Classifying asthma severity in children: mismatch between symptoms, medication use, and lung function

Current guidelines for asthma care categorize asthma severity based on the frequency of asthma symptoms, medication use, and lung function measures. The objective of this study was to determine whether lung function measures are consistent with levels of asthma severity as defined by the National Asthma Education and Prevention Program/Expert Panel Report 2 Guidelines. Parents of children aged 5-18 years with asthma seen in two outpatient subspecialty clinics completed questionnaires regarding asthma medication use and symptom frequency over the preceding 1 and 4 weeks, respectively. All children performed spirometry. When asthma severity was based on the higher severity of asthma symptom frequency or medication use, asthma was mild intermittent in 6.9% of participants, mild persistent in 27.9%, moderate persistent in 22.4%, and severe persistent in 42.9%. FEV(1) % predicted did not differ by level of asthma severity. FEV(1)/FVC decreased as asthma severity increased (p < 0.0001) and was abnormal in 33% of the participants, and a greater percentage of participants had an abnormal FEV(1)/FVC as asthma severity increased (p = 0.0001). In children, asthma severity classified by symptom frequency and medication usage does not correlate with FEV(1) categories defined by National Asthma Education and Prevention Program Guidelines. FEV(1) is generally normal, even in severe persistent childhood asthma, whereas FEV(1)/FVC declines as asthma severity increases.     

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本文摘自著名药学专家金有豫教授指导、北京药学会组织专家编译的内部学习资料《呼吸系统疾病的药物治疗》一书。本刊2006年第五期曾经刊载了部分内容,本期继续刊载有关章节,供广大临床药师和医师学习参考。为方便读者与文献原文对照,我们在译文中保留了原文的所有序号。     

Noninvasive mapping of regional response to segmental allergen challenge using magnetic resonance imaging and [F-18]fluorodeoxyglucose positron emission tomography.

Magnetic resonance (MR) and positron emission tomography (PET) imaging techniques were coregistered to demonstrate regional ventilation and inflammation in the lung for in vivo, noninvasive evaluation of regional lung function associated with allergic inflammation. Four Brown Norway rats were imaged pre- and post segmental allergen challenge using respiratory-gated He-3 magnetic resonance imaging (MRI) to visualize ventilation, T(1)-weighted proton MRI to depict inflammatory infiltrate, and [F-18]fluorodeoxyglucose-PET to detect regional glucose metabolism by inflammatory cells. Segmental allergen challenges were delivered and the pre- and postchallenge lung as well as the contralateral lung were compared. Coregistration of the imaging results demonstrated that regions of ventilation defects, inflammatory infiltrate, and increased glucose metabolism correlated well with the site of allergen challenge delivery and inflammatory cell recruitment, as confirmed by histology. This method demonstrates that fusion of functional and anatomic PET and MRI image data may be useful to elucidate the functional correlates of inflammatory processes in the lungs.     

Pulmonary antigen challenge in rats passively sensitized with a monoclonal IgE antibody induces immediate but not late changes in airway mechanics

Pulmonary antigen challenge in sensitized individuals results in isolated immediate, isolated late, or dual reactions consisting of both an immediate and late change in airway function. The immediate response appears to be dependent on the presence of IgE antibody and mast cell mediator release. Although the late phase of dual responses is considered to be related to or a continuum of the immediate hypersensitivity response, its precise pathogenesis remains to be determined. To increase both the sensitivity and specificity of analyzing the pathogenesis of IgE-dependent pulmonary responses, we have used a Sprague-Dawley rat model system in which rats are passively sensitized with a murine monoclonal IgE anti-dinitrophenol (DNP) antibody prior to challenge with DNP-bovine serum albumin (DNP-BSA). Pathogen-free rats were injected with IgE or saline in a randomized blinded protocol, and in 24 to 48 h were anesthetized with urethane (1.2 g/kg intraperitoneally) and instrumented to measure lung resistance (RL) and dynamic compliance (Cdyn). Rats were then challenged with aerosolized DNP-BSA (10 mg/ml), and RL and Cdyn monitored through 7 h after challenge. Both RL (0.30 +/- 0.10 versus 0.13 +/- 0.02 cm H2O/ml.sec-1) and Cdyn (0.41 +/- 0.10 versus 0.25 +/- 0.08 ml/cm H2O) were significantly different (p less than 0.05) in sensitized rats compared to control rats immediately after challenge. No late changes were observed in either the treated or control animals.(ABSTRACT TRUNCATED AT 250 WORDS)     

Analgesia with oral narcotics and added ibuprofen in cancer patients

A scheduled regimen of oral narcotic analgesics was compared with a regimen of oral narcotic analgesics plus ibuprofen for analgesic efficacy in patients with cancer. Ten patients with metastatic cancer were randomly assigned to receive either ibuprofen 400 mg or a look-alike placebo four times daily in addition to each patient's existing regimen of scheduled oral narcotics. A two-period changeover study design was used. The 24-hour narcotic intake equated to injectable morphine was computed for each patient at baseline and during the nine study days. A visual analogue scale was used to evaluate pain relief, nausea, mood depression, daytime drowsiness and nighttime sleeplessness. The analgesic efficacy of the narcotic-ibuprofen combination was significantly greater than the analgesic efficacy of the narcotic-placebo combination. Eight patients demonstrated a positive treatment effect with added ibuprofen; the overall improvement in analgesia averaged 39.1% in these patients. There was no significant increase from baseline in the incidence of nausea, mood depression, daytime drowsiness or nighttime sleeplessness. At the doses used in this study, a treatment regimen of oral narcotic analgesics plus ibuprofen was more effective than oral narcotics alone in relieving pain associated with cancer.     

