ASTHMA

 

Diagnosis, Diagnostics, Immunodiagnosis & Immunodiagnostics:

 

 

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January 2003 

 

5943.      Alonso-Llamazares A, Martinez-Cocera C, Dominguez-Ortega J, Robledo-Echarren T, Cimarra-Alvarez M, Mesa del Castillo M.  Nasal provocation test (NPT) with aspirin: a sensitive and safe method to diagnose aspirin-induced asthma (AIA). Allergy. 2002 Jul;57(7):632-5.

 

BACKGROUND: We have aimed to determine the sensitivity and specificity of a simpler technique with less risk than oral provocation to diagnose aspirin-induced asthma (AIA). METHODS: We studied a group of 20 AIA patients compared to a control group with 40 aspirin-tolerant patients (confirmed by oral provocation test): 10 asthmatic patients and 30 healthy subjects. A nasal provocation test (NPT) with lysine acetylsalicylic acid (L-ASA) was carried out. Nasal and pulmonary functions were monitored with anterior active rhinomanometry (AAR) and spirometry. An L-ASA solution (900 mg/ml L-ASA, equivalent to 500 mg/ml acetylsalicylic acid) was diluted with saline solution. We administered four increasing doses: 5, 25, 50 and 100 mg/ml acetylsalicylic acid (ASA) with saline solution control. Nasal and pulmonary functions were monitored with rhinomanometry and spirometry. The patients were controlled for nasal inspiratory peak flow and expiratory peak flow. RESULTS: The results showed high sensitivity and specificity: 80% and 92.5%, respectively, with an 84.2% positive predictive value and an 89.2% negative predictive value. The patients had no bronchial or systemic symptoms, and no decreases over 20% were recorded in the FEV1. CONCLUSION: NPT has a high sensitivity and specificity in the diagnosis of AIA. An oral provocation should be performed to confirm the result whenever the clinical situation of the patient permits it.

5944.      Benn CS, Thorsen P, Jensen JS, Kjaer BB, Bisgaard H, Andersen M, Rostgaard K, Bjorksten B, Melbye M.  Maternal vaginal microflora during pregnancy and the risk of asthma hospitalization and use of antiasthma medication in early childhood. J Allergy Clin Immunol. 2002 Jul;110(1):72-7.

 

BACKGROUND: Infants with wheezing and allergic diseases have a microflora that differs from that of healthy infants. The fetus acquires microorganisms during birth when exposed to the maternal vaginal microflora. It is therefore conceivable that the maternal vaginal microflora might influence the establishment of the infant flora and, as a consequence, the development of wheezing and allergic diseases. OBJECTIVE: We sought to study the associations between the composition of the maternal vaginal microflora and the development of wheezing and asthma in childhood. METHODS: We performed a population-based cohort study in Denmark. Vaginal samples for bacterial analysis were obtained during pregnancy. A total of 2927 women (80% of the invited women) completed the study and had 3003 live infants. Infant wheezing was assessed as one or more hospitalizations for asthma between 0 and 3 years of age. Asthma was assessed as use of 3 or more packages of antiasthma medication between 4 and 5 years of age. RESULTS: Maternal vaginal colonization with Ureaplasma urealyticum during pregnancy was associated with infant wheezing (odds ratio [OR], 2.0; 95% CI, 1.2-3.6), but not with asthma, during the fifth year of life. Maternal colonization with staphylococci (OR, 2.2; 95% CI, 1.4-3.4) and use of antibiotics in pregnancy (OR, 1.7; 95% CI, 1.1-2.6) were associated with asthma during the fifth year of life. CONCLUSION: The composition of the maternal vaginal micro-flora might be associated with wheezing and asthma in the offspring up to 5 years of age.

 

5945.      Boulay ME, Boulet LP. Influence of natural exposure to pollens and domestic animals on airway responsiveness and inflammation in sensitized non-asthmatic subjects. Int Arch Allergy Immunol. 2002 Aug;128(4):336-43.

 

BACKGROUND: Atopy may be a risk factor in the development of asthma. Indoor allergens are considered to be more potent asthma inducers than outdoor ones such as pollens. Lower airway inflammation may be present in non-asthmatic subjects during natural exposure to relevant allergens and may eventually lead to the development of asthma. AIMS: To document seasonal variation in lower airway responsiveness and inflammation in sensitized non-asthmatic subjects, during natural exposure to allergens, and to determine whether it is more marked in those exposed to animals to which they are sensitized. METHODS: Twenty-two atopic subjects were seen during and out of the pollen season. All (but the controls) were sensitized to domestic animals, and to trees, grasses or ragweed. Eleven were not exposed to animals at home and 8 were exposed. They were compared with 3 normal controls. A respiratory questionnaire was administered, allergy skin prick tests, spirometry, methacholine challenge, blood and induced sputum with differential cell counts were obtained during the pollen season for all subjects. These tests were repeated out of the pollen season. RESULTS: Throughout the study, none of the subjects had asthma symptoms. Mean PC(20) was significantly lower in subjects exposed to animals compared with unexposed subjects or controls, both during and out of the pollen season. In season, subjects exposed to animals had significantly higher sputum eosinophil numbers than unexposed or normal control subjects. CONCLUSIONS: Non-asthmatic atopic subjects show variable degrees of airway responsiveness and inflammation. However, subjects exposed to animals show higher airway eosinophilia, which may suggest they are at increased risk of developing airway hyperresponsiveness and asthma. Copyright 2002 S. Karger AG, Basel

5946.      Celedon JC, Litonjua AA, Ryan L, Platts-Mills T, Weiss ST, Gold DR. Exposure to cat allergen, maternal history of asthma, and wheezing in first 5 years of life. Lancet. 2002 Sep 7;360(9335):781-2.

 

We looked for an association between early exposure to pets and asthma and wheezing in children whose mothers or fathers did or did not have a history of asthma. We followed up 448 children, who had at least one parent with a history of atopy, from birth to 5 years. Among children whose mothers had no history of asthma, exposure to a cat or a Fel d 1 concentration of at least 8 microg/g at the age of 2-3 months was associated with a reduced risk of wheezing between the ages of 1 and 5 years. However, among children whose mothers did have a history of asthma, such exposures were associated with an increased risk of wheezing at or after the age of 3 years. There was no association between wheezing and exposure to dog or dog allergen, and the father's allergy status had no effect on the relation between childhood wheezing and cat exposure.

5947.      Currie GP, Lipworth BJ. Bronchoprotective effects of leukotriene receptor antagonists in asthma: a meta-analysis. Chest. 2002 Jul;122(1):146-50.

 

STUDY OBJECTIVE: Cysteinyl leukotrienes are important proinflammatory mediators in the pathogenesis of asthma. Since bronchial hyperresponsiveness is a noninvasive surrogate marker of asthmatic airway inflammation, we evaluated the bronchoprotection afforded by leukotriene receptor antagonists (LTRAs). DESIGN: Systematic review of randomized, placebo-controlled trials in which LTRAs were administered for >or= 5 days. Studies in which active drug was administered as a first-line or second-line therapy were used. SETTING: MEDLINE, BIDS, and Cochrane Library data registers. MEASUREMENTS: The doubling dose/dilution difference that caused a 20% fall in the FEV(1) between LTRA and placebo. RESULTS: Thirteen trials (353 subjects) fulfilled eligibility criteria. Combining the results the overall weighted estimated protection amounted to a 0.85 doubling dose shift (95% confidence interval, 0.69 to 1.02). CONCLUSION: Since the estimated protection amounted to almost one doubling dose, this reinforces the role of LTRAs as anti-inflammatory therapy in asthma.

5948.      Frieri M, Therattil J, Dellavecchia D, Rockitter S, Pettit J, Zitt M. A preliminary retrospective treatment and pharmacoeconomic analysis of asthma care provided by allergists, immunologists, and primary care physicians in a teaching hospital. J Asthma. 2002 Aug;39(5):405-12.

