Karen Hardy

Pulmonary, Gonadal, and Central Nervous System Status after Bone Marrow Transplantation for Sickle Cell Disease

We conducted a prospective, multicenter investigation of human-leukocyte antigen (HLA) identical sibling bone marrow transplantation (BMT) in children with severe sickle cell disease (SCD) between 1991 and 2000. To determine if children were protected from complications of SCD after successful BMT, we extended our initial study of BMT for SCD to conduct assessments of the central nervous system (CNS) and of pulmonary function 2 or more years after transplantation. In addition, the impact on gonadal function was studied. After BMT, patients with stroke who had stable engraftment of donor cells experienced no subsequent stroke events after BMT, and brain magnetic resonance imaging (MRI) exams demonstrated stable or improved appearance. However, 2 patients with graft rejection had a second stroke after BMT. After transplantation, most patients also had unchanged or improved pulmonary function. Among the 11 patients who had restrictive lung changes at baseline, 5 were improved and 6 had persistent restrictive disease after BMT. Of the 2 patients who had obstructive changes at baseline, 1 improved and 1 had worsened obstructive disease after BMT. There was, however, significant gonadal toxicity after BMT, particularly among female recipients. In summary, individuals who had stable donor engraftment did not experience sickle-related complications after BMT, and were protected from progressive CNS and pulmonary disease.

EUR-1008 pancreatic enzyme replacement is safe and effective in patients with cystic fibrosis and pancreatic insufficiency

BACKGROUNDnEUR-1008 (Zenpep [pancrelipase]) is a new, enteric-coated, porcine-derived pancreatic enzyme product (PEP) developed for the treatment of cystic fibrosis (CF) patients with malabsorption associated with exocrine pancreatic insufficiency (EPI). Unlike currently marketed PEPs, EUR-1008 contains the label-claimed lipase content. Safety and efficacy were assessed in younger (<7 years) and older (> or =7 years) CF patients with EPI.nnnMETHODSnTwo multicenter studies were conducted: a randomized, double-blind, placebo-controlled, crossover trial in patients > or =7 years of age (N=34) and a supplemental, open-label study in children <7 years of age (N=19). Use of any medications altering gastric pH/motility was prohibited during the studies. Outcome measures in the randomized trial included changes in the coefficient of fat absorption (CFA), coefficient of nitrogen absorption (CNA), and signs/symptoms of malabsorption for EUR-1008 vs. placebo. Outcome measures in the supplemental study included safety and response (defined as no steatorrhea and no overt signs/symptoms of malabsorption) to EUR-1008 vs. previous enzyme treatment.nnnRESULTSnIn the randomized trial, EUR-1008 treatment compared to placebo resulted in a significantly higher mean CFA (88.3% vs. 62.8%, respectively) and CNA (87.2% vs. 65.7%, respectively) (both p<0.001) and reduced the incidence of malabsorption signs and symptoms in 32 evaluable patients. In the supplemental study, 11 of 19 patients met the criteria for responder with EUR-1008 at the end of the study vs. 10 of 19 patients at screening (previous PEP), and improvements in clinical symptoms were reported with EUR-1008 treatment. EUR-1008 was safe and well tolerated, and no serious drug-related AEs were reported in either study.nnnCONCLUSIONSnEUR-1008 was safe, well tolerated, and effective in CF patients of all ages with EPI-associated malabsorption in two clinical trials. Treatment led to clinically and statistically significant improvements in CFA and CNA in the randomized study, and control of malabsorption and clinical symptoms in both studies.

Novel CFTR Variants Identified during the First 3 Years of Cystic Fibrosis Newborn Screening in California

California uses a unique method to screen newborns for cystic fibrosis (CF) that includes gene scanning and DNA sequencing after only one California-40 cystic fibrosis transmembrane conductance regulator (CFTR) panel mutation has been identified in hypertrypsinogenemic specimens. Newborns found by sequencing to have one or more additional mutations or variants (including novel variants) in the CFTR gene are systematically followed, allowing for prospective assessment of the pathogenic potential of these variants. During the first 3 years of screening, 55 novel variants were identified. Six of these novel variants were discovered inxa0five screen-negative participants and three were identified in multiple unrelated participants. Ten novelxa0variants (c.2554_2555insT, p.F1107L, c.-152G>C, p.L323P, p.L32M, c.2883_2886dupGTCA, c.2349_2350insT, p.K114del, c.-602A>T, and c.2822delT) were associated with a CF phenotype (42% of participants were diagnosed at 4 to 25 months of age), whereas 26 were associated with CFTR-related metabolic syndrome to date. Associations with the remaining novel variants were confounded by the presence of other diseases or other mutations in cis or by inadequate follow-up. These findings have implications for how CF newborn screening and follow-up is conducted and will help guide which genotypes should, and which should not, be considered screen positive for CF in California and elsewhere.

A novel nutritional intervention improves lung function in overweight/obese adolescents with poorly controlled asthma: the Supplemental Nutrition in Asthma Control (SNAC) pilot study

Asthma in the obese is often severe, difficult to treat, and characterized by less eosinophilic inflammation than asthma in the nonobese. Obesity‐associated metabolic dysregulation may be a causal factor. We previously reported that a nutrient‐ and fiber‐dense bar [Childrens Hospital Oakland Research Institute (CHORI)‐bar], which was designed to fill gaps in poor diets, improved metabolism in healthy overweight/obese (OW/OB) adults. In this pilot trial, OW/OB adolescents with poorly controlled asthma were randomized to weekly nutrition/exercise classes with or without twice‐daily CHORI‐bar consumption. Intent‐to‐treat analysis did not indicate CHORI‐bar‐specific effects. However, restricting the analysis to participants with acceptable compliance and a relatively low fraction of exhaled nitric oxide (FENO; <50/ppb, a surrogate for noneosinophilic asthma; study participants: CHORI‐bar, n = 16; controls, n = 15) indicated that CHORI‐bar‐specific, significant improvements in lung function (forced vital capacity, percent‐predicted forced expiratory volume in 1 s, and percent‐predicted forced expiratory flow between 25 and 75% of forced vital capacity), primarily in participants with low chronic inflammation (high‐sensitivity C‐reactive protein <1.5 mg/L). (We previously observed that chronic inflammation blunted CHORI‐bar‐induced metabolic improvements in healthy OW/OB adults.) Lung function improvement occurred without weight loss and was independent of improvements in metabolic and anthropometric end points and questionnaire‐based measures of asthma control and quality of life. This study suggests that a nutritional intervention can improve lung function in OW/OB adolescents with asthma and relatively low FENO without requiring major changes in dietary habits, lifestyle, or weight loss and that this effect is blunted by chronic inflammation.—Bseikri, M., McCann, J. C., Lal, A., Fong, E., Graves,K., Goldrich, A., Block, D., Gildengoren, G. L., Mietus‐Snyder, M., Shigenaga, M., Suh, J., Hardy, K., Ames, B. N. A novel nutritional intervention improves lung function in overweight/obese adolescentswith poorly controlled asthma: the Supplemental Nutrition in Asthma Control (SNAC) pilot study. FASEB J. 32, 6643–6654 (2018). www.fasebj.org