A randomized double blind, placebo controlled phase 2 trial of BIIL 284 BS (an LTB4 receptor antagonist) for the treatment of lung disease in children and adults with cystic fibrosis.

BACKGROUND: Airway inflammation, mediated in part by LTB4, contributes to lung destruction in patients with cystic fibrosis (CF). LTB(4)-receptor inhibition may reduce airway inflammation. We report the results of a randomized, double-blind, placebo-controlled study of the efficacy and safety of the leukotriene B(4) (LTB(4))-receptor antagonist BIIL 284 BS in CF patients. METHODS: CF patients aged ≥6 years with mild to moderate lung disease were randomized to oral BIIL 284 BS or placebo once daily for 24 weeks. Co-primary endpoints were change in FEV(1) and incidence of pulmonary exacerbation. RESULTS: After 420 (155 children, 265 adults) of the planned 600 patients were randomized, the trial was terminated after a planned interim analysis revealed a significant increase in pulmonary related serious adverse events (SAEs) in adults receiving BIIL 284 BS. Final analysis revealed SAEs in 36.1% of adults receiving BIIL 284 BS vs. 21.2% receiving placebo (p = 0.007), and in 29.6% of children receiving BIIL 284 BS vs. 22.9% receiving placebo (p = 0.348). In adults, the incidence of protocol-defined pulmonary exacerbation was greater in those receiving BIIL 284 BS than in those receiving placebo (33.1% vs. 18.2% respectively; p = 0.005). In children, the incidence of protocol-defined pulmonary exacerbation was 19.8% in the BIIL 284 BS arm, and 25.7% in the placebo arm (p = 0.38). CONCLUSIONS: While the cause of increased SAEs and exacerbations due to BIIL 284 BS is unknown, the outcome of this trial provides a cautionary tale for the administration of potent anti-inflammatory compounds to individuals with chronic infections, as the potential to significantly suppress the inflammatory response may increase the risk of infection-related adverse events.

Inflammatory cytokines in cystic fibrosis lungs.

Chronic pulmonary infection with Pseudomonas aeruginosa continues to be the major cause of morbidity and mortality in cystic fibrosis (CF). Several characteristics of CF, including the excessive influx of neutrophils into the airways, cachexia, and hyperglobulinemia, could reflect the effects of cytokines, such as interleukin-1 (IL-1), IL-6, IL-8, and tumor necrosis factor (TNF-alpha). We hypothesized that these pro-inflammatory cytokines, produced by alveolar macrophages in response to pseudomonas and/or other microorganisms, promote the destructive inflammatory process in the lung. We evaluated bronchoalveolar lavage (BAL) fluid and BAL macrophages from 22 CF patients and 13 healthy control (HC) subjects, measuring soluble TNF-alpha, IL-1 beta, IL-6, and IL-8 and the regulatory molecules TNF soluble receptor (TNF-sR), IL-1 receptor antagonist (IL-1Ra), and IL-10 (cytokine synthesis inhibitory factor). Levels of the proinflammatory cytokines were higher in CF versus HC BAL (p < or = 0.05 for IL-1, TNF, and IL-8; p = 0.06 for IL-6). In contrast, HC BAL contained significantly more IL-10 than CF BAL (p < 0.05), but TNF-sR and IL-1Ra were similar. Immunocytochemistry demonstrated a higher percentage of CF than control BAL macrophages expressing intracellular cytokines (p < 0.05). Thus, enhanced macrophage production of proinflammatory cytokines and decreased production of the regulatory molecule IL-10 may have important roles in the pathogenesis of CF lung disease.

Bronchoalveolar lavage findings in cystic fibrosis patients with stable, clinically mild lung disease suggest ongoing infection and inflammation.