 

Allergy immunology specialists (AIs) differ from primary care physicians (PCP) in their treatment of asthma. A limited retrospective chart review of several visits over a 1-year period in 1997 evaluating the quality of asthma care by Ais vs. PCPs was conducted in an academic center. Data concerning quality, effectiveness and cost of asthma care was randomly collected from 15 AIs and 15 PCPs from charts at 3-month intervals over a 1-year period. Information obtained from data collection forms revealed that asthma patients evaluated by AIs had more visits and received a greater quantity of medication compared to those treated by PCPs. All 15 patients with persistent asthma followed by AIs were treated with inhaled corticosteroids at each visit in contrast to only 80% of those treated by PCPs. The total numbers of controller medications (i.e., inhaled corticosteroids, salmeterol, cromolyn, and theophylline) that were utilized, as recommended, by the National Asthma Expert Panel (NAEP) of the National Heart, Lung, and Blood Institute (NHLBI) guidelines were 70 by Ais vs. 24 by PCPs over three visits. Cromolyn was prescribed five times over three visits by AIs and not at all by PCPs. Recognition and treatment of coexisting allergic rhinitis was evident in only 13% of patients treated by PCPs as compared to 80% in those treated by AIS. (p < 0.0001). However, all patients treated by AIs were skin tested to explore the presence of allergic triggers, while no patients treated by PCPs were evaluated for IgE-mediated reactions. Treatment cost for allergic rhinitis was therefore higher, at $2039, for AIs as compared to $741 for PCPs. There were no peakflow values in charts obtained from PCPs. However, all charts from AIs had peakflow values, which improved during the course of therapy in 33% of patients. Total medication costs for asthma were higher for AIs @ $5,646.30 vs. $1,932.25 for PCPs. Total medication costs for allergic rhinitis plus asthma were higher for AIs @ $7615 vs. $2681 for PCPs. However, patients treated by AIs had more severe asthma and required more frequent visits. Ipratropium bromide was prescribed a total of four times over several visits by PCPs vs. only once by AIs. In comparing asthma care between AI specialists and PCPs, it was found that AI specialists treat more severe asthmatics, provide more frequent follow-up visits, utilize peak flow rates, prescribe more controller medications, and more often recognize and treat comorbid conditions such as allergic rhinitis that impact on asthma care. Thus, although treatment costs for AIs are higher, these costs are justified by a quality of care that is more consistent with national (NHLBI) guidelines.

5949.      Graif Y, Yigla M, Tov N, Kramer MR. Value of a negative aeroallergen skin-prick test result in the diagnosis of asthma in young adults: correlative study with methacholine challenge testing. Chest. 2002 Sep;122(3):821-5.

 

 

BACKGROUND: None of the existing tests for the diagnosis of asthma are

- considered to be definitive. Certain circumstances require prompt diagnosis, and a test able to predict the absence of asthma would be very useful. OBJECTIVE: To evaluate the contribution of a skin-prick test (SPT) to the diagnostic workup of subjects with suspected asthma. PATIENTS AND METHODS: The study included three groups of subjects aged 18 to 24 years: group A, asthmatic patients (n = 175); group B, control subjects (n = 100); and group C, subjects with suspected asthma (n = 150) with normal spirometry findings and a negative exercise challenge test result. All underwent an SPT to a battery of common aeroallergens, and group C underwent a methacholine challenge test (MCT) in addition. The sensitivity, specificity, positive predictive value, and negative predictive values (NPV) of the SPT were calculated using provocative concentrations of methacholine causing a 20% fall in FEV(1) (PC(20)) of < 4 mg/mL and < 8 mg/mL as diagnostic cutoff values for asthma in the MCT. Bayes' formula was used to determine posttest probabilities of having asthma, both for positive and negative SPT results. RESULTS: A positive SPT result to at least one allergen was found in 95.5%, 54%, and 69% of patients in the three groups, respectively. The sensitivity, specificity, and NPV of the SPT were 90.7%, 52.0%, and 84.8%, respectively, with a cutoff value of PC(20) < 8 mg/mL. The lower cutoff, PC(20) < 4 mg/mL, increased the sensitivity and NPV to 98.2% and 97.8%, respectively. A negative SPT result decreased the probability of having asthma by 10-fold to 20-fold in subjects whose pretest probability was low to moderate. CONCLUSIONS: Incorporating an SPT into the workup of subjects with suspected asthma can reduce the cost of this process significantly. The SPT may be used as a simple, fast, safe, inexpensive, and reliable method to predict the absence of asthma in young adults.

5950.      Jogi R, Bjorksten B, Boman G, Janson C. Serum eosinophil cationic protein (S-ECP) in a population with low prevalence of atopy. Respir Med. 2002 Jul;96(7):525-9.

 

The study is a part of the European Community Respiratory Health Survey. A random sample (n = 351) of 20-44-year olds and persons of the same age with asthma-like symptoms or current asthma medication according to a postal questionnaire (n = 95) were studied. Interview was taken, methacholine challenge was done and ECP, total and specific IgE were measured from serum. The median S-ECP value was 8.0 micrograms/l in the random sample. The geometric mean of S-ECP was higher in subjects with, than without atopy (10.2 vs 8.9 micrograms/l, P < 0.01) and in subjects with bronchial hyperresponsiveness (BHR) than in subjects without BHR (9.9 vs 8.0 micrograms/l, P < 0.01). The levels correlated weakly to forced expiratory volume in one second (FEV1) (r = 0.13, P < 0.01) and were not independently correlated with respiratory symptoms, asthma or FEV1 after adjusting for BHR, IgE, sensitisation and smoking. Our results indicate that the level of eosinophil activation is low in a population with a low prevalence of atopy, even when BHR is common.

5951.      Kalpaklioglu AF, Turan M. Possible association between cockroach allergy and HLA class II antigens. Ann Allergy Asthma Immunol. 2002 Aug;89(2):155-8.

 

BACKGROUND: Susceptibility to the development of allergic diseases is known to be associated with genetic components, as well as environmental factors.

-Although the genetics of immunoglobulin E, atopy, and asthma are complex, genetic markers are needed to identify populations at risk and to plan intervention studies. OBJECTIVE: Human leukocyte antigen (HLA) class II genes play a major role in the control of immune response. We investigated the association between HLA class II alleles of DRB1 and DQB1 and the expression of atopy in cockroach-sensitive patients. METHODS: Levels of total and specific immunoglobulin E were determined. Skin prick tests were performed. HLA class II typing was performed by the Polymerase chain reaction with sequence-specific primers. Distribution of the HLA genotypes of 32 cockroach-positive atopic patients from the inner city were compared with those of 32 healthy, nonatopic controls of Turkish Caucasian origin. RESULTS: HLA class II gene analysis showed an increase of the HLA-DRB1*0701 and HLA-DQB1*02 alleles in atopic patients compared with nonatopic controls (31.3% vs 3.1% and 50% vs 15.6%, Pc < 0.036 and Pc < 0.021, respectively). Conversely, HLA-DRB1*15 allele was encountered more frequently in the control subjects. An association between cockroach sensitivity and cutaneous reactivity to other aeroallergens was observed (P < 0.001). CONCLUSIONS: It is suggested that the higher frequencies of HLA-DRB1*0701 and HLA-DQB1*02 alleles are probably related to atopy rather than an association between class II antigens and cockroach allergy in this group of polysensitized, atopic individuals. Further studies may lead to a better understanding of the genetically determined susceptibility, and evaluate the individual effects of each locus (or allele) on sensitivity to specific allergens in the Turkish population.

5952.      Kuperman DA, Huang X, Koth LL, Chang GH, Dolganov GM, Zhu Z, Elias JA, Sheppard D, Erle DJ. Direct effects of interleukin-13 on epithelial cells cause airway hyperreactivity and mucus overproduction in asthma. Nat Med. 2002 Aug;8(8):885-9.

 

Asthma is an increasingly common disease that remains poorly understood and difficult to manage. This disease is characterized by airway hyperreactivity (AHR, defined by exaggerated airflow obstruction in response to bronchoconstrictors), mucus overproduction and chronic eosinophilic inflammation. AHR and mucus overproduction are consistently linked to asthma symptoms and morbidity. Asthma is mediated by Th2 lymphocytes, which produce a limited repertoire of cytokines, including interleukin-4 (IL-4), IL-5, IL-9 and IL-13. Although each of these cytokines has been implicated in asthma, IL-13 is now thought to be especially critical. In animal models of allergic asthma, blockade of IL-13 markedly inhibits allergen-induced AHR, mucus production and eosinophilia. Furthermore, IL-13 delivery to the airway causes all of these effects. IL-13 is thus both necessary and sufficient for experimental models of asthma. However, the IL-13-responsive cells causing these effects have not been identified. Here we show that mice lacking signal transducer and activator of transcription 6 (STAT6) were protected from all pulmonary effects of IL 13. Reconstitution of STAT6 only in epithelial cells was sufficient for IL-13-induced AHR and mucus production in the absence of inflammation, fibrosis or other lung pathology. These results demonstrate the importance of direct effects of IL-13 on epithelial cells in causing two central features of asthma.

