Efficacy of letermovir in HLA-haploidentical hematopoietic transplantation with posttransplant cyclophosphamide.

BACKGROUND: Cytomegalovirus reactivation (CMV-R) is a significant complication of allogeneic hematopoietic stem cell transplantation (allo-HCT), especially in human leukocyte antigen-haploidentical transplantation (haplo-HCT) with posttransplant cyclophosphamide (PTCy). Prophylactic letermovir (LTV) prevents CMV-R in patients undergoing allo-HCT. However, evidence regarding its use in haplo-HCTs with PTCy is limited. Therefore, we aimed to investigate the efficacy of prophylactic LTV in haplo-HCT with PTCy. METHODS: We retrospectively analyzed 52 patients seropositive for CMV who underwent haplo-HCT with PTCy at our institution between January 2015 and June 2021 and compared patients who received LTV prophylaxis (LTV group: n = 29) with those who did not receive prophylaxis for CMV (control group: n = 23). The primary endpoint was the 100-day cumulative CMV-R incidence. We used Gray's test and the Fine and Gray test to compare the two groups. RESULTS: The 100-day cumulative CMV-R incidence was lower in the LTV group than in the control group (17.2% vs 81.8%, p < 0.001). Multivariate analysis revealed that prophylactic LTV reduced the 100-day cumulative CMV-R incidence (hazard ratio: 0.17, 95% confidence interval: 0.06-0.44, p < 0.001). CONCLUSIONS: Prophylactic LTV effectively prevents CMV-R in patients undergoing haplo-HCT for PTCy.

Trajectories of the SARS-CoV-2 RNA load in patients with hematological malignancy.

OBJECTIVES: The higher risk of prolonged viral shedding in coronavirus disease (COVID-19) patients with hematological malignancies (HM) necessitates test-based de-isolation strategies. However, evidence to establish their appropriate isolation period is insufficient. This study investigated the factors affecting prolonged viral shedding and the requisite isolation period in these patients. METHODS: We retrospectively reviewed 14 COVID-19 patients with HM between January and April 2022, who were subjected to our test-based de-isolation strategy, followed by analysis of the viral load trajectory. The viral loads of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) were evaluated using the cycle threshold (Ct ) of the reverse-transcription quantitative polymerase chain reaction. The trajectories were classified according to the time-interval from COVID-19 onset to the attainment of Ct values >30. RESULTS: The median interval between onset and attainment of a Ct value >30 was 22 days. Five patients with mild or moderate COVID-19 without intense treatment histories achieved Ct values >30 within 20 days. The other nine patients needed more than 20 days, including three patients who did not meet this criterion during the observation period. CONCLUSIONS: The SARS-CoV-2 viral load trajectories in patients with HM can be stratified by treatment history for the underlying HM and severity of COVID-19.

Cardiac Tamponade as a Recurrence of Angioimmunoblastic T-Cell Lymphoma with the Detection of a p.Gly17Val RHOA Mutation in the Pericardial Effusion.

Angioimmunoblastic T-cell lymphoma (AITL) is an intractable type of T-cell lymphoma. We and others have identified that the p.Gly17Val RHOA mutation is specifically identified in AITL. We herein report a patient whose condition deteriorated, resulting from massive pericardial effusion one month after undergoing autologous transplantation for AITL. He was diagnosed with cardiac tamponade caused by AITL recurrence in the presence of the p.Gly17Val RHOA mutation as well as T-lineage cells with an aberrant immune-phenotype in the pericardial effusion. This case suggests that a precision medicine approach by detecting the presence of a p.Gly17Val RHOA mutation is useful for the management of AITL.

Humoral response and safety of the BNT162b2 and mRNA-1273 COVID-19 vaccines in allogeneic hematopoietic stem cell transplant recipients: An observational study.

BACKGROUND: The effectiveness of mRNA COVID-19 vaccines and the optimal timing of vaccine administration in allogeneic hematopoietic stem cell transplantation (Allo-HSCT) recipients remains inadequately investigated. We examine the effectiveness and safety of mRNA COVID-19 vaccines in allo-HSCT recipients. METHOD: This prospective observational study included 44 allo-HSCT recipients and 38 healthy volunteers. The proportion of subjects acquiring anti-S1 IgG antibodies were considered as the primary endpoint. The occurrence of adverse events after vaccination and objective deterioration of chronic graft-versus-host disease (GVHD) were defined as secondary endpoints. In addition, we compared the geometric mean titers (GMT) of anti-S1 antibody titers in subgroups based on time interval between transplantation and vaccination. RESULTS: A humoral response to the vaccine was evident in 40 (91%) patients and all 38 healthy controls. The GMT of anti-S1 titers in patients and healthy controls were 277 (95% confidence interval [CI]: 120-643) BAU/mL and 532 (95% CI 400-708) BAU/mL, respectively. (p = 0.603). A short time interval between transplantation and vaccination (≤6 months) was associated with low anti-S1 IgG antibody titers. No serious adverse events and deterioration of chronic GVHD were observed. Only one case of new development of mild chronic GVHD was recorded. CONCLUSION: Messenger RNA COVID-19 vaccines induce humoral responses in allo-HSCT recipients and can be administered safely.