To determine the extent of airway infection and inflammation in adolescents and adults with cystic fibrosis (CF) who have mild lung disease and are without symptoms of active infection, we performed bronchoalveolar lavage (BAL) on 18 CF patients > or = 12 yr of age who were stable, appeared clinically well, and had mean (+/- SEM) FEV1 of 79 +/- 4% of predicted. We quantitated the bacteria, inflammatory cells, immunoglobulins, and mediators of inflammatory tissue damage in the epithelial lining fluid (ELF) of these patients and in 23 healthy control subjects. All CF patients were found to be infected with Pseudomonas aeruginosa, Staphylococcus aureus, and/or Haemophilus influenzae; no organisms were isolated from the control subjects. The mean number of cells in the ELF was 14 times greater in the CF patients than in the control subjects. Neutrophils constituted 57% of the recovered cells in the CF patients versus 3% in the control subjects, and their concentration was 380 times greater in the CF patients versus the control subjects. IgG, IgA, and IgM were 2.5 to 6 times greater in CF ELF versus that of control subjects. Abundant active elastase was present in the ELF of the CF patients (2.3 +/- 0.9 microM) despite threefold elevated levels of alpha 1-protease inhibitor (alpha 1-PI). No active elastase was detectable in the control subjects. alpha 1-PI was functional in CF as demonstrated by elevated elastase:alpha 1-PI complex (0.045 microM in CF versus 0.002 microM in control subjects). This active elastase caused proteolytic destruction of surface complement receptors on airway neutrophils in situ.(ABSTRACT TRUNCATED AT 250 WORDS)

Leukotriene B4 markedly elevated in the epithelial lining fluid of patients with cystic fibrosis.

Persistent neutrophil infiltration into the airways of patients with cystic fibrosis (CF) results in lung destruction. Eicosanoid lipid mediators, particularly leukotriene B4 (LTB4), may play a role in neutrophil influx and activation. We compared the eicosanoid content of epithelial lining fluid (ELF) obtained by bronchoalveolar lavage (BAL) from 17 patients with CF and 10 healthy subjects. LTB4 was the predominant eicosanoid in the CF airway (16.7 +/- 9.1 ng/ml ELF in CF versus 0.5 +/- 0.1 ng/ml ELF in healthy subjects). Prostaglandins (PG) and thromboxane (TX) were also elevated in CF (PGE2, 8.5 +/- 2.2; PGF2 alpha, 6.0 +/- 2.0; and TXB2, 14.0 +/- 3.0 ng/ml ELF) compared with healthy subjects (PGE2, 0.4 +/- 0.2; PGF2 alpha, 0.5 +/- 0.2; and TXB2, 1.2 +/- 0.4 ng/ml ELF). We also developed a protocol for the storage and subsequent analysis of BAL fluid that assures accurate and reproducible measurements of these eicosanoids. BAL samples stored for up to 8 months retain greater than 80% of their original eicosanoid content if the BAL fluid is immediately treated with methanol, concentrated, and stored at -70 degrees C without further purification. These data suggest that CF airways contain sufficient amounts of LTB4 both to recruit additional neutrophils into the airways and to stimulate neutrophils to release their injurious products. Therapies aimed at interfering with the production or action of LTB4 may be beneficial in CF and other lung diseases with a significant neutrophil response.

Serosurvey for "acute hemorrhagic conjunctivitis" virus (Enterovirus 70) antibodies in the Southeastern United States, with review of the literature and some epidemiologic implications.

Acute hemorrhagic conjunctivitis (AHC) has been epidemic throughout much of the Eastern Hemisphere since its emergence in central West Africa in 1969. The disease had a distinctive clinical picture and an unusual geographic epidemiology. Between 1969 and 1975 AHC has occurred almost exclusively in crowded coastal areas of tropical countries during hot, rainy seasons. Only a few documented outbreaks have occurred in inland cities and in subtropical or temperate climate zones. Of 1014 residents of the eastern or southeastern United States who were screende for neutralizing antibodies to three or four strains of AHC virus (enterovirus type 70), three (0.3%) had titers ranging from 1:10 to 1:40. However, no clinical evidence of prior experience with AHC disease could be ascertained for these persons, so that the antigenic specificity of the detected antibodies is unknown. We conclude that populations of coastal tropical areas of northern South America and all of Central America are vulnerable to AHC epidemics.