5953.      Matricardi PM, Rosmini F, Panetta V, Ferrigno L, Bonini S. Hay fever and asthma in relation to markers of infection in the United States. J Allergy Clin Immunol. 2002 Sep;110(3):381-7.

 

BACKGROUND: The hygiene hypothesis proposes that declining exposure to infections is implicated in the rising trend of allergy and asthma. OBJECTIVE: We sought to test this hypothesis by examining the relationship of hay fever, asthma, and atopic sensitization with markers of infection in a large general population sample of the United States. METHODS: We analyzed the data of 33,994 US residents recorded in a public database of a nationally representative cross-sectional survey (Third National Health and Nutrition Examination Survey, 1988-1994). The variables examined were sociodemographic information, lifetime diagnosis and age at first diagnosis of hay fever or asthma, current skin sensitization to 9 airborne allergens and peanut, and current serology for Toxoplasma gondii, herpes simplex viruses type 1 and 2, and hepatitis A, B, and C viruses. RESULTS: Hay fever (adjusted odds ratio, 0.27; 95% CI, 0.18-0.41; P <.001) and asthma (adjusted odds ratio, 0.45; 95% CI, 0.31-0.66; P <.001) were less frequent in subjects seropositive for hepatitis A virus (HAV), T gondii, and herpes simplex virus 1 versus seronegative subjects after adjusting for age, sex, race, urban residence, census region, family size, income, and education. Skin sensitization to peanut and to all the airborne allergens examined, except for cockroach, was less frequent among HAV-seropositive versus HAV-seronegative subjects younger than 40 years of age. The prevalence of hay fever and asthma diagnosed at or before 18 years of age in HAV-seronegative subjects increased progressively from 2.7% (95% CI, 0.7%-4.7%) and 0.4% (95% CI, 0.1%-1.6%), respectively, in cohorts born before 1920 to 8.5% (95% CI, 7.3%-9.7%) and 5.8% (95% CI, 4.8%-6.8%), respectively, in cohorts born in the 1960s, whereas they remained constant at around 2% in all cohorts of HAV-seropositive subjects. CONCLUSION: In the United States serologic evidence of acquisition of certain infections, mainly food-borne and orofecal infection, is associated with a lower probability of having hay fever and asthma. Third National Health and Nutrition Examination Survey data support the hypothesis that hygiene is a major factor contributing to the increase in hay fever, asthma, and atopic sensitization in westernized countries.

5954.      Moverare R, Westritschnig K, Svensson M, Hayek B, Bende M, Pauli G, Sorva R, Haahtela T, Valenta R, Elfman L.  Different IgE reactivity profiles in birch pollen-sensitive patients from six European populations revealed by recombinant allergens: an imprint of local sensitization. Int Arch Allergy Immunol. 2002 Aug;128(4):325-35.

 

BACKGROUND: Sensitivity to birch pollen allergens is a common feature among European patients with seasonal pollen allergy. In this in vitro study, we examined the specific serum IgE binding profiles to individual birch pollen allergens in birch-sensitive patients from six European populations. METHODS: The study included 242 patients from Finland, Sweden, Austria, France, Switzerland and Italy. All suffered from seasonal rhinoconjunctivitis and/or asthma. Their sera were analyzed for specific IgE reactivity to individual birch pollen allergens (recombinant Bet v 1, Bet v 2 and Bet v 4) and natural birch pollen extract using Pharmacia CAP System and immunoblotting. RESULTS: Almost all Finnish, Swedish and Austrian sera contained IgE specific for Bet v 1 (>or=98%). Bet v 1-specific IgE antibodies were found in 90% of the French sera, and in 65 and 62% of the sera from Switzerland and Italy, respectively. Few Finnish (2%) and Swedish (12%) patients had IgE to Bet v 2, while Bet v 2 reactivity was more common in the other populations (20-43%). Reactivity to Bet v 4 was rare in all populations (5-11%) except for the Italian patients, in whom 3 of 11 sera were positive (27%). The immunoblot results supported the specific IgE profiles obtained with Pharmacia CAP System showing a broader IgE reactivity profile in patients from central and southern Europe as compared to northern Europe. CONCLUSION: Component-resolved allergy diagnosis with recombinant allergens reveals that the IgE reactivity profiles to individual birch pollen allergens vary between European populations. This observation may be explained by sensitization to different allergen sources and will have an impact on allergen-specific prevention and therapy strategies.

 

5955.      Polosa R, Rorke S, Holgate ST. Evolving concepts on the value of adenosine hyperresponsiveness in asthma and chronic obstructive pulmonary disease. Thorax. 2002 Jul;57(7):649-54. Review.

 

Adenosine is a purine nucleoside which mediates a variety of cellular responses relevant to asthma and COPD through interaction with specific receptors. Administration of adenosine by inhalation to patients with asthma and COPD is known to cause concentration related bronchoconstriction. Responses elicited by this purine derivative in asthma and COPD should not be considered as a mere reflection of non-specific airways hyperresponsiveness. Evaluation of airways responsiveness by adenosine induced bronchoconstriction may be valuable in differentiating asthma from COPD, monitoring of anti-inflammatory treatment in asthma, surveying disease progression, and assessing disease activity in relation to allergic airways inflammation.

5956.      Prieto L, Uixera S, Gutierrez V, Bruno L. Modifications of airway responsiveness to adenosine 5'-monophosphate and exhaled nitric oxide concentrations after the pollen season in subjects with pollen-induced rhinitis. Chest. 2002 Sep;122(3):940-7.

 

STUDY OBJECTIVE:s: To determine the effect of cessation of exposure to pollen on airway responsiveness to adenosine 5'-monophosphate (AMP) in subjects with pollen-induced rhinitis, and to explore the relationship between changes in airway responsiveness and changes in exhaled nitric oxide (ENO) levels. STUDY DESIGN: Subjects were studied during the pollen season and out of season. SETTING: Specialist allergy unit in a university hospital. PATIENTS: Fourteen subjects without asthma with pollen-induced rhinitis who showed bronchoconstriction in response to methacholine and AMP during the pollen season and 10 healthy nonatopic control subjects. MEASUREMENTS AND RESULTS: In subjects with pollen-induced rhinitis, ENO concentrations, provocative concentration of agonist causing a 20% fall in FEV(1) (PC(20)) methacholine, and PC(20) AMP were determined during the pollen season and out of season. Healthy control subjects were studied during the pollen season. In subjects with allergic rhinitis, PC(20) AMP increased from a geometric mean of 79.4 mg/mL (95% confidence interval [CI], 31.6 to 199.5 mg/mL) during the pollen season to 316.2 mg/mL (95% CI, 158.5 to 400.0 mg/mL) out of season (p = 0.004). The ENO concentrations decreased from 63.1 parts per billion (ppb) [95% CI, 50.1 to 79.4 ppb] during the pollen season to 30.2 ppb (95% CI, 23.4 to 38.0 ppb) out of season (p < 0.001). The ENO concentrations out of pollen season were still significantly increased in subjects with pollen-induced rhinitis when compared with healthy control subjects. There was no relationship between individual changes in ENO levels and changes in either PC(20) methacholine or PC(20) AMP. CONCLUSIONS: In pollen-sensitive subjects with allergic rhinitis, the cessation of exposure to pollen is associated with a significant reduction of airway responsiveness to inhaled AMP. However, no association was found between allergen-induced changes in ENO values and in airway responsiveness to either direct or indirect bronchoconstrictors. These findings suggest that modifications in ENO and in airway responsiveness are the consequence of different alterations induced by allergen exposure on the lower airways.

5957.      Romanet-Manent S, Charpin D, Magnan A, Lanteaume A, Vervloet D. Allergic vs nonallergic asthma: what makes the difference? Allergy. 2002 Jul;57(7):607-13.

