Advertisement

Beyond Our Pages

      Articles of note…

       Chronic productive cough predicts occurrence of chronic obstructive pulmonary disease

      A chronic productive cough is a common manifestation of chronic obstructive pulmonary disease. But is the presence of a chronic productive cough in an otherwise healthy individual predictive of the development of typical chronic obstructive pulmonary disease (COPD)? This study was a prospective evaluation of more than 5000 Italian adults (aged 20-44 years) with normal pulmonary function at baseline. By the follow-up evaluation 10 years later, COPD was present in 123 individuals. Those with a chronic productive cough at baseline were 4 times more likely to later manifest COPD. A smoking history was present in 77% of those with COPD; this compared with a 55% smoking prevalence in the entire study group. These findings confirm a common clinical impression that a chronic productive cough is often predictive of the development of full-blown COPD and may be the first manifestation of this disorder. Smoking is a definite risk factor for such development of COPD.
      (DeMarco et al. Am J Respir Crit Care Med 2007;175:32-9.)

       Hyper-IgE syndrome gene identified

      Cytokine receptors often associate with tyrosine kinases that participate in receptor activation primarily by regulating binding of signal transducer and activator of transcription proteins. Tyrosine kinase 2 (Tyk2) is a nonreceptor tyrosine kinase that belongs to the Janus kinase (Jak) family. Investigators explored the role of Tyk2 in a patient who had been clinically diagnosed with hyper-IgE syndrome. This patient showed unusual susceptibility to various microorganisms, including viruses, fungi, and mycobacteria, and had atopic dermatitis with elevated serum IgE. The patient's cells displayed defects in multiple cytokine signaling pathways, including those for type I interferon, IL-6, IL-10, IL-12, and IL-23. Notably, the patient was demonstrated to have a homozygous deletion of 4 nucleotides in the Tyk2 gene; conversely, transduction of the patient's cells with the Tyk2 gene restored the cytokine signaling pathways. Thus, Tyk2 deficiency is likely to account for the patient's complex clinical manifestations, including the phenotype of impaired TH1 differentiation and accelerated TH2 differentiation. This study identifies human Tyk2 deficiency and demonstrates that Tyk2 plays obligatory roles in multiple cytokine signals involved in innate and acquired immunity. As such, genetic mutations in Tyk2 (or single nucleotide polymorphisms) are likely to significantly contribute to IgE-associated diseases.
      (Minegishi et al. Immunity 2006;25:745-55.)

       Antibiotic use leads to microbial resistance

      It has long been believed that frequent use of antibiotic treatment leads to increased resistance to such antibiotics in the bacteria isolated from treated individuals. However, the evidence supporting this concept has generally been indirect. This randomized, double-blind study compared the effects of daily treatment with the macrolide antibiotics azithromycin and clarithromycin versus placebo on the Streptococcus species subsequently present in the oropharynx of treated individuals. The authors found that within 8 days of treatment with either azithromycin or clarithromycin, there was a 50% to 53% increase in the resistance to these macrolides of Streptococcus species present in the oropharynx. There was also a significant alteration in the pattern of nonpathogenic normal flora at 8 days in such macrolide-treated individuals. In contrast, there was no increase in the resistance of streptococci in the placebo-treated individuals. These findings offer direct and sobering evidence that relatively short-term treatment with 2 commonly used antibiotics can lead to significant bacterial resistance to subsequent treatment.
      (Malhotra-Kumar et al. Lancet 2007;369:482-90.)

       Twitchy macrophages and obesity

      Obesity is associated with low-grade inflammation that is thought to contribute to insulin resistance, at least in part. Mechanistically, adipose tissue macrophages (ATMs) are thought to contribute to this process. Now, investigators aimed to test the effect of a high-fat diet on ATMs. A novel F4/80+CD11c+ population of ATMs in adipose tissue of obese mice (not seen in lean mice) was observed. Whereas ATMs from lean mice expressed many genes characteristic of M2 or “alternatively activated” macrophages (eg, Ym1, arginase 1, and IL-10), obese mice expressed ATM genes characteristic of M1 or “classically activated” macrophages (TNF-α and inducible nitric oxide synthase). To prove the potential importance of this ATM switch, the anti-inflammatory cytokine IL-10, which was overexpressed in M2 ATMs, was demonstrated to protect adipocytes from insulin resistance. Thus, diet-induced obesity leads to a shift in the activation state of ATMs from an M2-polarized state in lean animals that may protect adipocytes from inflammation to an M1 proinflammatory state that contributes to insulin resistance. Because M2 macrophages are induced by TH2 cytokines (IL-4 and IL-13), these results have implications for allergic responses.
      (Lumeng et al. J Clin Invest 2007;117:175-84.)

