Ariadna Pérez

The kinetics of torque teno virus plasma DNA load shortly after engraftment predicts the risk of high-level CMV DNAemia in allogeneic hematopoietic stem cell transplant recipients

Monitoring Torque teno virus (TTV) DNA load helps to estimate the risk of opportunistic infections in solid organ transplant recipients. We investigated whether the early kinetic pattern of plasma TTV DNA load after allogeneic hematopoietic stem cell transplantation (allo-HSCT) associates with subsequent CMV and EBV DNAemia. This study included 71 allo-HSCT patients. We found that the area under the curve (AUC) for log10 TTV DNA loads quantified by days 20 and 30 after transplantation (TTV DNA load AUC20-30), was significantly lower (P=0.036) in patients who subsequently developed CMV DNAemia requiring preemptive antiviral therapy (n=17) than in those who did not (n=8) or had no CMV DNAemia (n=19). Patients displaying TTV DNA load AUC20-30⩽2.8 copies × days × mL−1 were more likely to have high-level CMV DNAemia. A trend towards a direct correlation between TTV DNA AUC20-30 and CMV-specific interferon-γ CD8+ T-cell counts by day +30 was noted (P=0.095). However, this dynamic parameter was not useful for anticipating the occurrence of either CMV recurrences (n=12) or EBV DNAemia (n=34). In summary, it may be possible to identify a subset of allo-HSCT patients at a high risk of developing high-level CMV DNAemia by analyzing the kinetics of plasma TTV DNA load early after engraftment.

A polymorphism in the TYMP gene is associated with the outcome of HLA-identical sibling allogeneic stem cell transplantation

Thymidine phosphorylase (TYMP), an enzyme involved in nucleotide synthesis, has been implicated in critical biological processes such as DNA replication, protection against mutations, and tissue repair. In this work, we retrospectively evaluated the influence of a polymorphism in the TYMP gene (rs112723255; G/A) upon the outcome of 448 patients subjected to allogeneic stem cell transplantation (allo‐SCT) from an human leukocyte antigen (HLA)‐identical sibling donor. The TYMP genotype of patients correlated with overall survival—carriers of the minor allele (A) being at an increased risk of dying after transplantation (hazard ratio, HR = 1.9; P = 0.004). This effect was mostly due to differences in transplant toxicity‐related mortality (HR = 2.5; P = 0.029). In addition, the TYMP genotype of donors was associated with the risk of chronic graft‐versus‐host disease (GVHD)—carriers of the minor allele being at an increased risk of developing this complication ([HR] = 1.7; P = 0.039). The impact of such polymorphism on the risk of chronic GVHD is limited to patients transplanted in early stage disease (HR = 2.2; P = 0.019). The combination of a donor harboring the minor allele with a patient homozygous for the major allele was associated with the highest risk of chronic GVHD (HR = 2.8; P = 0.008). These findings provide the first evidence of the significant impact of the TYMP genotype upon the clinical outcome of patients treated with HLA‐identical sibling allo‐SCT. Am. J. Hematol. 88:883–889, 2013.

Epidemiologic and Clinical Characteristics of Coronavirus and Bocavirus Respiratory Infections after Allogeneic Stem Cell Transplantation: A Prospective Single-Center Study

Abstract Epidemiologic data about coronaviruses (CoVs) and human bocavirus (HBoV) in the setting of allogeneic hematopoietic stem cell transplantation (allo-HSCT) are scarce. We conducted a prospective longitudinal study on respiratory viral infections (RVIs) in allo-HSCT recipients with respiratory symptoms from December 2013 until June 2016. Respiratory virus in upper and/or lower respiratory tract (URT and LRT) specimens were tested using Luminex xTAG RVP Fast v1 assay. Seventy-nine consecutive allo-HSCT recipients developed a total of 192 virologically documented RVI episodes over 30 months. The median follow-up after RVI was 388 days (range, 5 to 923). CoV or HBoV was detected in 27 of 192 episodes (14%); 18 of 79 recipients (23%) developed a total of 21 CoV RVI episodes, whereas 6 recipients (8%) had 1 HBoV RVI episode each. Fourteen CoV RVI episodes were limited to the URT, whereas 7 affected the LRT. Co-pathogens were detected in 8 (38%) CoV cases. Type OC43 CoV was the dominant type (48%) followed by NL63 (24%), KHU1 (19%), and 229E (9%); the CoV hospitalization rate was 19%, whereas mortality was 5% (1 patient without any other microbiologic documentation). Among the 6 recipients with HBoV (3%), only 1 had LRT involvement and no one died from respiratory failure. In 5 cases (83%) HBoV was detected along with other viral co-pathogens. CoV RVIs are common after allo-HSCT, and in a significant proportion of cases CoV progressed to LRT and showed moderate to severe clinical features. In contrast, HBoV RVIs were rare and mostly presented in the context of co-infections.

