Milica S. Chernick

Pulmonary Nontuberculous Mycobacterial Disease: Prospective Study of a Distinct Preexisting Syndrome

RATIONALE Pulmonary nontuberculous mycobacterial (PNTM) disease is increasing, but predisposing features have been elusive. OBJECTIVES To prospectively determine the morphotype, immunophenotype, and cystic fibrosis transmembrane conductance regulator genotype in a large cohort with PNTM. METHODS We prospectively enrolled 63 patients with PNTM infection, each of whom had computerized tomography, echocardiogram, pulmonary function, and flow cytometry of peripheral blood. In vitro cytokine production in response to mitogen, LPS, and cytokines was performed. Anthropometric measurements were compared with National Health and Nutrition Examination Survey (NHANES) age- and ethnicity-matched female control subjects extracted from the NHANES 2001-2002 dataset. MEASUREMENTS AND MAIN RESULTS Patients were 59.9 (+/-9.8 yr [SD]) old, and 5.4 (+/-7.9 yr) from diagnosis to enrollment. Patients were 95% female, 91% white, and 68% lifetime nonsmokers. A total of 46 were infected with Mycobacterium avium complex, M. xenopi, or M. kansasii; 17 were infected with rapidly growing mycobacteria. Female patients were significantly taller (164.7 vs. 161.0 cm; P < 0.001) and thinner (body mass index, 21.1 vs. 28.2; P < 0.001) than matched NHANES control subjects, and thinner (body mass index, 21.1 vs. 26.8; P = 0.002) than patients with disseminated nontuberculous mycobacterial infection. A total of 51% of patients had scoliosis, 11% pectus excavatum, and 9% mitral valve prolapse, all significantly more than reference populations. Stimulated cytokine production was similar to that of healthy control subjects, including the IFN-gamma/IL-12 pathway. CD4(+), CD8(+), B, and natural killer cell numbers were normal. A total of 36% of patients had mutations in the cystic fibrosis transmembrane conductance regulator gene. CONCLUSIONS Patients with PNTM infection are taller and leaner than control subjects, with high rates of scoliosis, pectus excavatum, mitral valve prolapse, and cystic fibrosis transmembrane conductance regulator mutations, but without recognized immune defects.

Aerosol α1 -antitrypsin treatment for cystic fibrosis

Abstract In cystic fibrosis neutrophil-dominated inflammation on the respiratory epithelial surface results in a chronic epithelial burden of the destructive enzyme, neutrophil elastase. α1-antitrypsin (α1AT), the main inhibitor of neutrophil elastase in lung, was given in aerosol form to 12 cystic fibrosis patients. It suppressed neutrophil elastase in the respiratory epithelial lining fluid (ELF) and restored the ELF anti-neutrophil elastase capacity when ELF α1AT reached 8 μmol/l. This treatment also reversed the inhibitory effect of cystic fibrosis ELF on pseudomonas killing by neutrophils, which suggests that it may augment host defence in cystic fibrosis.

A serum test for cystic fibrosis using monoclonal antibody 19-9.

Monoclonal antibody 19-9 detects a sialosylated Lea antigen with the following sugar sequence: NeuNAc alpha 2-3Gal beta 1-3[Fuc alpha 1-4]GlcNAc beta 1-3Gal. . . . This antigen is detected as a mucin in the sera of many patients with gastrointestinal and pancreatic cancer. Elevated levels of sialosylated Lea antigen are also detected in serum from 14 of 16 patients with cystic fibrosis (87%). One of the two negative patients belongs to the Le(a-b-) blood group and so is unable to synthesize the sialosylated Lea antigen. The high percentage of cystic fibrosis patients with elevated sialosylated Lea antigen suggests that the 19-9 antibody may be useful for diagnosis of cystic fibrosis. Antibodies to other sialosylated carbohydrates in mucins may also be useful for detection of cystic fibrosis and may allow diagnosis of patients belonging to the Le(a-b-) blood group.