Additional diagnostic value of electron microscopic examination in endomyocardial biopsy in patients with suspected non-ischemic cardiomyopathy.

BACKGROUND: Electron microscopy enables a finely detailed analysis of ultra-structural features, and hence, it generally has an added diagnostic value to light microscopy alone. However, no studies have verified the additional diagnostic value of electron microscopic examination in patients with suspected non-ischemic cardiomyopathy. METHODS: A total of 294 consecutive patients with non-ischemic cardiomyopathy who underwent endomyocardial biopsy were prospectively enrolled. Patients were divided into three groups according to left ventricular morphology assessed using echocardiography. Myocardial specimens were collected from the right ventricular septum and examined by light microscopy. Electron microscopy was performed subsequently to evaluate the additional diagnostic value. RESULTS: Altogether, 294 patients were analyzed, including 160 (55 %), 96 (33 %), and 35 (12 %) patients who were diagnosed with primary, secondary, and unclassified cardiomyopathy, respectively. In patients with dilated cardiomyopathy-like morphology, the detection rate of disease-specific histological findings was relatively low compared to that in patients with other cardiac morphologies. The additional diagnostic value of electron microscopy was observed in eight patients, including five with Fabry disease, one with cardiac amyloidosis, one with mitochondrial cardiomyopathy, and one with triglyceride deposit cardiomyovasculopathy. Among the 18 cardiac amyloidosis cases, electron microscopy detected amyloid fibrils in all patients, whereas light microscopy could not detect amyloid deposition in 1 patient. Among one of five patients with Fabry disease, light microscopy did not show obvious vacuolated cardiomyocytes, but zebra bodies were detected by electron microscopy, leading to the diagnosis of cardiac Fabry disease. The diagnostic value of electron microscopic examination in patients with cardiac sarcoidosis was not observed. CONCLUSIONS: The additional diagnostic value of electron microscopy was observed in patients with secondary cardiomyopathy, in whom light microscopy did not show disease-specific histological findings. Electron microscopy should be performed in cases where secondary cardiomyopathy is strongly suspected with no disease-specific findings by light microscopy.

Cold agglutinin anti-I antibodies in two patients with COVID-19.

BACKGROUND: Cold agglutinin syndrome (CAS) is associated with various diseases. Several studies of CAS associated with coronavirus disease 2019 (COVID-19) reported hemolytic anemia and thrombosis; however, the clinical significance of cold agglutinins (CA) in patients with COVID-19 is unclear. Here, we present two cases of CA identified in the context of COVID-19 without hemolytic anemia and clotting. CASE REPORT AND DISCUSSION: Two patients with no known risk factors for CA were diagnosed with COVID-19; peripheral blood smears reveal red blood cells (RBCs) agglutination. These patients showed a high CA titer. We confirmed retrospectively that the CA was an anti-I antibody. The two COVID-19 cases with a high CA titer showed no hemolysis or thrombosis. Mycoplasma pneumoniae is known to cause CAS, but not all patients who have a high CA titer show hemolysis. Coagulation abnormalities are documented in severe COVID-19 cases. Although CA increases the risk of thrombosis in those with lymphoproliferative diseases, the role of anti-I antibodies in COVID-19 is unclear. The impact of CAS on clinical presentations in COVID-19 remains a matter of verification. CONCLUSIONS: A high CA titer was identified in COVID-19 patients without hemolytic anemia and clotting. Anti-I antibodies were identified. Further studies are required to clarify the pathophysiology of CA in COVID-19.

Clinical Characteristics of Non-Valvular Atrial Fibrillation Patients With a Large Left Atrial Appendage Ostium-Limiting Percutaneous Closure.

