Inhaled mRNA therapy for treatment of cystic fibrosis: Interim results of a randomized, double-blind, placebo-controlled phase 1/2 clinical study.

BACKGROUND: MRT5005, a codon-optimized CFTR mRNA, delivered by aerosol in lipid nanoparticles, was designed as a genotype-agnostic treatment for CF lung disease. METHODS: This was a randomized, double-blind, placebo-controlled Phase 1/2 study performed in the US. Adults with 2 severe class I and/or II CFTR mutations and baseline ppFEV1 values between 50 and 90% were randomized 3:1 (MRT5005: placebo). Six dose levels of MRT5005 (4, 8, 12, 16, 20, and 24 mg) or placebo (0.9% Sodium Chloride) were administered by nebulization. The single ascending dose cohort was treated over a range from 8 to 24 mg; the multiple ascending dose cohort received five weekly doses (range 8-20 mg); and the daily dosing cohort received five daily doses (4 mg). RESULTS: A total of 42 subjects were assigned to MRT5005 [31] or placebo [11]. A total of 14 febrile reactions were observed in 10 MRT5005-treated participants, which were mild [3] or moderate [11] in severity; two subjects discontinued related to these events. Additionally, two MRT5005-treated patients experienced hypersensitivity reactions, which were managed conservatively. The most common treatment emergent adverse events were cough and headache. No consistent effects on FEV1 were noted. CONCLUSIONS: MRT5005 was generally safe and well tolerated through 28 days of follow-up after the last dose, though febrile and hypersensitivity reactions were noted. The majority of these reactions resolved within 1-2 days with supportive care allowing continued treatment with MRT5005 and careful monitoring. In this small first-in-human study, FEV1 remained stable after treatment, but no beneficial effects on FEV1 were observed.

Newborn Screening Saves Lives but Cannot Replace the Need for Clinical Vigilance.

Newborn screening for cystic fibrosis (CF) enables early diagnosis and treatment leading to improved health outcomes for patients with CF. Although the sensitivity of newborn screening is high, false-negative results can still occur which can be misleading if clinicians are not aware of the clinical presentation of CF. We present a case of a young male with negative newborn screen diagnosed for CF. He was diagnosed at 3 years of age despite having symptoms indicative of CF since infancy. The delayed diagnosis resulted in diffuse lung damage and poor growth.

Refining the continuum of CFTR-associated disorders in the era of newborn screening.

Clinical heterogeneity in cystic fibrosis (CF) often causes diagnostic uncertainty in infants without symptoms and in older patients with milder phenotypes. We performed a cross-sectional evaluation of a comprehensive set of clinical and laboratory descriptors in a physician-defined cohort (N = 376; Children's Hospital of Wisconsin and the American Family Children's Hospital CF centers in Milwaukee and Madison, WI, USA) to determine the robustness of categorizing CF (N = 300), cystic fibrosis transmembrane conductance regulator (CFTR)-related disorder (N = 19), and CFTR-related (CRMS) metabolic syndrome (N = 57) according to current consensus guidelines. Outcome measures included patient demographics, clinical measures, sweat chloride levels, CFTR genotype, age at diagnosis, airway microbiology, pancreatic function, infection, and nutritional status. The CF cohort had a significantly higher median sweat chloride level (105 mmol/l) than CFTR-related disorder patients (43 mmol/l) and CFTR-related metabolic syndrome patients (35 mmol/l; p ≤ 0.001). Patient groups significantly differed in pancreatic sufficiency, immunoreactive trypsinogen levels, sweat chloride values, genotype, and positive Pseudomonas aeruginosa cultures (p ≤ 0.001). An automated classification algorithm using recursive partitioning demonstrated concordance between physician diagnoses and consensus guidelines. Our analysis suggests that integrating clinical information with sweat chloride levels, CFTR genotype, and pancreatic sufficiency provides a context for continued longitudinal monitoring of patients for personalized and effective treatment.

Efficacy of recombinant human deoxyribonuclease I in the hospital management of respiratory syncytial virus bronchiolitis.