Chronic postbronchiolitis airway instability induced with anti-IFN-gamma antibody in F344 rats

Analogous to childhood-onset asthma in humans, rats may develop a chronic asthmalike phenotype, depending on their genetic background and the age at which they experience a viral airway injury. Brown Norway rats develop a postbronchiolitis asthmalike phenotype that may be prevented with supplements of interferon-gamma (IFN-gamma); we hypothesized that the normally resistant F344 rat strain would develop the asthmalike phenotype if the IFN-gamma response were suppressed during viral illness. Weanling F344 rats were pretreated with anti-IFN-gamma or control antibody, and inoculated with Sendai virus or vehicle. Anti-IFN-gamma treatment reduced lung IFN-gamma and increased IL-4 mRNA during the infection. Physiologic studies performed 8 wk later revealed premature airway closure (p = 0.03) and elevated specific pulmonary resistance (p < 0.01) in the postbronchiolitis anti-IFN-gamma group compared with noninfected controls and untreated postbronchiolitis rats. However, unlike the postbronchiolitis asthmalike phenotype in Brown Norway rats, bronchiolar inflammation and fibrosis were absent in the F344 rats. Lung elastic recoil and alveolar surface density also were unchanged compared with noninfected control rats. We conclude that there is an interactive effect of a weak IFN-gamma response and viral bronchiolitis at an early age that may result in persistent postbronchiolitis airway dysfunction. The presence of premature airway closure that is independent of airway wall inflammation or changes in lung elastic recoil suggests peripheral airway instability as a mechanism for the airway obstruction.     

Persistence of viral RNA in 2 rat strains differing in susceptibility to postbronchiolitis airway dysfunction

After viral bronchiolitis at an early age, a chronic asthma-like syndrome develops in BN, but not F344, rats. We hypothesized that the BN strain is less effective at clearing virus from the involved tissues. Weanling BN and F344 rats were inoculated with Sendai virus, and lung and peribronchial lymph nodes were harvested from each strain at 5 to 84 days after infection; control tissues were obtained from noninfected rats. Lung viral titers were similar for the 2 strains, with no infectious virus detectable by day 10. However, viral RNA was detected consistently by means of RT-PCR analyses in lungs and lymph nodes of both strains from days 10 to 27 and was still present at day 84 in some of the tissues from each strain. In contrast, there were strain-related differences in immune responses because IL-13 levels remained increased in the lung secretions of BN rats at 4 weeks after inoculation. Thus although Sendai virus could persist for at least 3 months after an acute infection in rats, this did not differ with strain. The persistent increase in IL-13 suggests instead that the strain-related variability in virus-associated airway pathology might be determined by the host response to infection rather than by the intensity or duration of infection.     

Viral bronchiolitis during early life induces increased numbers of bronchiolar mast cells and airway hyperresponsiveness.

The objectives of this study were to determine the kinetics of Sendai virus-induced increases in bronchiolar mast cells and to determine whether virus-induced increases in bronchiolar mast cells were associated with increased airway responsiveness to methacholine and with altered allergic inflammatory responses to antigen stimulation. Mast cell density in intrapulmonary airways was measured in outbred CD (Crl:CDBR) rats by use of morphometric techniques at 7, 15, 30, 60, and 90 days after viral or sham inoculation. Density of bronchiolar mast cells was higher in virus-inoculated rats than in control rats at 30, 60, and 90 days after inoculation (P less than 0.01), but not at 7 or 15 days after inoculation. Total pulmonary mast cell numbers were increased in virus-inoculated rats at 30 days after inoculation. Rats at 42 days after viral inoculation had over a threefold increase in sensitivity to the concentration of nebulized metbacholine that would stimulate a 50% increase in respiratory resistance. Virus-inoculated rats sensitized to ovalbumin had over a 10-fold increase (P less than 0.02) in pulmonary neutrophils that were recovered by bronchoalveolar lavage at 4 hours after ovalbumin aerosol challenge. Virus-inoculated rats at this time also had higher densities of neutrophils in bronchiolar walls than allergen-exposed control rats. The results indicate that Sendai virus induces increases in numbers of bronchiolar mast cells at times from 30 to 90 days after inoculation, and that mast cell increases are associated with airway hyperresponsiveness to methacholine and heightened allergic airway inflammatory reactions.