Adult‐onset cystic fibrosis liver disease: Diagnosis and characterization of an underappreciated entity

Cystic fibrosis (CF) liver disease (CFLD), a leading cause of death in CF, is mostly described in pediatric populations. Adult‐onset CFLD lacks sufficient characterization and diagnostic tools. A cohort of CF patients without CFLD during childhood were followed for up to 38 years with serologic testing, imaging, and noninvasive fibrosis markers. Historical CFLD diagnostic criteria were compared with newly proposed CFLD criteria. Thirty‐six CF patients were followed for a median of 24.5 years (interquartile range 15.6‐32.9). By the last follow‐up, 11 (31%) had died. With conventional criteria, 8 (22%) patients had CFLD; and by the new criteria, 17 (47%) had CFLD at a median age of 36.6 years (interquartile range 26.5‐43.2). By the new criteria, those with CFLD had higher median alanine aminotransferase (42 versus 27, P = 0.005), aspartate aminotransferase (AST; 26 versus 21, P = 0.01), direct bilirubin (0.13 versus 0.1, P = 0.01), prothrombin time (14.4 versus 12.4, P = 0.002), and AST‐to‐platelet ratio index (0.31 versus 0.23, P = 0.003) over the last 2 years of follow‐up. Subjects with a FibroScan >6.8 kPa had higher alanine aminotransferase (42 versus 28U/L, P = 0.02), AST (35 versus 25U/L, P = 0.02), AST‐to‐platelet ratio index (0.77 versus 0.25, P = 0.0004), and Fibrosis‐4 index (2.14 versus 0.74, P = 0.0003) and lower platelet counts (205 versus 293, P = 0.02). One CFLD patient had nodular regenerative hyperplasia. Longitudinally, mean platelet counts significantly declined in the CFLD group (from 310 to 230 U/L, P = 0.0005). Deceased CFLD patients had lower platelet counts than those alive with CFLD (143 versus 258 U/L, P = 0.004) or those deceased with no CFLD (143 versus 327U/L, P = 0.006). Conclusion: Adult‐onset CFLD may be more prevalent than previously described, which suggests a later wave of CFLD that impacts morbidity; routine liver tests, radiologic imaging, noninvasive fibrosis markers, and FibroScan can be used algorithmically to identify adult CFLD; and further evaluation in other CF cohorts should be performed for validation. (Hepatology 2017;66:591–601).

848 Cystic Fibrosis Liver Disease -Development of a Novel Criteria to Identify a Second Wave of Liver Disease in Adults

Introduction: Cystic fibrosis liver disease (CFLD) is the 3rd leading cause of death in cystic fibrosis (CF) patients, contributing to 2.5-5% of overall mortality. Onset of CFLD has been mostly described in pediatric populations, but with improving life expectancy, adult onset CFLD is increasingly recognized with an estimated prevalence of 2-37%. Criteria for the diagnosis of adult CFLD are lacking and inconsistent; with few studies evaluating noninvasive biomarkers and radiographic data for classification systems. Aims: To characterize adult CFLD and develop a set of novel criteria for the diagnosis of adult CFLD utilizing biochemical, clinical and radiographic markers in an adult CF cohort followed at the NIH Clinical Center for up to 37 years (yrs). Methods: Patients with CF were evaluated with hepatic biomarkers of inflammation, synthetic function, portal hypertension, radiologic imaging, and transient elastography (TE). Charts were extracted for clinical data. Utilizing these biomarkers along with TE, APRI, and FIB-4, criteria were defined for the diagnosis CFLD. Patients who met CFLD criteria were compared to CF patients without evidence of liver disease. Results: 36 patients with CF (33% F508 homozygous, 23% F508 heterozygous) were studied (65% males, 97% white). The median age of CF diagnosis was 11 yrs, and the median follow-up duration was 23 yrs (range 2 to 37). At the time of last follow-up (mean age=46 yrs), 11 (31%) had died (respiratory failure=3, infection=3, complications of transplantation=2, or other causes=3). 17 of 36 (47%) patients met criteria for CFLD (mean age of diagnosis=31 yrs). Patients with CFLD had significantly higher mean ALT (44.3 vs 28.1, p=0.01), direct bilirubin (0.2 vs 0.1, p =0.04), PT (14.4 vs 12.8, p=0.01), and APRI (0.6 vs 0.2, p=0.04) over the last year of follow-up. In the CFLD group, 4 patients had radiographic evidence of advanced liver disease and 1 patient had nodular regenerative hyperplasia and experienced hepatic decompensation. On longitudinal comparison, platelet counts significantly declined in the CFLD group (312 to 237 U/L, p=0.007) as compared to patients without CFLD (328 to 297 U/L, p=0.11). Conclusions: By evaluating non-invasive markers of liver disease, a novel criteria can be employed to identify adult CFLD. These biomarkers not only suggest that a second wave of liver disease exists in adult CF patients, but also that it may be more prevalent than previously described. Further evaluation of this diagnostic criteria in other CF cohorts should be performed to evaluate its utility in adult CFLD.