OBJECTIVE: To evaluate the effect of recombinant human deoxyribonuclease I (rhDNase) in shortening the length of the hospitalization and improving the chest radiographs (CXRs) in hospitalized infants with respiratory syncytial virus (RSV) infection as a result of its mucolytic properties. METHODS: Randomized, double-blind, placebo-controlled investigation of 75 patients with RSV bronchiolitis. The study was conducted at the University of Michigan Medical Center and St. Joseph Mercy Hospital, both in Ann Arbor, MI. RESULTS: The respiratory rate, wheezing, and retraction difference scores, obtained by subtracting the hospital discharge score from the corresponding hospital admission score, show no difference between the two groups, but the CXR difference scores show that the rhDNase group improved by 0.46 while the placebo group worsened by 0.60 (p < 0.001). Analysis of covariance for the hospital discharge CXR score after adjusting for the hospital admission score for both groups was done. There was a difference in scores between the two groups, with adjusted mean for the study group of 2.03, and 2.76 for the placebo group (p < 0.001). Paired t test statistics in each of the two groups were computed. For the placebo group, the mean increase of 0.60 was significant (p = 0.02), and the mean decrease of 0.46 for the rhDNase group was also significant (p = 0.02). A one-way analysis of covariance with the hospital discharge CXR scores as the dependent variable and the hospital admission score as the covariate showed that there was a significant difference between the groups (p = 0.01). CONCLUSION: In patients with RSV bronchiolitis, there was significant improvement in the CXRs with the use of rhDNase compared to significant worsening in the placebo group. To our knowledge, this is the first report of the use of rhDNase to treat RSV bronchiolitis.

Use of computerized tomography and chest x-rays in evaluating efficacy of aerosolized recombinant human DNase in cystic fibrosis patients younger than age 5 years: a preliminary study.

The aim of this study was to evaluate the ability of high-resolution computerized tomography (HRCT) of the chest and chest x-rays (CXR) to determine efficacy of inhaled recombinant human DNase (rhDNase) in cystic fibrosis (CF) patients younger than 5 years of age. A randomized, double-blind, placebo-controlled pilot study of 12 patients with CF younger than 5 years of age, attending the University of Michigan Cystic Fibrosis Center (Ann Arbor, MI) was conducted. The changes in the HRCT and CXR score from baseline to day 100 of therapy were assessed using a previously validated scoring system. The mean changes of HRCT scores between the rhDNase and placebo groups were found to be significant at the 95% level, with mean change +/- SE mean of - 1.00 +/- 0.53 and 0.58 +/- 0.24 for rhDNase and placebo groups, respectively (P = 0.02). The difference in CXR score was not significant between the two groups. An analysis was performed to relate HRCT subscores to CXR score; only thickening of the intra-interlobular septae was significantly correlated with the total CXR score (r = - 0.7, P < 0.01). There was improvement in the parents' assessments of the patients' well-being, with improvement in physical activity, decreased cough, sleep quality, and appetite in those subjects receiving rhDNase. We conclude that the administration of rhDNase was associated with improvement in the HRCT scan in CF patients younger than 5 years of age. Findings indicate that HRCT of the chest is useful and sensitive in studying responses to therapy in patients with CF lung disease. To our knowledge, this is the first report of the use of HRCT to assess the effectiveness of a therapeutic modality in so young a CF patient population.

Cystic fibrosis in adolescents and young adults.

Advances in knowledge and medical science have resulted in an increased life span and quality of life of patients with cystic fibrosis (CF). The median age of survival for CF patients is 32.3 years of age and patients 18 years of age or older now constitute one third of the total patients with CF. Because of these advances, a new patient population has emerged: the adolescents and young adults with CF. Adolescence is normally a time of great cognitive, social and developmental changes. Adolescents with CF not only have to deal with the normal changes expected, but also have to deal with the transition of assuming responsibility for their care from the parents and transitioning their care from a pediatric to an adult care team. Moreover, many of these young adults have to deal with the impact of the progressive deterioration of their CF disease. This review discusses issues of significance to this emerging patient population, including medical care, issues of disability, and psychosocial and other medical conditions associated with an increased life expectancy.

Innate lung defenses and compromised Pseudomonas aeruginosa clearance in the malnourished mouse model of respiratory infections in cystic fibrosis.

Cystic fibrosis (CF) is characterized by dysfunction of the digestive and respiratory tracts resulting in generalized malnutrition and chronic respiratory infections. Chronic lung infections with Pseudomonas aeruginosa, intense neutrophil-dominated airway inflammation, and progressive lung disease are the major cause of high morbidity and mortality in CF. Here we investigated the effects of malnutrition in CF on innate lung defenses, susceptibility to P. aeruginosa colonization, and associated inflammation, using aerosol models of acute and chronic infections in normal, malnourished, and transgenic mice. CFTR(m1Unc-/-) knockout mice displayed body weight variations and showed variable pulmonary clearance of P. aeruginosa. This variability was not detected in bitransgenic CFTR(m1Unc-/-)(FABP-hCFTR) mice in which the intestinal defect had been corrected. Diet-induced protein calorie malnutrition in C57BL/6J mice resulted in impaired pulmonary clearance of P. aeruginosa. Tumor necrosis factor alpha (TNF-alpha) and nitrite levels detected upon exposure to P. aeruginosa aerosols were lower in the lungs of the malnourished C57BL/6J mice relative than in lungs of mice fed a normal diet. The role of TNF-alpha and reactive nitrogen intermediates in P. aeruginosa clearance was tested in TNF-alpha and inducible nitric oxide synthase (iNOS) knockout mice. P. aeruginosa clearance was diminished in transgenic TNF-alpha- and iNOS-deficient mice. In contrast to the effects of TNF-alpha and iNOS, gamma interferon knockout mice retained a full capacity to eliminate P. aeruginosa from the lung. Malnutrition also contributed to excessive inflammation in C57BL/6J mice upon chronic challenge with P. aeruginosa. The repeatedly infected malnourished host did not produce interleukin-10, a major anti-inflammatory cytokine absent or diminished in the bronchoalveolar fluids of CF patients. These results are consistent with a model in which defective CFTR in the intestinal tract leads to nutritional deficiency which in turn contributes to compromised innate lung defenses, bacterial colonization, and excessive inflammation in the CF respiratory tract.