BACKGROUND: The left atrial appendage (LAA) is a therapeutic target for preventing cardioembolic stroke in patients with non-valvular atrial fibrillation (NVAF). A large LAA ostium limits percutaneous LAA closure. This study investigated the characteristics and factors associated with a large LAA ostium in Japanese patients with NVAF.Methods and Results: In 1,102 NVAF patients, the maximum LAA diameter was measured using transesophageal echocardiography (TEE). A large LAA ostium was defined by a maximum diameter of >30 mm. Forty-four participants underwent repeated TEEs, and changes in LAA size under lasting AF were assessed. A large LAA ostium was observed in 3.1% of all participants and 8.9% of patients with long-standing persistent AF (LSAF). The large LAA group had greater CHA2DS2-VASc (P=0.024) and HAS-BLED scores (P=0.046) and a higher prevalence of LAA thrombus (P=0.004) than did the normal LAA group. LSAF, moderate or severe mitral regurgitation, left atrial volume ≥42 mL/m2, E/E' ratio ≥9.5, and left ventricular mass ≥85 mg/m2were independently associated with a large LAA ostium (P<0.001, P<0.001, P=0.009, P=0.009, and P=0.032, respectively). In 44 patients with lasting AF, the LAA ostial diameter increased over time (P<0.001). CONCLUSIONS: NVAF patients with a large LAA ostium may have a higher risk of stroke and bleeding. LSAF and factors leading to LA overload may be closely associated with LAA ostial dilatation and can promote it.

Right bundle branch block and risk of cardiovascular mortality: the Ibaraki Prefectural Health Study.

Historically, a right bundle branch block has been considered a benign finding in asymptomatic individuals. However, this conclusion is based on a few old studies with small sample sizes. We examined the association between a complete right bundle branch block (CRBBB) and subsequent cardiovascular mortality in the general population in Japan. In this large community-based cohort study, data of 90,022 individuals (mean age, 58.5 ± 10.2 years; 66.2% women) who participated in annual community-based health check-ups were assessed. Subjects were followed up from 1993 to the end of 2016. Cox proportional hazards' models and log-rank tests were used for the data analysis. CRBBB was documented in 1,344 participants (1.5%). Among all included participants, CRBBB was associated with an increased risk of cardiovascular mortality after adjustment for all potential confounders (hazard ratio [HR] 1.21; 95% confidence interval [CI] 1.06-1.38). The increased risk of cardiovascular mortality was particularly evident in women aged < 65 years (HR 2.00; 95% CI 1.34-2.98) and men aged ≥ 65 years (HR 1.28; 95% CI 1.06-1.55). CRBBB is associated with an increased risk of cardiovascular mortality in women aged < 65 years and men aged ≥ 65 years. Clinicians should be aware of the presence of CRBBB in young women and elderly men, even if they exhibit no symptoms.

Pathophysiological role of right ventricular function and interventricular functional mismatch in the development of pulmonary edema in acute heart failure.

BACKGROUND: Parameters of cardiac function related to the development of pulmonary edema (PE) in acute heart failure (AHF), including right ventricular (RV) function and a mismatch of interventricular function, are not fully elucidated. The aim of this study was to verify the hypothesis that a relatively preserved RV function compared with left ventricular function may be associated with the development of PE by using two-dimensional speckle tracking echocardiography (2DSTE). METHODS: Hospitalized patients with AHF at 11 institutions were enrolled. PE was defined as lung congestion on chest X-ray with hypoxemia. Patients with systolic blood pressure ≥140 mmHg on admission were defined to have hypertensive AHF. Echocardiographic analyses, including 2DSTE, were performed prior to discharge. The index of mismatch between RV and left ventricular systolic function was assessed by interventricular longitudinal strain difference (IVLSD) which was defined as RV free wall longitudinal strain and left ventricular global longitudinal strain. RESULTS: Of 610 patients with AHF, 422 (69.2%) had PE. In patients with PE, IVLSD (p = 0.007) and RV fractional area change ratio (p<0.001) was significantly higher than those in patients without PE. In patients with non-hypertensive AHF, RV fractional area change ratio, age, ischemic etiology, and serum brain natriuretic peptide (BNP) levels were independent predictors of PE. In patients with hypertensive AHF, IVLSD, age, and serum BNP levels were independent predictors of PE. CONCLUSIONS: Preserved RV function might be one of the underlying mechanisms of the development of PE in AHF. Furthermore, interventricular functional mismatch might be related to the development of PE in hypertensive AHF.

Comparison of Soluble ST2, Pentraxin-3, Galectin-3, and High-Sensitivity Troponin T of Cardiovascular Outcomes in Patients With Acute Decompensated Heart Failure.