 

BACKGROUND: The aim of this work was to describe clinical similarities and differences between allergic and nonallergic asthmatics, notably concerning the nasosinusal involvement. METHODS: A total of 165 asthmatics (122 allergics and 43 nonallergics) and 193 controls (40 allergics and 153 nonallergics), recruited in the frame of EGEA study (Epidemiological study on the Genetics and Environment of Asthma, bronchial hyperresponsiveness and atopy), were included. Asthmatics were included on the basis of positive answer to four standardized items. To establish differences and similarities between allergic and nonallergic asthmatics, general characteristics (age, sex, smoking habits, history of hay fever and allergic dermatitis), history of asthma, severity and nasosinusal involvement were examined. Clinical assessment was based on the answers to a detailed questionnaire, and spirometry. RESULTS: Greater age, female sex, sinusal polyposis, and FEV1 below 80% of the predicted value increased the risk of displaying a nonallergic type of asthma, whereas historyof hay fever, seasonal exacerbation of asthma, and asthma duration lowered this risk. Unexpectedly, we found no difference in terms of rhinitic symptoms between both groups, probably resulting from distinct causes. CONCLUSION: These results give new insights into the contrasts between clinical features of allergic and nonallergic asthma. The terminology of extrinsic asthma was first introduced by Rackeman in 1947 (1) and referred to the triggering role of allergens in asthma. By symmetry, he described intrinsic asthma as a disease characterized by later onset in life, female predominance, higher degree of severity, and more frequent association to nasosinusal polyposis. As these asthmatics were not improved by conventional treatment, this author considered their disease as caused by a nonallergic, unknown phenomenon. It is now widely admitted that nonallergic asthma can be objectively distinguished from allergic asthma based on negative skin tests to usual aeroallergens. On the other hand, positive skin test shows a tendency to produce IgE antibodies in response to low doses of allergens. "Atopy" and "atopic" are the terms used to describe this clinical trait and predisposition (2). Allergic clinical manifestations of atopy are of various types, for example rhinitis and asthma. Nowadays the terminology of "extrinsic" and "intrinsic" asthma should no longer be used, and should be replaced by the terminology of "allergic" or "nonallergic" asthma (2).

 

5958.      Sears MR, Greene JM, Willan AR, Taylor DR, Flannery EM, Cowan JO, Herbison GP, Poulton R. Long-term relation between breastfeeding and development of atopy and asthma in children and young adults: a longitudinal study. Lancet. 2002 Sep 21;360(9337):901-7.

 

BACKGROUND: Breastfeeding is widely advocated to reduce risk of atopy and asthma, but the evidence for such an effect is conflicting. We aimed to assess long-term outcomes of asthma and atopy related to breastfeeding in a New Zealand birth cohort. METHODS: Our cohort consisted of 1037 of 1139 children born in Dunedin, New Zealand, between April, 1972, and March, 1973, and residing in Otago province at age 3 years. Children were assessed every 2-5 years from ages 9 to 26 years with respiratory questionnaires, pulmonary function, bronchial challenge, and allergy skin tests. History of breastfeeding had been independently recorded in early childhood. FINDINGS: 504 (49%) of 1037 eligible children were breastfed (4 weeks or longer) and 533 (51%) were not. More children who were breastfed were atopic at all ages from 13 to 21 years to cats (p=0.0001), house dust mites (p=0.0010), and grass pollen (p<0.0001) than those who were not. More children who were breastfed reported current asthma at each assessment between age 9 (p=0.0008) and 26 years (p=0.0008) than those who were not. Breastfeeding effects were not affected by parental history of hayfever or asthma. Multifactor analysis controlling for socioeconomic status, parental smoking, birth order, and use of sheepskin bedding in infancy, showed odds ratios of 1.94 (95% CI 1.42-2.65, p<0.0001) for any allergen positive at age 13 years, 2.40 (1.36-4.26, p=0.0003) for current asthma at 9 years, and 1.83 (1.35-2.47, p<0.0001) for current asthma at 9-26 years by repeated-measures analysis. INTERPRETATION: Breastfeeding does not protect children against atopy and asthma and may even increase the risk.

5959.      Smart JM, Horak E, Kemp AS, Robertson CF, Tang ML. Polyclonal and allergen-induced cytokine responses in adults with asthma: resolution of asthma is associated with normalization of IFN-gamma responses. J Allergy Clin Immunol. 2002 Sep;110(3):450-6.

 

BACKGROUND: Atopic disease is associated with skewing of immune responses away from a T(H)1 toward a T(H)2 profile. Previous studies have implicated this cytokine imbalance in the development of disease. However, it is not known whether normalization of this imbalance is conversely associated with disease resolution. OBJECTIVE: To further delineate the role of reduced T(H)1 and increased T(H)2 cytokine production in the pathogenesis of atopic disease and to determine whether disease resolution is associated with alteration of cytokine  profiles, we investigated cytokine responses in a cohort of adult patients with asthma followed from childhood. METHODS: A cohort of wheezy children and control subjects aged 7 to 10 years were recruited from 1964 to 1967. Subjects were reevaluated every 7 years to monitor the outcome of childhood asthma. At the 42-year follow-up, 89 subjects from this cohort were evaluated for mitogen and house dust mite (HDM)-induced T(H)1 (IFN-gamma) and T(H)2 (IL-4, IL-5, and IL-13) cytokine responses. Cytokine responses were compared in patients with ongoing asthma, patients with resolved asthma, and control subjects. RESULTS: Patients with severe ongoing asthma had significantly reduced HDM-induced IFN-gamma production compared with that of control subjects and patients with resolved asthma. In contrast, HDM-induced IFN-gamma production in patients with resolved asthma was equivalent to that seen in control subjects. Patients with ongoing and resolved asthma produced significantly higher levels of IL-5 in response to HDM compared with that seen in control subjects, with levels being equivalent in patients with active and resolved asthma. HDM-induced IL-13 production was significantly increased in the patients with resolved asthma when compared with that seen in the control subjects. PHA-induced cytokine responses did not parallel HDM-induced responses. CONCLUSION: Patients with persistent and severe atopic asthma have a reduced HDM-induced T(H)1 response, whereas those with resolved asthma do not. This suggests that reduced HDM-induced IFN-gamma production might be an important factor contributing to ongoing severe asthma and that normalization of allergen-induced T(H)1 responses might be important for disease resolution. The finding that all subjects with a history of asthma displayed increased HDM-induced T(H)2 (IL-5 and IL-13) cytokine responses, irrespective of the presence or absence of asthma, suggests that increased T(H)2 responses reflect the presence of the atopic state per se rather than being specifically linked to asthma.

5960.      Thomas PS, Heywood G. Effects of inhaled tumour necrosis factor alpha in subjects with mild asthma. Thorax. 2002 Sep;57(9):774-8.

 

BACKGROUND: Inhaled tumour necrosis factor alpha (TNF alpha) has previously been shown to induce airway neutrophilia and increased airway reactivity in normal subjects. It was hypothesised that a similar challenge would increase airway reactivity in those with mild asthma, but that the inflammatory profile may differ. METHODS: Ten mild asthmatic subjects were recruited on the basis of clinical asthma and either a sensitivity to methacholine within the range defined for asthma or a 20% improvement in forced expiratory volume (FEV(1)) after 200 micro g salbutamol. Subjects inhaled either vehicle control or 60 ng recombinant human (rh)TNF alpha and were studied at baseline, 6, 24, and 48 hours later. Variables included spirometric parameters, methacholine provocative concentration causing a 20% fall in FEV(1) (PC(20)), induced sputum differential cell count, relative sputum level of mRNA of interleukins (IL)-4, IL-5, IL-9, IL-14, IL-15 and TNF alpha, and the exhaled gaseous markers of inflammation, nitric oxide and carbon monoxide. RESULTS: PC(20) showed an increase in sensitivity after TNF alpha compared with control (p<0.01). The mean percentage of neutrophils increased at 24-48 hours (24 hour control: 1.1 (95% CI 0.4 to 2.7) v 9.2 (95% CI 3.5 to 14.9), p<0.05), and there was also a rise in eosinophils (p=0.05). Relative levels of sputum mRNA suggested a rise in expression of TNF alpha, IL-14, and IL-15, but no change in IL-4 and IL-5. Spirometric parameters and exhaled gases showed no significant change. CONCLUSION: The increase in airway responsiveness and sputum inflammatory cell influx in response to rhTNF alpha indicates that TNF alpha may contribute to the airway inflammation that characterises asthma.

