL. Rates of ADV disease were 10-fold greater in TCD HSCT recipients compared with CONV HSCT recipients, predominantly in patients who developed acute GVHD. The benefit of preemptive therapy for an ADV viral load ≥10,000 copies/mL for preventing ADV disease in TCD HSCT recipients should be evaluated in prospective clinical trials.     

Infections after Allogenic Transplant with Post-Transplant Cyclophosphamide: Impact of Donor HLA Matching

Incidence and outcome of infections after allogeneic hematopoietic stem cell transplantation (HSCT) with post-transplant cyclophosphamide (PT-Cy) as graft-versus-host disease (GVHD) prophylaxis are largely unknown. Study aims were to estimate the incidence of pre-engraftment bloodstream infections (PE-BSIs) and viral infections (VIs; cytomegalovirus [CMV], adenovirus [ADV], human herpes virus 6 [HHV6], and BK-polyomavirus hemorrhagic-cystitis [BKPyV-HC]), their predictive factors, and infection-related mortality (IRM) after HSCT with PT-Cy. We analyzed 235 patients: 62%, 21%, and 17% received haploidentical (haplo), matched-unrelated donor (MUD), and matched-related donor, respectively. Overall, 72 patients had 77 PE-BSI episodes at a median time of 13 days after HSCT: cumulative incidence function (CIF) at 28 days was 32%, without differences among donor types (P = .988). By multivariate analysis, CIF of PE-BSI was higher in patients with severe neutropenia before HSCT (adjusted hazard ratio [AHR] = 2.90) and in multidrug-resistant Gram-negative bacteria rectal carriers (AHR = 2.68). IRM at 30 days was 5%, without differences by donor type (P = .106). Overall, 208 patients experienced ≥1 VIs (first occurrence among CMV, HHV6, ADV, BKPyV-HC) at a median time of 20 days after HSCT: CIF at 90 days was 91%, significantly higher in MUD and haplo (P = .0089). By multivariate analysis, also acute GVHD grade ≥2 (AHR = 1.32) and host/donor CMV-serology mismatch (positive/positive versus negative/negative: AHR = 2.95, positive/negative versus negative/negative: AHR = 2.41, negative/positive versus negative/negative: AHR = 2.35) affected VIs occurrence. IRM at 180 days was 8%, without differences among donor types (P = .106). In conclusion, study results did not show a significant impact of donor type on PE-BSI incidence; conversely, MUD and haploidentical transplants retained a higher occurrence of VIs in the early phase after HSCT.