Treatment of anorexia and weight loss with megestrol acetate in patients with cystic fibrosis.

Four patients with severe cystic fibrosis lung disease, anorexia and weight loss, received Megestrol Acetate (MA), as an appetite stimulant. The initial dose was 400-800 mg daily and was continued for 6-15 months. Appetite was improved, with significant weight gain in all patients and an increase in their weight for age percentile from <5% at the start of the study to approximately the 25(th) percentile after 6 months of use and improvement in quality of life. One patient discontinued MA after 6 months, and subsequently appetite and weight were depressed.

Liquid ventilation in an infant with pulmonary alveolar proteinosis.

Partial liquid ventilation (PLV) has been applied in various pulmonary diseases. We describe the use of partial liquid ventilation as a lavage method following normal saline (NS) lavage in an infant with pulmonary alveolar proteinosis (PAP) and severe hypoxemia. A 6 weeks old 3.4 kg former 36 weeks gestation boy on supplemental oxygen was transferred to our NICU with persistent tachypnea, dry cough, and increasing oxygen requirements. A lingular open lung biopsy revealed PAP. He developed progressive respiratory failure requiring ventilatory support, necessitating conventional NS lavage, followed by lung lavage with perflubron (LiquiVent; Alliance Pharmaceutical Corp. and Hoechst Marion Roussel) while on venovenous extracorporeal life support (ECLS). Lung lavage with NS and perflubron yielded minimal cloudy effluent. Gas exchange and pulmonary function deteriorated following NS lavage and attempts to discontinue ECLS were poorly tolerated. In contrast, tidal volume, PaO2, and pulmonary compliance increased after PLV, while the (A-a) D(O2) decreased to a point where ECLS was no longer required. Once perflubron was added repeatedly to the ventilator circuit to correct for evaporation over the 4 days of PLV. Cardiovascular status remained stable for several days; however, eventually he required reinitiation of ECLS and more mechanical ventilatory support with each trial off ECLS. He was maintained on high pressures and FiO2 without any possibility to wean him from mechanical ventilation. Life support was withdrawn 1 month after admission. The survival from PAP in infants remains dismal, even with total lung NS lavage. While both NS and perflubron lavage in this patient were not effective in removing the proteinaceous alveolar debris, PLV following NS lavage was associated with an improvement in gas exchange and lung compliance.

Arginine vasopressin levels in nursing home residents with nighttime urinary incontinence.

OBJECTIVES: To examine the relationship between diurnal urine volume and plasma arginine vasopressin levels (AVP) in nursing home residents with nighttime urinary incontinence and a comparison group of frail but nondemented, continent geriatric board and care residents. DESIGN: Case series. SETTING: Four nursing homes and two board and care facilities. PARTICIPANTS: Sixty-two nursing home residents and 27 board and care residents. MEASUREMENTS: Daytime (7:00 a.m. to 7:00 p.m.) and nighttime (7:00 p.m. to 7:00 a.m.) urine volumes of incontinent nursing home residents were measured over 3 days and 3 nights by reweighing preweighed adults diapers and toileting inserts emptied by research staff for the comparison group. AVP levels were drawn in the early morning (5:00 a.m. to 7:00 a.m.) before subjects arose and in the evening after an hour of lying in bed (8:00 p.m. to 11:00 p.m.), and plasma levels were determined by radioimmunoassay. RESULTS: Half of the nursing home residents and 82% of the comparison group had night/total urine volume ratios > or = 50%. Forty-nine percent of the total of 89 subjects had undetectable morning AVP levels, 61% had undetectable evening AVP levels, and 42% had undetectable AVP levels in both morning and evening. There were no significant differences in AVP levels between those with night/total urine volume ratios > or = 50% and < 50% in either the nursing home or comparison groups though the small number of comparison group subjects with ratios < 50% may have limited our statistical power to detect differences. CONCLUSION: Our data suggest that a substantial proportion of both nursing home residents with nighttime incontinence and frail geriatric patients with a reversal of the normal diurnal pattern of urine excretion have an accompanying deficiency in AVP production and/or secretion. More detailed physiologic studies are needed to understand better the pathophysiology of geriatric nocturia and nighttime incontinence and the role that AVP deficiency may play in these conditions. Until such studies are carried out, we do not recommend the routine use of exogenous AVP for geriatric patients with unexplained nocturnal polyuria.