 

5961.      Viksman MY, Bochner BS, Peebles RS, Schleimer RP, Liu MC. Expression of activation markers on alveolar macrophages in allergic asthmatics after endobronchial or whole-lung allergen challenge. Clin Immunol. 2002 Jul;104(1):77-85.

 

We examined the effect of endobronchial (EB) or whole-lung (WL) challenge with ragweed or Timothy grass extract on alveolar macrophage (AM) activation. Expression of 17 constitutive activation markers on AM was examined by flow cytometry. Late-phase bronchial obstruction was greater after WL challenge, while changes in bronchoalveolar lavage cytology (eosinophil accumulation) were greater after EB challenge. After EB challenge, levels of 10 of 17 markers (CD11a, CD11b, CD14, CD18, CD23, CD32, CD63, CD64, HLA-class I, and HLA-DR) were significantly increased (by 33-234%, P < 0.05). Six markers (CD16, CD29, CD33, CD35, CD44, CD71, and HLA-DQ) remained unchanged. Levels of seven markers following EB challenge (CD14, CD16, CD18, CD29, CD32, HLA-class I, and HLA DQ) correlated with airway sensitivity to methacholine. WL challenge only increased expression of HLA-class I. The different results obtained with the two challenge methods probably depend on higher local concentrations of allergen in the EB challenge. We suggest that activation of AM occurs following EB challenge with antigen in asthmatics.

 

 

5962.      Zureik M, Neukirch C, Leynaert B, Liard R, Bousquet J, Neukirch F. Sensitisation to airborne moulds and severity of asthma: cross sectional study from European Community respiratory health survey. BMJ. 2002 Aug 24;325(7361):411-4.

 

OBJECTIVE: To assess whether the severity of asthma is associated with sensitisation to airborne moulds rather than to other seasonal or perennial allergens. DESIGN: Multicentre epidemiological survey in 30 centres. SETTING: European Community respiratory health survey. PARTICIPANTS: 1132 adults aged 20-44 years with current asthma and with skin prick test results. MAIN OUTCOME MEASURES: Severity of asthma according to score based on forced expiratory volume in one second, number of asthma attacks, hospital admissions for breathing problems, and use of corticosteroids in past 12 months. RESULTS: The frequency of sensitisation to moulds (Alternaria alternata or Cladosporium herbarum, or both) increased significantly with increasing asthma severity (odds ratio 2.34 (95% confidence interval 1.56 to 3.52) for either for severe v mild asthma). This association existed in all of the study areas (gathered into regions), although there were differences in the frequency of sensitisation. There was no association between asthma severity and sensitisation to pollens or cats. Sensitisation to Dermatophagoides pteronyssinus was also positively associated with severity. In multivariable logistic regressions including sensitisation to moulds, pollens, D pteronyssinus, and cats simultaneously, the odds ratios for sensitisation to moulds were 1.48 (0.97 to 2.26) for moderate v mild asthma and 2.16 (1.37 to 3.35) for severe v mild asthma (P<0.001 for trend). CONCLUSIONS: Sensitisation to moulds is a powerful risk factor for severe asthma in adults. This should be taken into account in primary prevention, management, and patients' education.

 

        Pathogenesis:

5963.      Braun-Fahrlander C, Riedler J, Herz U, Eder W, Waser M, Grize L, Maisch S, Carr D, Gerlach F, Bufe A, Lauener RP, Schierl R, Renz H, Nowak D, von Mutius E. Environmental exposure to endotoxin and its relation to asthma in school-age children. N Engl J Med. 2002 Sep 19;347(12):869-77.

 

BACKGROUND: In early life, the innate immune system can recognize both viable and nonviable parts of microorganisms. Immune activation may direct the immune response, thus conferring tolerance to allergens such as animal dander or tree and grass pollen. METHODS: Parents of children who were 6 to 13 years of age and were living in rural areas of Germany, Austria, or Switzerland where there were both farming and nonfarming households completed a standardized questionnaire on asthma and hay fever. Blood samples were obtained from the children and tested for atopic sensitization; peripheral-blood leukocytes were also harvested from the samples for testing. The levels of endotoxin in the bedding used by these children were examined in relation to clinical findings and to the cytokine-production profiles of peripheral-blood leukocytes that had been stimulated with lipopolysaccharide and staphylococcal enterotoxin B. Complete data were available for 812 children. RESULTS: Endotoxin levels in samples of dust from the child's mattress were inversely related to the occurrence of hay fever, atopic asthma, and atopic sensitization. Nonatopic wheeze was not significantly associated with the endotoxin level. Cytokine production by leukocytes (production of tumor necrosis factor alpha, interferon-gamma, interleukin-10, and interleukin-12) was inversely related to the endotoxin level in the bedding, indicating a marked down-regulation of immune responses in exposed children. CONCLUSIONS: A subject's environmental exposure to endotoxin may have a crucial role in the development of tolerance to ubiquitous allergens found in natural environments. Copyright 2002 Massachusetts Medical Society

5964.      Glare EM, Divjk M, Bailey MJ, Walters EH. beta-Actin and GAPDH housekeeping gene expression in asthmatic airways is variable and not suitable for normalising mRNA levels. Thorax. 2002 Sep;57(9):765-70.

 

BACKGROUND: The use of reverse transcription-polymerase chain reaction (RT-PCR) to measure mRNA levels has led to the common use of beta-actin and GAPDH housekeeping genes as denominators for comparison of samples. Expression of these genes is assumed to remain constant, so normalising for variations in processing and signal quantitation. However, it is well documented that beta-actin and GAPDH expression is upregulated with proliferation, activation, and differentiation. We hypothesised that airway samples which differ in their cellular profiles and activation status have different levels of expression of GAPDH and beta-actin. METHODS: The mRNA for beta-actin, GAPDH, and interleukin (IL)-2 was measured in bronchoalveolar lavage (BAL) fluid cells and endobronchial biopsy tissue by competitive RT-PCR in a cross sectional study of 26 normal controls and 92 asthmatic subjects. RESULTS: For both BAL fluid cells and biopsy tissue, asthmatics overall had reduced expression of GAPDH and beta-actin mRNA. In asthmatic subjects not using inhaled corticosteroids (ICS), GAPDH mRNA levels in both BAL fluid and biopsy tissue, and beta-actin mRNA in BAL fluid cells were 10 times lower than samples from both normal controls and from asthmatic subjects using ICS. beta-Actin mRNA in biopsy specimens showed the same pattern of expression, but asthmatic subjects not using ICS were not significantly different from those receiving ICS treatment. IL-2 mRNA levels did not differ between the subject or treatment groups but, when expressed as a ratio with beta-actin, significant differences were seen. CONCLUSIONS: beta-Actin and GAPDH used as denominators of gene expression quantitation in asthma research can cause confounding. Housekeeping genes need careful validation before their use in such quantitative mRNA assays.

5965.                  Jaakkola MS, Laitinen S, Piipari R, Uitti J, Nordman H, Haapala AM, Jaakkola JJ. Immunoglobulin G antibodies against indoor dampness-related microbes and adult-onset asthma: a population-based incident case-control study. Clin Exp Immunol. 2002 Jul;129(1):107-12.

 

Immunoglobulin G (IgG) antibodies against microbes related to indoor dampness problems have been used as potential biomarkers of fungal exposure in clinical investigations. There is limited information on their relation to asthma. We conducted a population-based incident case-control study to assess the risk of asthma in relation to specific IgG antibodies to eight dampness-related microbes: Aspergillus fumigatus, A. versicolor, Cladosporium cladosporioides, Fusarium oxysporum, Sporobolomyces salmonicolor, Stachybotrys chartarum, Streptomyces albus and Trichoderma citrinoviride. We recruited systematically all new cases of asthma during a 2.5-year study period and randomly selected controls from a source population of adults 21-63 years of age living in the Pirkanmaa Hospital District, South Finland. The clinically diagnosed case series consisted of 521 adults with newly diagnosed asthma and the control series of 932 controls selected randomly from the source population. IgG antibodies were analysed with ELISA. An increased risk of developing asthma in adulthood was significantly related to IgG antibodies to T. citrinoviride, but not to the other moulds. There was no evidence of a dose-response relation between the IgG antibody level and the risk of asthma. T. citrinoviride may play a role in the aetiology of adult-onset asthma or serve as an indicator of other causal factors.