Community-acquired respiratory virus lower respiratory tract disease in allogeneic stem cell transplantation recipient: Risk factors and mortality from pulmonary virus-bacterial mixed infections

Risk factors (RFs) and mortality data of community‐acquired respiratory virus (CARVs) lower respiratory tract disease (LRTD) with concurrent pulmonary co‐infections in the setting of allogeneic hematopoietic stem cell transplantation (allo‐HSCT) is scarce. From January 2011 to December 2017, we retrospectively compared the outcome of allo‐HSCT recipients diagnosed of CARVs LRTD mono‐infection (n = 52, group 1), to those with viral, bacterial, or fungal pulmonary CARVs LRTD co‐infections (n = 15, group 2; n = 20, group 3, and n = 11, group 4, respectively), and with those having bacterial pneumonia mono‐infection (n = 19, group 5). Overall survival (OS) at day 60 after bronchoalveolar lavage (BAL) was significantly higher in group 1, 2, and 4 compared to group 3 (77%, 67%, and 73% vs 35%, respectively, P = .012). Recipients of group 5 showed a trend to better OS compared to those of group 3 (62% vs 35%, P = .1). Multivariate analyses showed bacterial co‐infection as a RF for mortality (hazard ratio[HR] 2.65, 95% C.I. 1.2‐6.9, P = .017). We identified other 3 RFs for mortality: lymphocyte count <0.5 × 109/L (HR 2.6, 95% 1.1‐6.2, P = .026), the occurrence of and CMV DNAemia requiring antiviral therapy (CMV‐DNAemia‐RAT) at the time of BAL (HR 2.32, 95% C.I. 1.1‐4.9, P = .03), and the need of oxygen support (HR 8.3, 95% C.I. 2.9‐35.3, P = .004). CARV LRTD co‐infections are frequent and may have a negative effect in the outcome, in particular in the context of bacterial co‐infections.

Monitoring of oral cytomegalovirus DNA shedding for the prediction of viral DNAemia in allogeneic hematopoietic stem cell transplant recipients

Preemptive antiviral therapy based on detecting cytomegalovirus (CMV) DNAemia above a preestablished threshold is the mainstay strategy for the prevention of CMV disease in allogeneic hematopoietic stem cell transplant (allo‐HSCT) recipients; nevertheless, CMV DNAemia, even at low levels, may increase mortality. We investigated whether surveillance of saliva for the presence of CMV DNA may anticipate the occurrence of CMV DNAemia. This was a prospective observational study with 53 consecutively enrolled allo‐HSCT recipients. Saliva and plasma specimens were collected on a weekly basis from Day 0 to Day 100 after transplantation. CMV DNA was quantified in both specimen types using the Abbott Real‐Time PCR assay (Abbott Molecular, Des Plaines, IL). CMV DNA was quantifiable in 44 (83%) patients: either in saliva (n = 1) or plasma (n = 12) only, or in both specimen types (n = 31). CMV oral shedding preceded the occurrence of CMV DNAemia in eight patients (18.2%), while the opposite pattern was observed in 21 patients (47.7%). The CMV DNA loads quantified in saliva and plasma correlated modestly (P = 0.33; P = 0.013) and did not differ in magnitude (P = 0.527). No transplantation factors, other than recipient CMV seropositivity, were associated with oral CMV DNA shedding; serum CMV IgG levels were comparable, regardless of the timing of the detection of CMV DNA at both sites. In summary, screening of saliva specimens for the presence of CMV DNA appear to be of limited value for anticipating the occurrence of CMV DNAemia in allo‐HSCT recipients.

