The role of bronchoscopy in patients with SARS-CoV-2 pneumonia

BackgroundThe role of bronchoscopy in coronavirus disease 2019 (COVID-19) is a matter of debate. Patients and methods: This observational multicenter study aimed to analyse the prognostic impact of bronchoscopic findings in a consecutive cohort of patients with suspected or confirmed COVID-19. Patients were enrolled at 17 hospitals from February to June, 2020. Predictors of in-hospital mortality were assessed by multivariate logistic regression.ResultsA total of 1027 bronchoscopies were performed in 515 patients (age 61.5±11.2; 73% men), stratified into a clinical suspicion cohort (n=30) and a COVID-19 confirmed cohort (n=485). In the clinical suspicion cohort, the diagnostic yield was 36.7%. In the COVID-19 confirmed cohort, bronchoscopies were predominantly performed in the intensive care unit (n=961; 96.4%) and major indications were: difficult mechanical ventilation (43.7%), mucus plugs (39%) and persistence of radiological infiltrates (23.4%). One hundred forty-seven bronchoscopies were performed to rule out superinfection, and diagnostic yield was 42.9%. There were abnormalities in 91.6% of bronchoscopies, the most frequent being mucus secretions (82.4%), haematic secretions (17.7%), mucus plugs (17.6%), and diffuse mucosal hyperemia (11.4%). The independent predictors of in-hospital mortality were: older age (Odds ratio [OR]=1.06; p<0.001), mucus plugs as indication for bronchoscopy (OR=1.60; p=0.041), absence of mucosal hyperemia (OR=0.49; p=0.041) and the presence of haematic secretions (OR=1.79; p=0.032).ConclusionsBronchoscopy may be indicated in carefully selected patients with COVID-19 to rule out superinfection and solve complications related to mechanical ventilation. The presence of haematic secretions in the distal bronchial tract may be considered a poor prognostic feature in COVID-19.

Detecting and predicting neutralization of alemtuzumab responses in MS

ObjectiveTo test the hypothesis that antidrug antibodies (ADAs) against alemtuzumab could become relevant after repeated treatments for some individuals, possibly explaining occasional treatment resistance.MethodsRecombinant alemtuzumab single-chain variable fragment antibody with a dual tandem nanoluciferase reporter linker was made and used to detect binding ADAs. Alemtuzumab immunoglobulin G Alexa Fluor 488 conjugate was used in a competitive binding cell-based assay to detect neutralizing ADAs. The assays were used to retrospectively screen, blinded, banked serum samples from people with MS (n = 32) who had received 3 or more cycles of alemtuzumab. Lymphocyte depletion was measured between baseline and about 1 month postinfusion.ResultsThe number of individuals showing limited depletion of lymphocytes increased with the number of treatment cycles. Lack of depletion was also a poor prognostic feature for future disease activity. ADA responses were detected in 29/32 (90.6%) individuals. Neutralizing antibodies occurred before the development of limited depletion in 6/7 individuals (18.8% of the whole sample). Preinfusion, ADA levels predicted limited, postinfusion lymphocyte depletion.ConclusionsAlthough ADAs to alemtuzumab have been portrayed as being of no clinical significance, alemtuzumab-specific antibodies appear to be clinically relevant for some individuals, although causation remains to be established. Monitoring of lymphocyte depletion and the antidrug response may be of practical value in patients requiring additional cycles of alemtuzumab. ADA detection may help to inform on retreatment or switching to another treatment.

Clinical Utility of Chromosomal Microarray in Establishing Clonality and High Risk Features in Patients with Richter Transformation

Background: Richter Transformation (RT) is defined as the transformation of chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) into an aggressive lymphoma. Diffuse large B-cell lymphoma (DLBCL) makes up the vast majority of RT and these patients have a poor prognosis compared to de novo DLBCL (Rossi D, et al. Blood, 2011; 117(12):3391-3401). Prognostic factors include therapy for CLL/SLL prior to transformation, TP53/CDKN2A abnormalities, as well as clonal relationship between CLL/SLL and RT. There are no randomized controlled trials to direct treatment of RT and many centers use clonal relationship to direct treatment decisions including whether or not patients should receive consolidation with autologous or allogeneic stem cell transplantation (Parikh SA, et al. Blood; 123(11): 1647-1657). One method for establishing clonality involves genetic analysis of the immunoglobulin heavy variable chain (IgHV) gene in both the CLL/SLL portion as well as the RT portion by means of IGHV V-D-J sequencing. Whole genome Chromosomal microarray (CMA) provides a method of tracking duplications or deletions of chromosomal segments sometimes referred to as copy number variants (CNVs). CMA is used at our institution to establish chromosomal aberrations at diagnosis for all CLL/SLL patients. This provides prognostic information at diagnosis as well as the ability to track aberrations in the event of progression or transformation of disease. Use of CMA at diagnosis of CLL/SLL and upon transformation to DLBCL (RT) provides a method to determine clonal relationship. It also identifies aberrations involving TP53 and CDKN2A, which are known to be markers of poor prognosis. Methods: We performed a single center retrospective analysis of all patients at MUSC with pathologically confirmed CLL or SLL and Richter transformation between 1/01/2010 to 02/14/2019. We collected baseline demographic, clinical, laboratory, pathology, and outcomes data from the electronic medical record. Chromosomal Microarray Analysis (CMA) was performed on genomic DNA extracted from peripheral blood and fresh or formalin fixed paraffin-embedded lymph node samples using the Infinium HD Human Omni1 BeadChip or the CytoSNP-850K v1.1 BeadChip Array (Illumina, Inc., San Diego, CA). Copy number and genotype data were analyzed using NxClinical (BioDiscovery, Inc) software. Aberrations that were in 100% of cells were considered constitutional and were not included in the data analysis; whereas regions noted to be in less than 100% of cells were considered clonal changes. Results: We identified a total of 24 patients with a diagnosis of Richter transformation to DLBCL with prior history of CLL/SLL. Of these patients, 7 had CMA performed on both the CLL/SLL and RT samples. Clinical characteristics were collected for each patient and are included in table 1. CMA data including deletions, duplications, LOH, loss of TP53 and/or CDKN2A is displayed for each patient in table 2. Six of the 7 patients (85%) had common CMA aberrations identified in the CLL/SLL and RT samples providing evidence of a common clonality. Five of the 7 patients (71%) were identified to have TP53 loss and/or CDKN2A loss by CMA at the time of RT diagnosis. Discussion: Chromosomal microarray was able to provide proof of common clonality in 6 of 7 patients with Richter transformation to DLBCL, which is a poor prognostic feature of RT. It also identified a loss of TP53 and/or CDKN2A in 5 of 7 patients which is also a poor prognostic feature of RT. This information can be used to counsel patients on prognosis and could effect clinical recommendations such as treatment with Allogeneic stem cell transplantation. Institutions with the ability to run CMA should utilize this modality in patients Richter transformation to DLBCL. Disclosures No relevant conflicts of interest to declare.