 

5966.      Kim MH, Agrawal DK. Effect of interleukin-1beta and tumor necrosis factor-alpha on the expression of G-proteins in CD4+ T-cells of atopic asthmatic subjects. J Asthma. 2002 Aug;39(5):441-8.

 

Chronic use of beta2-agonists and increased production of inflammatory mediators during the late allergic reaction after the antigen challenge result in the desensitization of beta-adrenoceptors in the airways with an accompanying rise in non-specific airway hyperresponsiveness. Several proinflammatory cytokines, including interleukin-1beta (IL-1beta) and tumor necrosis factor-alpha (TNF-alpha), play a significant role in orchestrating and perpetuating the inflammatory response and induce the decreased response to bronchodilators in vitro. However, the underlying mechanisms are unknown. In this study, we examined the effect of two cytokines, IL-1beta and TNF-alpha, on the expression of guanine nucleotide binding regulatory proteins (G-proteins), Gs alpha and Gi alpha-3, by Western blotting in the CD4+ cells of nonatopic nonasthmatic (NANA), atopic nonasthmatic (ANA), and atopic asthmatic (AA) subjects. In the purified CD4+ cells, the basal expression of Gs alpha was higher in the ANA group, and significantly lower in the AA group as compared to the NANA group. The basal expression of Gi alpha-3 was significantly greater (3-15 fold) than Gs alpha, with no significant difference between any of the three groups. Both cytokines IL-1beta and TNF-alpha significantly decreased the expression of Gs alpha in the CD4+ cells of the NANA and ANA groups, with no effect in the AA group. However, these cytokines increased the expression of Gi alpha-3, proteins in the AA group, but had no effect in the CD4+ cells of the NANA and ANA groups. These data suggest that a decreased response to beta2-agonists in the late allergic response in allergic asthmatic subjects could be due to the release of inflammatory cytokines, which induce a decrease in the stimulatory G-proteins and an increase in the inhibitory G-proteins.

5967.      Morahan G, Huang D, Wu M, Holt BJ, White GP, Kendall GE, Sly PD, Holt PG. Association of IL12B promoter polymorphism with severity of atopic and non-atopic asthma in children. Lancet. 2002 Aug 10;360(9331):455-9.

 

BACKGROUND: Severe asthma is a frequent cause of hospital admission, especially among children. The main environmental triggers of airway inflammation in asthma are viruses and aeroallergens. These agents elicit reciprocal immune responses, characterised by production of T helper 1 and T helper 2 cytokines, respectively. There is no genetic explanation for how hyper-responsiveness to these disparate environmental stimuli develops among individuals with asthma. Our aim was to assess relation between an IL12B promoter polymorphism and asthma. METHODS: We did a cohort study in which we initially genotyped 411 6-year olds for the IL12B promoter polymorphism. We then assessed the relation between this polymorphism and asthma severity. A further 85 asthmatic children in an additional sample of 433 children from the same cohort were then assessed to confirm these findings. We also examined in-vitro interleukin-12 responses in a subgroup of individuals. FINDINGS: Heterozygosity for the IL12B promoter polymorphism was observed in 76% (16) of atopic and non-atopic individuals with severe asthma in the initial sample. By comparison, heterozygotes comprised only 31% (17) of the moderate asthma group, and 48% (20) of individuals with mild asthma were heterozygous, as were unaffected controls. These findings were confirmed in the second sample (overall p<0.0001). Our data suggest that IL12B promoter heterozygosity contributes to asthma severity rather than susceptibility per se. The severity-predisposing genotype was associated with reduced interleukin 12 p40 gene transcription and decreased interleukin 12 p70 secretion. INTERPRETATION: Interleukin 12 plays a key part in antagonism of T helper 2 differentiation, and in induction of antiviral host defense.Genetically determined attenuation of interleukin-12 response capacity would, therefore, provide a plausible common immunological pathway to disease severity for the two major forms of asthma.

5968.      Platts-Mills TA. Paradoxical effect of domestic animals on asthma and allergic sensitization. JAMA. 2002 Aug 28;288(8):1012-4.  No abstract.

5969.      Risma KA, Wang N, Andrews RP, Cunningham CM, Ericksen MB, Bernstein JA, Chakraborty R, Hershey GK. V75R576 IL-4 receptor alpha is associated with allergic asthma and enhanced IL-4 receptor function. J Immunol. 2002 Aug 1;169(3):1604-10.

 

Asthma is a complex polygenic disease. Many studies have implicated the importance of IL-4R alpha in the development of allergic inflammation and its gene has been implicated in the genetics of asthma and atopy. In this study, we examined the functional consequences of two of the human IL-4R alpha allelic variants that have been found to associate with asthma and atopy. We examined the effects of each variant alone and in combination on IL-4-dependent gene induction. We found that neither the Q576R nor the I75V variants affected IL-4-dependent CD23 expression. However, the combination of V75R576 resulted in expression of an IL-4R alpha with enhanced sensitivity to IL-4. We next examined the genetics of five of the known IL-4R alpha allelic variants in asthmatic and nonatopic populations. Strikingly, the association of V75/R576 with atopic asthma was greater than either allele alone and the association of R576 with atopic asthma was dependent on the coexistence of V75. A haplotype analysis revealed a single IL-4R alpha haplotype that was associated with allergic asthma, VACRS, further confirming the importance of the V75 and R576 combination in the genetics of asthma. This is the first report demonstrating that a functional alteration in IL-4R alpha requires the coexistence of two naturally occurring single nucleotide polymorphisms (snps) in combination; neither snp alone is sufficient. These data illustrate the importance of studying snps in combination, because the functional significance of a given snp may only be evident in a specific setting of additional snps in the same or different genes.

5970.      Sly PD, Holt PG. Breast is best for preventing asthma and allergies--or is it? Lancet. 2002 Sep 21;360(9337):887-8.  No abstract.

         Vaccines:

5971.      Peebles RS, Hartert TV. Highlights from the annual scientific assembly: patient-centered approaches to asthma management: strategies for treatment and management of asthma. South Med J  2002 Jul;95(7):775-9 

 

Asthma is a chronic inflammatory disease in which the genetic predisposition to allergic disease is the strongest identifiable predisposing factor. (1) Optimal outpatient treatment of asthma includes identifying and minimizing exposure to asthma triggers, whether they Me allergens or irritants. When these triggers are not obvious, referral to an allergist may be appropriate to ideniify potential exacerbating factors. In addition, pulmonary consultation may be helpful in patients who do not have the typical features of asthma on chest radiograph or pulmonary function testing, or who are not responding well to standard therapy. The primary care physician is the most important component in the care of the asthmatic patient, however, managing acute exacerbations, determining long-term medical therapy, and providing preventive measures, such as yearly influenza vaccinations.

 

 

 

    Therapy:

5972.      Babu KS, Holgate ST. The role of anti-IgE therapies in the treatment of asthma. Hosp Med. 2002 Aug;63(8):483-6. Review.

 

The prevalence of asthma, a chronic inflammatory disease often linked to allergy, is on the increase. The introduction of a blocking anti-IgE monoclonal antibody (omalizumab) as a new therapy has not only confirmed the pathogenic role of IgE in asthma but has also provided a novel therapy for a chronic severe disease where there are limited therapeutic options.

5973.      Bajel AR; Jadhav DL; Moulick ND. Department of Medicine, LTMM College and General Hospital. Sion. Mumbai 400022 India Magnesium in health and disease Indian Practitioner. 2002 Apr; 55(4): 238-42.

 

ABSTRACT: Magnesium, the second most abundant cation, plays a crucial role in human physiology. This article reviews magnesium balance, its metabolism and predisposing factors for magnesium deficiency-a relatively common condition. Magnesium has been reported as an effective therapy in an expanding array of conditions-ischaemic heart disease, cardiac arrhythmias, asthma and seizures. However in some of these conditions, it has been uncertain whether magnesium administration serves the purpose of merely correcting the underlying deficiency state or of utilizing a specific pharmacological affect of magnesium. This article reviews current status of magnesium therapy and presents guidelines for parenteral administration.