Validation of a plasma metabolomics model that allows anticipation of the occurrence of cytomegalovirus DNAaemia in allogeneic stem cell transplant recipients

A plasma metabolomic model obtained by means of untargeted 1H nuclear magnetic resonance, to which taurine, choline, methylamine, total glutathione, trimethylamine N-oxide, lactate, lysine, isoleucine, total fatty acids and unsaturated fatty acids contributed, was validated for the prediction of first episodes of cytomegalovirus (CMV) DNAaemia in a cohort of 79 allogeneic stem haematopoietic stem cell transplant (allo-HSCT) recipients. The predictive success rate was nearly 65 % for patients at both low and high risk of CMV-related complications according to their baseline characteristics. Plasma metabolomics profiling shortly after engraftment (day 21 after transplantation) allowed the anticipation of the occurrence of CMV DNAaemia in 71 % of patients. Plasma metabolomics analyses may be ancillary for identifying allo-HSCT patients at the highest risk of CMV DNAaemia who may benefit from early targeted antiviral prophylaxis.

Clinical effectiveness of influenza vaccination after allogeneic hematopoietic stem cell transplantation: A cross-sectional prospective observational study

Abstract Background Vaccination is the primary method for preventing influenza respiratory virus infection (RVI). Although the influenza vaccine is able to achieve serological responses in some allogeneic hematopoietic stem cell transplantation (allo-HSCT) recipients, its clinical benefits are still uncertain. Methods In this prospective, cross-sectional study, we retrospectively analyzed the effect of inactivated trivalent influenza vaccination on the prevalence of influenza RVI in a consecutive cohort of 136 allo-HSCT adult recipients who developed 161 RVI over 5 flu seasons (from 2013 to 2018). Respiratory viruses in upper– and/or lower–respiratory tract specimens were tested using multiplex polymerase chain reaction panel assays. Results Overall, we diagnosed 74 episodes (46%) of influenza RVI in 70 allo-HSCT recipients. Influenza RVI occurred in 51% of the non-vaccinated compared to 36% of the vaccinated recipients (P = .036). A multivariate analysis showed that influenza vaccination was associated with a lower prevalence of influenza RVI (odds ratio [OR] 0.39, P = .01). A multivariate risk factor analysis of lower–respiratory tract disease (LRTD) identified 2 conditions associated with the probability of influenza RVI progression: influenza vaccination (OR 0.12, 95% confidence interval [CI] 0.014–1, P = .05) and a high-risk immunodeficiency score (OR 36, 95% CI 2.26–575, P = .011). Influenza vaccination was also associated with a lower likelihood of an influenza-related hospital admission (14% vs 2%, P = .04). Conclusions This study shows that influenza vaccination may have a clinical benefit in allo-HSCT recipients with virologically-confirmed RVI, in terms of a lower influenza RVI prevalence, slower LRTD progression, and lower likelihood of hospital admission.

Pre-engraftment cytomegalovirus DNAemia in allogeneic hematopoietic stem cell transplant recipients: incidence, risk factors, and clinical outcomes

To gauge the risk of delaying initiation of prophylaxis with letermovir from the time of donor infusion to prevent CMV infection in allo-HSCT recipients we investigated the clinical outcomes of CMV DNAemia episodes occurring before engraftment, and compared to that of episodes developing after engraftment (up to day +365). A total of 197 consecutive adult patients were included. Plasma CMV DNA load was monitored by real-time PCR assays [limit of detection: 31 IU/ml]. A total of 150 out of 197 patients had CMV DNAemia (cumulative incidence of 77%; 95% CI, 73–81%), and 38 out of the 197 patients developed it before engraftment (cumulative incidence, 19%; 95% CI, 10–30.3%). Nine episodes of CMV DNAemia were detected prior to the time of donor progenitor cell infusion. A greater number of post-engraftment episodes required preemptive antiviral therapy compared with pre-engraftment episodes (62.5% vs 44.7%; P = 0.05). The cellular content of the donor progenitor cell infusion and transplant characteristics of patients did not differ between patients with pre-engraftment or post-engraftment CMV DNAemia. The cumulative incidence of overall mortality by days 100 and 365, aGvHD by day 100 and relapse by day 365 were not significantly different between patients with pre-engraftment or post-engraftment CMV DNAemia.

Refractory cytomegalovirus DNAemia after allogeneic hematopoietic stem cell transplantation: when should genotypic drug resistance testing be requested?