Urinary incontinence in the elderly. Causes and treatment options.

Urinary incontinence is a prevalent and distressing condition that affects > 30% of elderly individuals. A wide variety of treatment modalities is available, and can be effective in reducing or eliminating the symptoms and adverse consequences of urinary incontinence. Pharmacological therapy is an important component of the successful management of this condition, but the agents currently used do not act selectively on the lower urinary tract. Adverse effects of drug treatment are common, and are especially problematic in the elderly. A careful assessment of the type of urinary incontinence and the institution of a rational management programme are the keys to improvement or even cure in patients with this condition.

Disability and quality of life in cystic fibrosis from early age to adulthood.

We evaluated the utility of the Social Security disability Insurance (SSD) program and the supplemental Security Income (SSI) program in cystic fibrosis (CF) patients with disability. Also, we evaluated the role of health care professionals in increasing the disabled patients awareness of the different resources available for them.

Symptomatic increase in intracranial pressure following pancreatic enzyme replacement therapy for cystic fibrosis.

A newly diagnosed 5-month-old infant with cystic fibrosis (CF) developed signs and symptoms of increased intracranial pressure (ICP) within days of starting pancreatic enzyme replacement therapy. Symptoms promptly resolved on two occasions after stopping enzyme replacement. At 10 months of age, enzyme replacement was well tolerated.

Continuous versus intermittent nebulized terbutaline: plasma levels and effects.

The purpose of this investigation was to compare continuous versus intermittent nebulization of a beta 2-agonist, terbutaline, to determine whether differences exist in plasma concentrations or adverse cardiovascular effects of the drug with these two techniques for its administration. Sixteen children 6 to 16 yr of age, admitted for acute asthma, were enrolled in this randomized double-blind clinical trial. Nebulization of 16 mg of terbutaline over an 8-h period was performed either continuously or intermittently, with a dose of 4 mg given over 20 min every 2 h. The peak plasma terbutaline concentration for the intermittent nebulization treatment (INT) group (5.1 +/- 2.1 ng/ml) occurred 1 h after the fourth inhalation treatment and was similar to the peak concentration for the continuous nebulization treatment (CNT) group, which was reached at the end of the 8 h period (4.7 +/- 2.3 ng/ml). The maximum heart rate increase for the INT group (19.6 +/- 18.3 bpm) occurred 1 h after the fourth dose and was similar to the peak observed in the CNT group (19.6 +/- 19.2 bpm), which occurred after 3 h. Similar increases in systolic and decreases in diastolic pressures were observed for the INT and CNT groups. No evidence of serious adverse myocardial complications was seen in either group, as evidenced by measurements of the MB fraction of creatine phosphokinase (CPK-MB) and Holter-monitor recordings. Continuous nebulization of the terbutaline produces similar plasma concentrations and cardiovascular physiologic responses as intermittent nebulization.(ABSTRACT TRUNCATED AT 250 WORDS)

Colonic strictures in children with cystic fibrosis.

PURPOSE: To determine the radiographic, clinical, surgical, and histologic findings in children with cystic fibrosis who develop strictures of the colon. MATERIALS AND METHODS: Ten children (five boys, five girls; age range, 2.5-9.0 years; mean age, 5.5 years), who were treated at the practices of the authors, were retrospectively identified and their medical records reviewed. RESULTS: Radiographic manifestations of the colonic disease included mucosal irregularity and spiculation with nodular thickening of the colonic wall and loss of normal colonic haustration. Luminal narrowing involved long segments of the colon. Longitudinal shortening of the colon was also a prominent feature. The decrease in caliber of the bowel ranged from mild narrowing to complete occlusion of the lumen. Histologic examination revealed severe submucosal fibrosis and fatty infiltration with transmural extension of the fibrosis to involve the serosa in some cases. Unlike in Crohn disease, however, acute inflammatory changes were minimal or absent. CONCLUSION: Colonic stricture in children with cystic fibrosis is due to irreversible and frequently progressive narrowing of the colonic lumen.

Correction of vitamin E deficiency with fat-soluble versus water-miscible preparations of vitamin E in patients with cystic fibrosis.

Of 27 patients with cystic fibrosis, 17 had levels of alpha-tocopherol more than 2 SD below the mean. Patients were randomly given either a water-miscible form of vitamin E or a fat-soluble form for 6 months. Either form was effective in achieving normal serum levels; the fat-soluble supplement has a significant cost advantage.