Research Spotlight

Deignan, J. L., C. Astbury, G. R. Cutting, D. Del Gaudio, A. R. Gregg, W. W. Grody, K. G. Monaghan and S. Richards (2020). “CFTR variant testing: a technical standard of the American College of Medical Genetics and Genomics (ACMG).” Genet Med May 14. [Epub ahead of print].

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Pathogenic variants in the CFTR gene are causative of classic cystic fibrosis (CF) as well as some nonclassic CF phenotypes. In 2001, CF became the first target of pan-ethnic universal carrier screening by molecular methods. The American College of Medical Genetics and Genomics (ACMG) recommended a core panel of 23 disease-causing variants as the minimal set to be included in pan-ethnic carrier screening of individuals with no family history of the disease, and these variants were usually assessed using targeted methods. The original recommendation also left open the option for laboratories to offer expanded CFTR variant panels; however, at the time, expanded CFTR variant panels were met with some controversy on the basis of the available technologies and the limited phenotypic knowledge of rare variants. Both of those aspects have now evolved, prompting this update of the ACMG technical standards for CFTR variant testing.

Davids, M., A. Pooran, C. Hermann, L. Mottay, F. Thompson, J. Cardenas, J. Gu, T. Koeuth, R. Meldau, J. Limberis, P. Gina, S. Srivastava, B. Calder, A. Esmail, M. Tomasicchio, J. Blackburn, T. Gumbo and K. Dheda (2020). “A Human Lung Challenge Model to Evaluate the Safety and Immunogenicity of PPD and Live Bacillus Calmette-Guérin.” Am J Respir Crit Care Med 201(10): 1277-1291.

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Rationale: A human model to better understand tuberculosis immunopathogenesis and facilitate vaccine development is urgently needed.Objectives: We evaluated the feasibility, safety, and immunogenicity of live bacillus Calmette-Guérin (BCG) in a lung-oriented controlled human infection model.Methods: We recruited 106 healthy South African participants with varying degrees of tuberculosis susceptibility. Live BCG, sterile PPD, and saline were bronchoscopically instilled into separate lung segments (n = 65). A control group (n = 34) underwent a single bronchoscopy without challenge. The primary outcome was safety. Cellular and antibody immune signatures were identified in BAL before and 3 days after challenge using flow cytometry, ELISA, RNA sequencing, and mass spectrometry.Measurements and Main Results: The frequency of adverse events was low (9.4%; n = 10), similar in the challenge versus control groups (P = 0.8), and all adverse events were mild and managed conservatively in an outpatient setting. The optimal PPD and BCG dose was 0.5 TU and 10(4) cfu, respectively, based on changes in BAL cellular profiles (P = 0.02) and antibody responses (P = 0.01) at incremental doses before versus after challenge. At 10(4) versus 10(3) cfu BCG, there was a significant increase in number of differentially expressed genes (367 vs. 3; P < 0.001) and dysregulated proteins (64 vs. 0; P < 0.001). Immune responses were highly setting specific (in vitro vs. in vivo) and compartment specific (BAL vs. blood) and localized to the challenged lung segments.Conclusions: A lung-oriented mycobacterial controlled human infection model using live BCG and PPD is feasible and safe. These data inform the study of tuberculosis immunopathogenesis and strategies for evaluation and development of tuberculosis vaccine candidates.

Curley, J. M., D. P. Ciceri and W. C. Culp, Jr. (2020). “Sugammadex Administration to Facilitate Timely Neurologic Examination in the Traumatic Brain Injury Patient.” Neurocrit Care 32(3): 880-882.

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Neuromuscular blocking agents are frequently administered to traumatic brain injury patients during initial airway management; however, paralytics can delay diagnosis and treatment by impeding the neurologic examination. Sugammadex is a relatively new medication approved for reversal of amino-steroid paralytic agents such as rocuronium or vecuronium. We describe the use of sugammadex to reverse prolonged rocuronium-induced paralysis in a dialysis-dependent patient who suffered a traumatic brain injury. This reversal allowed for immediate evaluation by a neurosurgeon, neurosurgical intervention, and subsequent detection of patient neurologic deterioration by examination which otherwise may have been mistaken for prolonged paralysis. To the authors’ knowledge, the use of sugammadex for this purpose has not previously been reported. [No abstract; excerpt from article].