 

5974.      Bielory L. 'Complementary and alternative medicine' population based studies: a growing focus on allergy and asthma. Allergy. 2002 Aug;57(8):655-8. Review.  No abstract.

5975.      Caress AL, Luker K, Woodcock A, Beaver K. A qualitative exploration of treatment decision-making role preference in adult asthma patients. Health Expect. 2002 Sep;5(3):223-35.

 

OBJECTIVES: To explore preferred treatment decision-making roles, and rationales for role preference, and to identify perceived facilitators to and barriers from attaining preferred role. DESIGN: Qualitative design. SETTING AND PARTICIPANTS: One secondary care and four primary care sites in North-west England. Purposive sample of 32 adult asthma patients with varied socio-economic backgrounds and disease severity. METHODS: Tape-recorded focused-conversation style interviews. Interview topic guide derived from the literature. Sort cards employed to provide the focus for exploration of role preferences. RESULTS: Active (n = 7), collaborative (n = 11) and passive (n = 14) decisional role preferences were identified. Respondents cited level of knowledge; trust; duration of condition; severity of condition at the decisional juncture; lifelong nature of asthma; a perception that 'it is my body'; characteristics of the individual and their response to health professionals as influencing role preference. Perceived facilitators and barriers to participation included condition-related knowledge, practical issues (e.g. lack of time during consultation) and clinicians' interpersonal skills. CONCLUSIONS: Most respondents wished to contribute to or feel involved in treatment decision-making, but not necessarily to control it. Some hindrances to participation would be amenable to intervention. The quality of the provider-patient relationship is central to facilitating participation.

5976.      Garramone SM. "Oversteroidization" of asthmatic patients. Ann Allergy Asthma Immunol. 2002 Sep;89(3):328; discussion 329.  No abstract.

5977.      Hegde SC; Shah PB; Mahashur AA. Department of Pharmacology, LTM Medical College & General Hospital, Sion, Mumbai Awareness regarding occupational asthma amongst general practitioners-a critical evaluation. Indian Journal of Occupational and Environmental Medicine. 2002 Jan-Mar; 6(1): 16-0 No abstract.

5978.      Kozyrskyj AL, Mustard CA, Simons FE. Development of a drug treatment-based severity measure in childhood asthma. J Asthma. 2002 Aug;39(5):421-8.

 

Valid measures of severity are crucial in asthma pharmacoepidemiological research. This study reports the development and validation of a severity measure in childhood asthma for application to health care administrative data. A drug treatment-based asthma severity measure was developed following the stepped care approach to treatment, and this was applied to a cohort of 16,862 children who met a case definition for asthma drug prescription use between January 1995 and March 1996. Assessments were made of the measure's reliability, validity, and responsiveness to change over time. The drug treatment-based asthma severity measure classified 42% of children as having mild asthma, 37% as having moderate asthma, 19% as having moderate-severe asthma, and 2% as having severe asthma. Agreement on severity classification between two successive time periods was excellent (kappa = 0.82). Children classified as having severe asthma were significantly more likely than children with mild-moderate asthma to have previous asthma hospitalizations, to visit asthma specialists, to have high physician utilization, and to require hospital critical care. They were more likely to be reclassified as having severe asthma 2 years later. These findings show that a drug treatment-based severity measure in childhood asthma, which can be applied to prescription data, has good reliability and validity, and is responsive to changes in asthma severity over time.

 

5979.      Mahakalkar SM; Tibdewal S; Khobragade BP. Department of Pharmacology, Department of Paediatrics, Indira Gandhi Medical College Nagpur-18 Cardio-pulmonary effects of various anti-asthmatic agents in patients of acute bronchial asthma Indian Practitioner. 2002 Feb; 55(2): 79-85.

 

Aims and Objectives: The cardio-pulmonary effects of beta-agonist are known to be aggravated by addition of steroids in patients of acute bronchial asthma therefore, this study was planned to assess the cardio-pulmonary effects of various bronchodilators alone and in combination with steroids by different modes of delivery. Material and Methods: Two hundred and fifty nine patients of acute bronchial asthma (age 1-65 years) were randomised to one of the nine (sc-Adr, sc-Ter, Neb-S, MDI-S, MDI-S S*, MDI-S+B, MDI-S+B S*, DPI-Salb, DPI-Salm) treatment groups. Heart rate, respiratory rate, blood pressure, wheezing, retraction and PEER was repeated one hour after therapy. For analysis patients were pooled into two groups-group A (age20 years) and group B (age-20 years). Results and Discussion: The mean wheezing scores and retraction scores improved significantly in all the treatment groups. A significant (p0.05) fall in respiratory rate was observed in all the treatment groups. Tachycardia was seen with subcutaneous adrenaline only and no significant changes were observed in blood pressure. The improvement in per cent predicted PEFR was better with adrenaline compared to terbutaline and was maximum (93.89 percent) with nebulised salbutamol amongst aerosol therapy. Conclusion: our study revealed tachycardia with conventional subcutaneous adrenaline only with no effects on blood pressure and the improvement in pulmonary status was better with aerosol therapy with improved PEFR, in particular.

 

5980.      Noppen M. Magnesium treatment for asthma: where do we stand? Chest. 2002 Aug;122(2):396-8.  No abstract.

5981.      Panigrahi L; Ghosal SK. College of Pharmaceutical Sciences, Tamando, Bubaneshwar Formulation and evaluation of pseudolatex transdermal drug delivery system of terbutaline sulphate Indian Journal of Pharmaceutical Sciences. 2002 Jan-Feb; 64(1): 79-82.

ABSTRACT: Since oral bioavailability of terbutaline sulphate is poor, pseudolatex transdermal patches incorporating terbutaline sulphate were prepared as an effective mode of therapy for nocturnal asthma in particular. The pseudolatex patches were formulated using combinations of Eudragit RS 100 and R L 100 and Eudraflex as plasticizer. The physicochemical characterization of the films were evaluated for suitability and drug release profile from the films as well as skin permeation aspects were evaluated for therapeutic efficacy. The resulted medicated patches were of average thickness (95-155 mium), and content uniformity of the drug varied from 94.5 to 99.1 percent. The formulation F3 showed least and F7 showed highest percentage of elongation. The percentage of moisture absorption varied from 2.91 to 3.65 at 63 percent relative humidity. The release profiles from the patches followed apparent zero order pattern up to a period 12 h, after which it leaves off. The cumulative amount of drug permeated over a period of 24 h was found to be 4.8 mg/cm square, which was about 50 percent of the loaded dose. The skin permeation took place at a steady rate over a period of 12 h after which the rate was reduced.

 

5982.      Shaikh GP; Pednekar S; Paidhungat AJ; Nabar ST. Asthma and COPD Clinic, B.Y.L. Nair Charitable Hospital and T.N. Medical College, Mumbai Central, Mumbai-400008 Steroids in bronchial asthma: potentiating effect of beta2 agonist Indian Practitioner. 2002 Feb; 55(2): 92-6

ABSTRACT: Asthma is a chronic inflammatory disorder of the airways in which many cells play a role, in particular mast cells, eosinophils and 'T' lymphocytes. Steroids and beta2 agonist are the main stay of treatment. Patients on chronic steroid therapy can be controlled on a smaller beta2 agonist dose during acute attack. This study showed that patients on chronic steroid maintenance dose had better improvement in PFT than those without.

5983.      Singh N; Syed Sadiq A; Singh V; Singh A National Institute of Pharmaceutical Education and Research S.A.S. Nagar Punjab Adaptogens anti stress agents a study focusing Indian plants Antiseptic. 2002 Jun; 99(6): 198-201.