       Incidence of angioedema with different antihypertension treatments

      Questions have been raised as to whether the angioedema that occurs in a small percentage of individuals treated with angiotensin-converting enzyme inhibitor (ACEI) agents may also occur during treatment with other antihypertension drugs. This study analyzed the occurrence of angioedema in a large hypertensive study population in which the clinical effects of ACEI were compared with those of other antihypertension treatments. They found that angioedema occurred in 53 (0.13%) of 42,418 studied patients. Of the 53 individuals, 70% were receiving lisinopril (an ACEI), 15% received chlorthalidone (a diuretic), 9% received doxazosin (an alpha blocker), and 6% received amlodipine (a Ca++ channel blocker). These findings are in line with those of smaller studies indicating that angioedema occurs in less than 1% of individuals receiving antihypertension treatment. The majority of such angioedema episodes occur in those treated with ACEI. Unfortunately, this study did not include a comparison with treatment with the commonly used angiotensin receptor blocker drugs. However, in another study, angioedema occurred during angiotensin receptor blocker drug therapy in only 2 of 26 patients who had previously manifested angioedema during treatment with ACEI (Arch Intern Med 2004;164:910-3). In a more recent smaller study, none of 6 patients with ACEI-induced angioedema manifested angioedema with angiotensin receptor blocker therapy (Ann Allergy Asthma Immunol 2007;98:57-63). It is still not known exactly why angioedema occurs in a small minority of ACEI-treated patients but not in others.
      (Diller et al. J Clin Hypertension 2006;8:649-56.)

       Finding fungus

      Innate immune responses are mediated by germline-encoded pattern-recognition receptors present on dendritic cells, phagocytes, and epithelial cells. In the case of fungal infections, β-glucans, carbohydrate polymers located within the cell wall, are critical activators of innate immunity. Now, 2 teams of investigators have explored the β-glucan receptor dectin-1 by generating independent genetically deficient mice. Dectin is a type II transmembrane C-type lectin-like receptor that expresses an immunoreceptor tyrosine-based activation motif. In one set of experiments, dectin-1–deficient mice were shown to have an impaired response to Candida albicans, and dectin-1–deficient leukocytes demonstrated impaired responses to fungi, even in the presence of opsonins. In the other set of experiments, dectin-1–deficient mice were shown to be more susceptible than wild-type mice to pneumocystis infection, even though their cytokine response was unaffected. Collectively, these results demonstrate that dectin-1 is a bona fide innate immune receptor required for the killing of different fungal pathogens.
      (Taylor et al. Nat Immunol 2007;8:31-8.
      Saijo et al. Nat Immunol 2007;8:39-46.)

       Effects of smoking on responses to therapy in patients with asthma

      It is generally believed that smoking adversely affects the course of persistent asthma. But does smoking alter the responses to controller asthma treatment agents? This placebo-controlled, double-blind, double-dummy, crossover trial compared the responses to treatment with the inhaled corticosteroid beclomethasone and the leukotriene receptor antagonist montelukast in 83 light smoker and nonsmoker adults with persistent mild asthma. At baseline, the FEV1 response to β-agonist bronchodilators and bronchial reactivity to inhaled methacholine were similar in the smoking and nonsmoking patients with asthma. However, the smokers had significantly more symptoms, worse quality of life, and lower daily peak flow rates than nonsmokers. Following treatment with beclomethasone, the sputum eosinophilia was reduced to similar degree in both groups, but the FEV1 improved significantly only in the nonsmokers (P = .0003). Somewhat surprisingly, treatment with montelukast led to a significant improvement in peak flow rates in smokers (P = .002) but not in nonsmokers. The authors concluded that beneficial airflow responses to inhaled corticosteroids are diminished in smokers even though reduction of sputum eosinophils is not significantly affected in such smokers. This finding raises questions about whether other effects are involved in the improvement of the FEV1 with inhaled corticosteroid treatment. The improved peak flow rate in smokers following montelukast therapy warrants further investigation to determine whether leukotriene antagonists can be recommended for managing asthma in patients who smoke.
      (Lazarus et al. Am J Respir Crit Care Med 2007 Jan 4 [epub ahead of print].)