Pathophysiology and causes of pulmonary hypertension

Pulmonary hypertension (PH) in the setting of critical illness may reflect the acute syndrome itself (such as acute massive pulmonary embolism or acute lung injury), and/or pre-existing ‘chronic’ causes of PH. To compound this, iatrogenic factors may also contribute to PH including the effects of positive pressure ventilation and certain vasoactive drugs. The presence of PH, especially when complicated by resulting right ventricular (RV) dysfunction and failure, is a poor prognostic feature in all settings. This chapter reviews the pathophysiology of acute PH in critical illness, and pre-existing chronic causes of PH, including acute decompensation in patients with pre-existing pulmonary arterial hypertension.

Infusional cyclophosphamide, doxorubicin, and etoposide in human immunodeficiency virus- and human T-cell leukemia virus type I-related non-Hodgkin's lymphoma: a highly active regimen

Fourteen patients with poor-prognosis intermediate- to high-grade non- Hodgkin's lymphoma (NHL) associated with human immunodeficiency virus (HIV) infection (12 patients) or human T-cell leukemia virus type I (HTLV-I) infection (two patients) received cyclophosphamide 750 mg/m2, doxorubicin 50 mg/m2, and etoposide 240 mg/m2 administered as a continuous intravenous (IV) infusion over 4 days (infusional CDE); treatment was repeated every 28 or more days for up to six cycles. All HIV-positive patients had at least one poor prognostic feature, which included either extranodal disease (10 patients), Karnofsky performance status less than 70% (six patients), a CD4 count less than 100/microL (six patients), or a prior history of acquired immunodeficiency syndrome (AIDS; one patient). Both HTLV-I-positive patients had an elevated serum lactate dehydrogenase (LDH) level, a poor prognostic feature in that setting. Complete response (CR) occurred in 10 patients (71%; 95% confidence interval, 48% to 95%) and partial response (PR) occurred in three patients (21%), yielding an overall objective response rate of approximately 93%. The estimated Kaplan-Meier median survival was 17.4 months; seven of 12 HIV-positive patients are alive and disease-free with a median follow-up of 15 months (range, 7 to 24 months). Hospitalization was required after 19% of treatment cycles due to fever associated with granulocytopenia. Documented or suspected opportunistic infection occurred in five patients (36%), bacteremia occurred in three patients (21%), and candidemia occurred in one patient (7%). There was one treatment-related death attributable to disseminated aspergillosis. This pilot study suggests that infusional CDE may be a highly active regimen capable of producing durable remissions in a high proportion of patients with HIV-related NHL. Further study is required to confirm this observation.

Infusional cyclophosphamide, doxorubicin, and etoposide in human immunodeficiency virus- and human T-cell leukemia virus type I-related non-Hodgkin's lymphoma: a highly active regimen

Fourteen patients with poor-prognosis intermediate- to high-grade non- Hodgkin's lymphoma (NHL) associated with human immunodeficiency virus (HIV) infection (12 patients) or human T-cell leukemia virus type I (HTLV-I) infection (two patients) received cyclophosphamide 750 mg/m2, doxorubicin 50 mg/m2, and etoposide 240 mg/m2 administered as a continuous intravenous (IV) infusion over 4 days (infusional CDE); treatment was repeated every 28 or more days for up to six cycles. All HIV-positive patients had at least one poor prognostic feature, which included either extranodal disease (10 patients), Karnofsky performance status less than 70% (six patients), a CD4 count less than 100/microL (six patients), or a prior history of acquired immunodeficiency syndrome (AIDS; one patient). Both HTLV-I-positive patients had an elevated serum lactate dehydrogenase (LDH) level, a poor prognostic feature in that setting. Complete response (CR) occurred in 10 patients (71%; 95% confidence interval, 48% to 95%) and partial response (PR) occurred in three patients (21%), yielding an overall objective response rate of approximately 93%. The estimated Kaplan-Meier median survival was 17.4 months; seven of 12 HIV-positive patients are alive and disease-free with a median follow-up of 15 months (range, 7 to 24 months). Hospitalization was required after 19% of treatment cycles due to fever associated with granulocytopenia. Documented or suspected opportunistic infection occurred in five patients (36%), bacteremia occurred in three patients (21%), and candidemia occurred in one patient (7%). There was one treatment-related death attributable to disseminated aspergillosis. This pilot study suggests that infusional CDE may be a highly active regimen capable of producing durable remissions in a high proportion of patients with HIV-related NHL. Further study is required to confirm this observation.