BACKGROUND: Data regarding a direct comparison of soluble suppression of tumorigenesis-2 (sST2), pentraxin 3 (PTX3), galectin-3 (Gal-3), and high-sensitivity troponin T of cardiovascular outcome in patients with heart failure (HF) are lacking. METHODS AND RESULTS: A total of 616 hospitalized patients with HF were evaluated prospectively. Biomarker data were obtained in the stable predischarge condition. sST2 levels were associated with age, sex, body mass index, inferior vena cava diameter, B-type natriuretic peptide (BNP), PTX3, C-reactive protein, and Gal-3 levels. During follow-up, 174 (28.4%) primary composite end points occurred, including 58 cardiovascular deaths and 116 HF rehospitalizations. sST2 predicted the end point after adjustment for 13 clinical variables (hazard ratio 1.422; 95% confidence interval [CI] 1.064 to 1.895, P = .018). The association between sST2 and the end point was no longer statistically significant after adjustment for BNP (P = .227), except in the subgroup of patients with preserved ejection fraction (hazard ratio 1.925, 95% CI 1.102-3.378, P = .021). Gal-3 and high-sensitivity troponin T predicted the risk for the end point after adjustment for age and sex, but were not significant after adjustment for clinical variables. The prognostic value of PTX3 was not observed (age and sex adjusted, P = .066). CONCLUSIONS: This study did not show significant additional value of biomarkers to BNP for risk stratification, except sST2 in patients with preserved ejection fraction.

Prognostic Impact of Changes in Intrarenal Venous Flow Pattern in Patients With Heart Failure.

BACKGROUND: It remains unclear whether intrarenal venous flow (IRVF) patterns in patients with heart failure (HF) could change over the clinical course, and whether the changes could have a clinical impact. Thus, this study aimed to clarify these characteristics as well as to identify the relation between changes in the IRVF pattern and renal impairment progression. METHODS AND RESULTS: Patients with HF with repetitive IRVF evaluations were enrolled. Doppler waveforms of IRVF were classified into the following 3 flow patterns: continuous, biphasic discontinuous, and monophasic discontinuous. Primary end points included death from cardiovascular diseases and unplanned hospitalization for HF. Finally, 108 patients with adequate images were enrolled. The IRVF in 35 patients (32.4%) shifted to another pattern at the follow-up examinations. The median brain natriuretic peptide level in the continuous flow pattern at follow-up was significantly decreased (183 to 60 pg/mL, P < .001), whereas that of the discontinuous flow pattern at follow-up was increased (from 339 to 366 pg/mL, P = .042) and the estimated glomerular filtration rate was decreased (from 55 to 50 mL/min/1.73 m2, P = .013). A multivariable Cox proportional hazard model analysis revealed that the discontinuous pattern at follow-up (P < .001) and brain natriuretic peptide (P = .021) were significantly associated with the end points, independent of age, estimated glomerular filtration rate, and serum sodium level. CONCLUSIONS: The IRVF pattern could be changed depending on the status of congestion. Persistent or worsened renal congestion, represented by discontinuous flow patterns, during the clinical courses indicated a poor prognosis accompanied by renal impairment in patients with HF.

Clinical impacts of changes of renal function during hospitalization depend on grades of renal dysfunction in acute decompensated heart failure.

Clinical impact of changes of renal function (RF) in heart failure (HF) hospitalization is controversial. This study aimed to clarify whether clinical impact of changes of RF during HF hospitalization depends on the intrinsic RF. In 786 hospitalized HF patients, RF were classified into 3 grades based on estimated glomerular filtration rate (eGFR, mL/min/1.73 m2) at discharge; ≥ 60 (n = 243), < 60 and ≥ 30 (n = 400), and < 30 (n = 143). Increase and decrease of serum creatinine over 0.3 mg/dL during HF hospitalization were defined as worsening renal function (WRF) and improved renal function (IRF), respectively, and remaining subjects were defined as stable RF. The primary endpoint was a composite of cardiovascular death and rehospitalization for HF. In all patients, WRF was not associated with clinical outcomes, although eGFR has a significant association with prognosis. Clinical outcomes did not differ between changes of RF patterns in both preserved and severely impaired RF groups. In contrast, IRF, not WRF, was an independent predictor of clinical outcomes in the moderately impaired RF group (HR 1.965, 95% CI 1.09-3.18, p = 0.01). Only in patients with moderately impaired RF, changes of RF were associated with clinical outcome, and IRF was an independent predictor of clinical outcomes.