KB001-A, a novel anti-inflammatory, found to be safe and well-tolerated in cystic fibrosis patients infected with Pseudomonas aeruginosa.

BACKGROUND: Chronic Pseudomonas aeruginosa (Pa) airways infection, exuberant local inflammation, and progressive lung function loss are hallmarks of cystic fibrosis (CF). KB001-A is an anti-PcrV PEGylated monoclonal antibody fragment to the Type III secretion system of Pa. This 16-week study evaluated KB001-A associated effect on time-to-need for antibiotics for worsening respiratory signs and symptoms, as well as safety, and treatment-associated changes in symptom scores, inflammatory markers, and spirometry. METHODS: This was a randomized, double-blind, placebo-controlled, repeat-dose study in CF subjects with Pa. Intravenous 10mg/kg KB001-A or placebo infusions were administered at baseline and weeks 2, 4, 8, and 16, with a 4-week follow-up. Sputum inflammatory markers were assessed in a sub-study. Time-to-need for antibiotics was compared between groups by Kaplan Meier analysis and Cox proportional hazards modeling adjusting for randomization strata. RESULTS: Of 182 subjects, 169 received at least one infusion of KB001-A (n=83) or placebo (n=86). KB001-A was generally safe and well-tolerated as compared to placebo, with no significant emergent adverse effects other than one serious adverse event of elevated hepatic enzymes of unclear etiology. Time to need for antibiotics did not differ between groups (HR: 1.00; 95% CI: 0.69, 1.45, p=0.995). A 3.2 increase in ppFEV1 from placebo favoring KB001-A was observed at week 16 (95% CI: 1.12, 5.30, p=0.003). Mean changes from baseline in log10 sputum neutrophil elastase (NE) had a non-significant decrease (-0.27, 95% CI: -0.58,0.04, p=0.084) while IL-8 concentrations at week 16 were significantly lower (-0.27, 95% CI: -0.55,0.00, p=0.048) among KB001-A subjects (n=16) relative to placebo (n=13). CONCLUSIONS: KB001-A was safe and well-tolerated and associated with a modest FEV1 benefit and reduction in select sputum inflammatory markers (IL-8). KB001-A was not associated with an increased time to need for antibiotics. The lack of efficacy seen with KB001-A may be due, in part, to the low levels of the type III secretion proteins previously reported in sputum of CF patients chronically infected with Pa.

Allergen-specific IgE as a biomarker of exposure plus sensitization in inner-city adolescents with asthma.

BACKGROUND: Relationships among allergen-specific IgE levels, allergen exposure and asthma severity are poorly understood since sensitization has previously been evaluated as a dichotomous, rather than continuous characteristic. METHODS: Five hundred and forty-six inner-city adolescents enrolled in the Asthma Control Evaluation study underwent exhaled nitric oxide (FE(NO)) measurement, lung function testing, and completion of a questionnaire. Allergen-specific IgE levels and blood eosinophils were quantified. Dust samples were collected from the participants' bedrooms for quantification of allergen concentrations. Participants were followed for 12 months and clinical outcomes were tracked. RESULTS: Among sensitized participants, allergen-specific IgE levels were correlated with the corresponding settled dust allergen levels for cockroach, dust mite, and mouse (r = 0.38, 0.34, 0.19, respectively; P < 0.0001 for cockroach and dust mite and P = 0.03 for mouse), but not cat (r = -0.02, P = 0.71). Higher cockroach-, mite-, mouse-, and cat-specific IgE levels were associated with higher FE(NO) concentrations, poorer lung function, and higher blood eosinophils. Higher cat, dust mite, and mouse allergen-specific IgE levels were also associated with an increasing risk of exacerbations or hospitalization. CONCLUSIONS: Allergen-specific IgE levels were correlated with allergen exposure among sensitized participants, except for cat. Allergen-specific IgE levels were also associated with more severe asthma across a range of clinical and biologic markers. Adjusting for exposure did not provide additional predictive value, suggesting that higher allergen-specific IgE levels may be indicative of both higher exposure and a greater degree of sensitization, which in turn may result in greater asthma severity.

IL-10 attenuates excessive inflammation in chronic Pseudomonas infection in mice.

