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BACKGROUND: IL-4 mediates important proinflammatory functions in asthma, including induction of the IgE isotype switch, increased expression of vascular cell adhesion molecule 1 and promotion of eosinophil transmigration across the endothelium, stimulation of mucus production, and T(H)2 lymphocyte differentiation, leading to release of IL-4, IL-5, IL-9, and IL-13. OBJECTIVE: The current study evaluated the therapeutic potential of inhaled recombinant human soluble interleukin-4 receptor (IL-4R) as an IL-4 antagonist. METHODS: This study was a randomized, double-blind, placebo-controlled study in 62 subjects involving 12 once weekly nebulizations of 0.75, 1.5, or 3.0 mg of IL-4R or placebo. During screening, subjects documented dependence on inhaled corticosteroids by an exacerbation in asthma induced by one or two 50% dose reductions at 2-week intervals. After restabilization for 2 weeks on the dose above which their asthma flared, inhaled steroids were discontinued, patients were randomized, and study medication was started on day 0. RESULTS: IL-4R was well tolerated. Efficacy was demonstrated by a decline in FEV(1) observed in the placebo group (-0.4 L and -13% predicted), which did not occur in the group receiving 3.0 mg of IL-4R (-0.1 L and -2% predicted; P =.05 over the 3-month treatment period). Daily patient-measured morning FEV(1) also demonstrated a significant decline in the placebo group (-0.5 L and -18% predicted), which did not occur in the group receiving 3.0 mg of IL-4R (-0.1 L and -4% predicted; P =.02 over the 3-month treatment period). The efficacy of IL-4R was further confirmed by the absence of increase in asthma symptom scores in the group receiving 3.0 mg of IL-4R (Delta 0.1) compared with that seen in the placebo group (Delta 1.4 over 1 month; P =.07). Study discontinuation for asthma exacerbation was not significantly different between groups (placebo, 56%; 3.0 mg of IL-4R, 47%; P = not significant). CONCLUSION: These promising data suggest that IL-4R is safe and effective in the treatment of moderate persistent asthma.

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UNLABELLED: Interleukin-4 mediates important proinflammatory functions in asthma, including induction of the IgE isotype switch, expression of VCAM-1 on endothelium, mucin production, 15-lipoxygenase activity, and Th2 lymphocyte stimulation leading to the secondary synthesis of IL-4, IL-5, and IL-13. Soluble recombinant human IL-4 receptor (IL-4R; Nuvance; altrakincept) inactivates naturally occurring IL-4 without mediating cellular activation. Nebulized IL-4R has a serum half-life of approximately 1 wk. In this double-blind, placebo-controlled trial, 25 patients with moderate asthma requiring inhaled corticosteroids were randomly assigned to receive a single nebulized dose of IL-4R 1,500 microg, IL-4R 500 microg, or placebo after stopping inhaled corticosteroids. No drug-related toxicity was observed. Treatment with IL-4R produced significant improvement in FEV(1) on Day 4 (1,500 microg versus placebo; p < 0.05) and in FEF(25-75) on Days 2 and 4 (1,500 microg versus placebo; p < 0.05). Asthma symptom scores stabilized among patients treated with IL-4R 1, 500 microg, despite abrupt withdrawal of corticosteroids, but not in the IL-4R 500 microg group or the placebo group (p < 0.05). Patients in the IL-4R 1,500 microg group also required significantly less beta(2)-agonist rescue use (p < 0.05). Anti-inflammatory effects were further demonstrated by significantly reduced exhaled nitric oxide (p < 0.05). CONCLUSIONS: A single dose of IL-4R appears safe and effective in moderate asthma. The 1,500 microg dose appears as safe but significantly more effective than the 500 microg dose.

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The incidence of disease caused by Mycobacterium tuberculosis (including drug-resistant strains) and M. avium complex (MAC) is increasing. Hypersensitivity reactions to antimycobacterial agents are relatively uncommon, but when they occur they may result in cessation of therapeutic medications. We report our experience with rapid oral desensitization to ethambutol and rifampin in a group of 10 patients with mycobacterial disease who had experienced cutaneous hypersensitivity reactions to these drugs. An adaptation of the rapid oral desensitization protocol for penicillin was used, with the dosing intervals increased to account for the different kinetics of these drugs. Adverse reactions were few and easily treated without necessitating cessation of therapy. We conclude that oral desensitization to rifampin and ethambutol by our protocol is safe and effective, allowing these patients to proceed with an optimal antimycobacterial regimen.

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We have found increased concentrations of granulocyte-macrophage colony-stimulating factor (GM-CSF) in the bronchoalveolar lavage fluid of 11 patients with nocturnal asthma (15.3 +/- 4.6 pg/ml) compared with normal subjects (2.3 +/- 6.1 pg/ml) (p = 0.03). In contrast to patients with asthma, low affinity IgE receptors (Fc epsilon RII or CD23) are not expressed on monocytes obtained from healthy, nonatopic donors. Fc epsilon RII expression was induced by the cytokines GM-CSF and interleukin (IL)-4 either alone or in combination. As assessed by flow cytometry, the combination of IL-4 and GM-CSF was found to be synergistic, inducing up to 54.8% +/- 4.6% Fc epsilon RII-positive monocytes compared with a maximum of 27.4% +/- 5.0% and 30.0% +/- 4.0% with IL-4 and GM-CSF alone, respectively (p < 0.05 compared with either cytokine alone). Human monocytes from the peripheral blood of seven normal subjects were cultured for 24 hours with and without IL-4 or GM-CSF. With IL-4, addition of IgE/anti-IgE complexes failed to induce IL-1 secretion and inhibited IL-1 secretion induced by lipopolysaccharides. The addition of GM-CSF or IgE immune complexes alone resulted in no additional IL-1 secretion in supernatants of the untreated monocytes, whereas the IgE complexes did stimulate IL-1 secretion by monocytes cultured in GM-CSF, as measured by ELISA (from 0.7 +/- 0.2 ng/ml to 2.3 +/- 0.5 ng/ml; p < 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

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This is the first case report of lymphangitic carcinomatosis from adenocarcinoma of the stomach presenting as interstitial lung disease in a patient with CVH. Adenocarcinoma of the stomach occurs with increased frequency and at an earlier age in CVH as compared with the normal population. This diagnosis should be kept in mind during evaluation of patients with CVH. Periodic examinations of stool for occult blood should be performed. Aggressive diagnostic evaluation should be undertaken in any CVH patient with gastric complaints, as well as careful follow-up in patients with pernicious anemia, atrophic gastritis, or achlorhydria with regard to cancer screening.

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