Cork, D. P., P. A. McCullough, H. S. Mehta, C. M. Barker, C. Gunnarsson, M. P. Ryan, E. R. Baker, J. Van Houten, S. Mollenkopf and P. Verta (2020). “Impact of mitral regurgitation on cardiovascular hospitalization and death in newly diagnosed heart failure patients.” ESC Heart Fail May 29. [Epub ahead of print].

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AIMS: Heart failure (HF) carries a poor prognosis, and the impact of concomitant mitral regurgitation (MR) is not well understood. This analysis aimed to estimate the incremental effect of MR in patients newly diagnosed with HF. METHODS AND RESULTS: Data from the IBM® MarketScan® Research Databases were analysed. Included patients had at least one inpatient or two outpatient HF claims. A 6 month post-period after HF index was used to capture MR diagnosis and severity. HF patients were separated into three cohorts: without MR (no MR), not clinically significant MR (nsMR), and significant MR (sMR). Time-to-event analyses were modelled to estimate the clinical burden of disease. The primary outcome was a composite endpoint of death or cardiovascular (CV)-related admission. Secondary outcomes were death and CV hospitalization alone. All models controlled for baseline demographics and co-morbidities. Patients with sMR were at significantly higher risk of either death or CV admission compared with patients with no MR [hazard ratio (HR) 1.26; 95% confidence interval (CI) 1.15-1.39]. When evaluating death alone, patients with sMR had significantly higher risk of death (HR 1.24; 95% CI 1.08-1.43) compared with patients with no MR. When evaluating CV admission alone, patients with MR were at higher risk of hospital admission vs. patients with no MR, and the magnitude was dependent upon the MR severity: sMR (HR 1.55; 95% CI 1.38-1.74) and nsMR (HR 1.23; 95% CI 1.08-1.40). CONCLUSIONS: Evidence of MR in retrospective claims significantly increases the clinical burden of incident HF patients. Time to death and CV hospitalizations are increased when MR is clinically significant.

Cooper, J. P., B. E. Storer, N. Granot, B. Gyurkocza, M. L. Sorror, T. R. Chauncey, J. Shizuru, G. N. Franke, M. B. Maris, M. Boyer, B. Bruno, F. Sahebi, A. A. Langston, P. Hari, E. D. Agura, S. L. Petersen, R. T. Maziarz, W. Bethge, J. Asch, J. A. Gutman, G. Olesen, A. M. Yeager, K. Hübel, W. J. Hogan, D. G. Maloney, M. Mielcarek, P. J. Martin, M. E. D. Flowers, G. E. Georges, A. E. Woolfrey, H. J. Deeg, B. L. Scott, G. B. McDonald, R. Storb and B. M. Sandmaier (2020). “Allogeneic hematopoietic cell transplantation with non-myeloablative conditioning for patients with hematologic malignancies: Improved outcomes over two decades.” Haematologica Jun 4;haematol.2020.248187. [Epub ahead of print].

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We have used a non-myeloablative conditioning regimen for allogeneic hematopoietic cell transplantation for the past twenty years. During that period, changes in clinical practice have been aimed at reducing morbidity and mortality from infections, organ toxicity, and graft-versus-host disease. We hypothesized that improvements in clinical practice led to better transplantation outcomes over time. From 1997-2017, 1,720 patients with hematologic malignancies received low-dose total body irradiation +/- fludarabine or clofarabine before transplantation from HLA-matched sibling or unrelated donors, followed by mycophenolate mofetil and a calcineurin inhibitor ± sirolimus. We compared outcomes in three cohorts by year of transplantation: 1997 +/- 2003 (n=562), 2004 +/- 2009 (n=594), and 2010 +/- 2017 (n=564). The proportion of patients ≥60 years old increased from 27% in 1997 +/- 2003 to 56% in 2010-2017, and with scores from the Hematopoietic Cell Transplantation Comborbidity Index of ≥3 increased from 25% in 1997 +/- 2003 to 45% in 2010 +/- 2017. Use of unrelated donors increased from 34% in 1997 +/- 2003 to 65% in 2010-2017. When outcomes from 2004 +/- 2009 and 2010-2017 were compared to 1997 +/- 2003, improvements were noted in overall survival (P=.0001 for 2004-2009 and P <.0001 for 2010-2017), profression-free survival (P=.002 for 2004-2009 and P <.0001 for 2010 +/- 2017), non-relapse mortality (P<.0001 for 2004 +/- 2009 and P <.0001 for 2010 +/- 2017), and in rates of grades 2 +/- 4 acute and chronic graft-vs.-host disease. For patients with hematologic malignancies who underwent transplantation with non-myeloablative conditioning, outcomes have improved during the past two decades.