Cystic fibrosis (CF) lung disease is characterized by an excessive inflammatory response associated with chronic Pseudomonas aeruginosa endobronchial infection. Compared with bronchoalveolar lavage fluid from healthy subjects, lavage fluid from patients with CF contains elevated proinflammatory cytokines but negligible amounts of the anti-inflammatory cytokine interleukin-10 (IL-10). We sought to determine whether IL-10 deficiency results in increased local and systemic morbidity in mice with chronic endobronchial infection with P. aeruginosa embedded in agar beads and to determine if exogenous IL-10 might reduce these effects. Infected IL-10 knockout mice had more severe weight loss (p = 0.04) and increased area of lung inflammation (28 +/- 4 versus 10 +/- 2%, p < 0.002) but no alterations in bacterial burden compared with wild-type mice. Infected CD-1 mice treated with IL-10 had improved survival (p = 0. 035), less severe weight loss (p < 0.005), fewer bronchoalveolar lavage neutrophils (3 x 10(5)/ml versus 5 x 10(6)/ml, p < 0.02), and decreased area of lung inflammation (11 +/- 2 versus 35 +/- 7%, p < 0.01) but no alterations in bacterial burden compared with placebo-treated mice. These data suggest that IL-10 is an important regulator of the inflammatory response to P. aeruginosa endobronchial infection and that further investigation into the use of IL-10 in CF is warranted.

Pitfall in the use of genotype analysis as the sole diagnostic criterion for cystic fibrosis.

In this report, we present an asymptomatic infant, seen for a second opinion, who was given the diagnosis of cystic fibrosis (CF) as a neonate based on the presence of two mutant alleles, DeltaF508 and R117H. The diagnosis of CF adversely affected the family's emotional, employment, and financial statuses. Our evaluation included sweat chloride, nasal transepithelial potential difference, and bronchoscopy with bronchoalveolar lavage measurements, all which were consistent with findings expected from an individual without CF. Genotype analysis for the sequence polymorphism in intron 8 of the cystic fibrosis transmembrane conductance regulator (CFTR) gene revealed the 7 thymidines and 9 thymidines alleles. We conclude that this patient probably expresses enough epithelial cell surface CFTR function such that she has a normal phenotype. Based on our evaluation, she does not meet the current diagnostic criteria for CF. Although genotype analysis can be an useful adjunct, it should not be the sole diagnostic criterion for CF.

Pulmonary fibrosis and myositis in a child with anti-Jo-1 antibody.

This is the first report of a child with anti-Jo-1 antibody. At 10, she had a chronic cough, wheezing, dyspnea on exertion, a combined obstructive and restrictive ventilatory defect, and a decreased diffusion capacity compatible with alveolar fibrosis (lung biopsy). By age 12, she developed arthralgias, malar rash, frontal alopecia, Raynaud's phenomenon, and was seropositive for antinuclear antibodies, (SSA)Ro, Jo-1 and rheumatoid factor. At 16, symptomatic inflammatory myositis (elevated creatinine kinase, muscle biopsy) was documented with persistent anti-Jo-1. Her pulmonary symptoms have progressed despite appropriate therapy. Although her digits have become sausage shaped with swan neck deformities, joint pain is not frequent.

Symptom relief after endoscopic sinus surgery: an outcomes-based study.

Previous studies of patients outcomes after sinus surgery have generally described only a summary measure of overall change in symptoms or health status. This paper describes an outcomes-based longitudinal study of sinus symptom prevalence among thirty-one patients treated with endoscopic surgery for chronic sinusitis. Patients completed structured data collection forms to quantify the prevalence of commonly experienced sinus-related symptoms during an eight-week period both before surgery and six months after undergoing sinus surgery. Significant decreases in nasal symptom prevalence (post-surgery versus pre-surgery) were noted for headaches, nasal drainage, nasal congestion, sinus infection, and breathing difficulties. In addition, the proportion of subjects who rated their current health as "better" compared to one year previously increased from 27% pre-surgery to 58% six months after sinus surgery. These findings aid in quantifying the magnitude of improvement experienced by sinus surgery patients and provide further evidence that endoscopic sinus surgery represents an effective treatment for chronic sinusitis.