Persisting cytomegalovirus (CMV) DNAemia in spite of appropriate antiviral therapy is a risk factor for CMV disease and non-relapse mortality in allogeneic hematopoietic stem cell transplant recipients (allo-HSCT) [1], and may be due to a lack of adequate expansion of functional CMVspecific T cells in response to viral replication (clinical resistance), to the emergence of antiviral resistant strains carrying specific point mutations or deletions within the sequence of the viral genes UL97, UL54 (virological resistance) or both [2, 3]. Currently, there is no consensus on when antiviral CMV resistance should be suspected and genotypic drug resistance testing be ordered. Several indicators reflecting therapeutic refractoriness have been proposed: [3–5] increase in CMV DNA load >20% (inter-assay coefficient of variation of the real-time PCR assays used) after 2 weeks of adequate treatment (Group 1), increase in CMV DNA load >0.5 log10 (Group 2) or >1 log10 (Group 3) after 2 weeks of treatment, and decrease in CMV DNA load <1 log10 after 2 (Group 4) or 2 (Group 5) weeks of treatment, in all categories with respect to CMV DNA load at the time of treatment initiation. In this study, refractory CMV DNAemia met one or more of the above criteria. A total of 203 patients who underwent allo-HSCT between January 2010 and June 2017 were included in this retrospective observational study. The median age of patients was 55 years (range, 18-69 years). Plasma CMV DNA load was monitored as previously indicated [6], using the CMV PCR Kit or the CMV RealTime CMV PCR (both from Abbott Molecular, Des Plaines, IL, USA). Antiviral therapy with (val)ganciclovir or foscarnet at conventional doses was initiated when the plasma CMV DNA load reached levels of >1500 IU/ml, or when the CMV dt was ≤2.0 days, whatever occurred first (this latter strategy since May 2014) [7]. A total of 147 patients had CMV DNAemia within the first year after allo-HSCT (cumulative incidence, 72.38%; 95% CI, 67.80%–76.41%), of whom 79 developed a single episode and 68 experienced one or more recurrences. The total number of episodes of CMV DNAemia was 246, of which 123 (50%) occurring in 96 patients required antiviral therapy (Table 1). (Val)ganciclovir was the first-choice drug in 110 episodes, whereas the remaining 13 episodes were initially treated with foscarnet. Switching of antiviral therapy was done in 30 episodes due either to hematological toxicity (n= 19) or to CMV DNAemia persistence through 3–4 weeks after treatment inception (n= 11). Out of the 123 treated episodes, 113 eventually cleared; the remaining 10 were still ongoing at the time of patient’s death. A total of 14 episodes in 14 patients (11.3%) were deemed to be refractory (Table 2). Specifically, 9, 3, 2, 12, and 6 episodes met Group 1, 2, 3, 4, and 5 criteria, respectively. Most of these were first episodes that occurred within the first 100 days after allo-HSCT and were initially treated with (val)ganciclovir. The CMV-serostatus pair D −/R+ and the occurrence of grades II–IV acute GvHD, both known factors associated with protracted or severely impaired reconstitution of CMV-specific T-cell immunity [2], were overrepresented in these episodes. Regretably, the * David Navarro david.navarro@uv.es

Epstein-Barr virus DNA load kinetics analysis in allogeneic hematopoietic stem cell transplant recipients: Is it of any clinical usefulness?

BACKGROUND There is a lack of clinical information regarding the usefulness of plasma Epstein-Barr virus (EBV) DNA load kinetics analyses in the management of EBV infections in allogeneic hematopoietic stem cell transplantation (allo-HSCT) recipients. Namely, it remains unknown whether this type of analysis can help physicians to anticipate the development of high-level EBV DNAemia episodes requiring rituximab treatment or predict the risk of recurrent EBV DNAemia or post-transplant lymphoproliferative disorders (PTLDs). STUDY DESIGN Unicentric, retrospective, observational study including 142 consecutive patients undergoing T-cell replete allo-HSCT. The plasma EBV DNA load was monitored on a weekly basis using the artus® EBV PCR kit. RESULTS Fifty-five of the 142 patients (38.7%) developed at least one episode of EBV DNAemia; 13 of the 55 initial EBV DNAemia episodes (23.6%) were preemptively treated with rituximab, 7 patients had a recurrent episode of EBV DNAemia, and biopsy-proven PTLDs were diagnosed in 4 patients. The initial plasma EBV DNA load was not significantly different (P=0.269) in episodes of self-resolving EBV DNAemia, those requiring rituximab treatment, or those leading to PTLDs. The plasma EBV DNA load doubling times were similar across all the groups (P=0.799), and the EBV DNA-load half-life was not associated with the occurrence of recurrent EBV DNAemia (P=0.550). CONCLUSION Plasma EBV DNA-load kinetics analyses are unlikely to be useful in predicting the occurrence of high-level EBV DNAemia, PTLD, or recurrent EBV DNAemia.