 

ABSTRACT: This article has been presented with a view to acquaint the readers about plant adaptogens/ antistress agent. Although relation of stress has been recognized in genesis of diseases long back, a scientific database is still missing. The pharmaco-clinical studies carried out in this regard are a new venture in Stress-Pharmacology. It is meant to provide new research awareness in the field regarding the fact about stress, Stress-disease and their prevention and treatment. This is more important in view of the fact that there are no drugs for such stress-related diseases in the armamentarium of modern drug therapy. Simple animal models like swimming endurance, immobilization induced gastric ulcers, adrenal function during stress, CCI4 hepatotoxicity, anoxia tolerance test, brain neurotransmitters and enzyme and CNS receptors levels of neurohumorals after swimming immobilization and gravitational stress, milk induced leucocytosis, lipid peroxidase assessment for prevention of cell damage through anti-oxidant activity were carried out to evaluate the adaptogenic activity of these plants in rats and mice. Clinical trial in diseases related to stress like bronchial asthma, hypertension, cellular immunity, viral encephalitis, chronic fatigue syndrome were carried out in man.

 

5984.      Sterling GM. Bronchoconstrictor effect of deep inspiration in asthma. Thorax. 2002 Aug;57(8):751; discussion 751.  No abstract.

5985.      Wood PR, Smith LA, Romero D, Bradshaw P, Wise PH, Chavkin W. Relationships between welfare status, health insurance status, and health and medical care among children with asthma. Am J Public Health. 2002 Sep;92(9):1446-52.

 

OBJECTIVES: This study evaluated the relationships between health insurance and welfare status and the health and medical care of children with asthma. METHODS: Parents of children with asthma aged 2 to 12 years were interviewed at 6 urban clinical sites and 2 welfare offices. RESULTS: Children whose families had applied for but were denied welfare had more asthma symptoms than did children whose families had had no contact with the welfare system. Poorer mental health in parents was associated with more asthma symptoms and higher rates of health care use in their children. Parents of uninsured and transiently insured children identified more barriers to health care than did parents whose children were insured. CONCLUSIONS: Children whose families have applied for welfare and children who are uninsured are at high risk medically and may require additional services to improve health outcomes.

 

April 2003

6548.  Altman KW, Simpson CB, Amin MR, Abaza M, Balkissoon R, Casiano RR. Cough and paradoxical vocal fold motion. Otolaryngol Head Neck Surg. 2002 Dec;127(6):501-11. No abstract.

6549.  Anderson SD, Brannan JD, Chan HK. Use of aerosols for bronchial provocation testing in the laboratory: where we have been and where we are going. J Aerosol Med. 2002 Fall;15(3):313-24.

Bronchial provocation testing with pharmacological agents that act directly on airway smooth muscle has important limitations. These include the inability to identify exercise-induced asthma (EIA), to differentiate the airway hyperresponsiveness (AHR) of airway remodelling from the AHR of active inflammation and to differentiate between doses of steroids. Recent studies show that tests that act indirectly to narrow airways are more sensitive than pharmacological agents for identifying airway inflammation and response to treatment. Adenosine monophosphate (AMP) is an indirect challenge that acts on mast cells to cause release of mediators. Hypertonic saline is another and, since its development in the 1980s, has become widely used in Australia. Hypertonic (4.5%) saline is used to identify those with active asthma, those with EIA and those who wish to enter certain occupations or sports (e.g., diving). The recent development, again in Australia, of a test that uses dry powder mannitol has promise for use in the laboratory, the office, or for testing in the field. AHR to mannitol identifies people with EIA and is an estimate of its severity. The mannitol response is modified by drugs used to prevent EIA, implying that similar mediators are involved. A mannitol test can be used to monitor response to steroids and is more sensitive than histamine for identifying persistent airway hyperresponsiveness in asthmatics well controlled on steroids. These findings suggest that indirect challenges give more useful clinical information about currently active asthma and the response to treatment than direct challenge and they will become more widely used.

6550.  Arnaiz NO, Kaufman JD. New developments in work-related asthma. Clin Chest Med. 2002 Dec;23(4):737-47. No abstract

6551.  Asero R, Mistrello G, Roncarolo D, Amato S, Caldironi G, Barocci F, van Ree R. Immunological cross-reactivity between lipid transfer proteins from botanically unrelated plant-derived foods: a clinical study. Allergy. 2002 Oct;57(10):900-6. No abstract.

6552.  Baldwin DR, Gannon P, Bright P, Newton DT, Robertson A, Venables K, Graneek B, Barker RD, Cartier A, Malo JL, Wilsher M, Pantin CF, Burge PS.  Interpretation of occupational peak flow records: level of agreement between expert clinicians and Oasys-2. Thorax. 2002 Oct;57(10):860-4.

BACKGROUND: Oasys-2 is a validated diagnostic aid for occupational asthma that interprets peak expiratory flow (PEF) records as well as generating summary plots. The system removes inconsistency in interpretation, which is important if there is limited agreement between experts. A study was undertaken to assess the level of agreement between expert clinicians interpreting serial PEF measurements in relation to work exposure and to compare the responses given by Oasys-2. METHOD: 35 PEF records from workers under investigation for suspected occupational asthma were available for review. Records included details of nature of work, intercurrent illness, drug therapy, predicted PEF, rest periods, and holidays. Simple plots of PEF and the Oasys-2 generated plots were available. Experts were advised that approximately 1 hour was available to review the records. They were asked to score each work-rest-work (WRW) period and each rest-work-rest (RWR) period for evidence of occupational effect. At the end of each record scores of 0-100% were given for evidence of "asthma" and "occupational effect" for the whole record. Kappa values were calculated for each scored period and for the opinions on the whole record. The scores were converted into four groups (0-25%, 26-50%, 51-75%, 76-100%) and two groups (0-50% and 51-100%) for analysis. This is relevant to scores produced by Oasys-2. Agreement between Oasys-2 scores and each expert was calculated. RESULTS: 24 of 35 records were analysed by seven experts in the allotted time. For whole record occupational effect, median kappa values were 0.83 (range0.56-0.94) for two groups and 0.62 (0.11-0.83) for four groups. For asthma, median kappa values were 0.58 (0-0.67) and 0.42 (0.15-0.70) for two and four groups respectively. For all WRW and RWR periods kappa values were 0.84 (0.42-0.94) and 0.70 (0.46-0.87) respectively. Agreement between Oasys-2 and individual experts showed a median kappa value of 0.75 (0.50-0.92) for two groups and 0.50 (0.39-0.70) for four groups. Kappa values for the median expert score v Oasys-2 were 0.75 for two groups and 0.67 for four groups. Agreement was poor for records with intermediate probability, as defined by Oasys-2. CONCLUSION: Considerable variation in agreement was seen in expert interpretation of occupational PEF records which may lead to inconsistencies in diagnosis of occupational asthma. There is a need for an objective scoring system which removes human variability, such as that provided by Oasys-2.

6553.  Barber J, Dawes P. A rare cause of rash, eosinophilia and asthma in rheumatology. Rheumatology (Oxford). 2002 Nov;41(11):1329-30.No abstract.

6554.  Baron RM, Palmer LJ, Tantisira K, Gabriel S, Sonna LA, Le L, Hallock A, Libermann TA, Drazen JM, Weiss ST, Silverman ES. DNA sequence variants in epithelium-specific ETS-2 and ETS-3 are not associated with asthma. Am J Respir Crit Care Med. 2002 Oct 1;166(7):927-32.

Epithelium-specific ETS-2 and ETS-3 are transcription factors that have been proposed as asthma candidate genes. To investigate the association of sequence variants in these genes with asthma, we conducted a case-control association analysis in a sample of 311 white subjects with asthma and 177 white subjects without asthma. Common polymorphisms in these genes were detected by sequencing DNA from 32 cell lines obtained from Coriel (Camden, NJ). Seven noncoding or synonymous single-nucleotide polymorphisms were detected: three in epithelium-specific ETS-2 and four in epithelium-specific ETS-3. Subjects were  genotyped at all loci by mass spectroscopy. To ensure the suitability of our control subjects, we also genotyped subjects at 49 unlinked polymorphisms evenly distributed throughout the autosomes and found no evidence of population stratification. Logistic regression adjusted for age and sex suggested a weak association of one epithelium-specific ETS-2 polymorphism with asthma diagnosis (odds ratio = 1.89, 95% confidence interval = 1.13-3.18, p = 0.02). Total serum immunoglobulin E and FEV1 predicted levels were not associated with any of the polymorphisms. Extended haplotyping indicated linkage disequilibrium in these genes; however, no association or epistatic interaction was found. This study suggests that epithelium-specific ETS-2 and ETS-3 genes are unlikely to contain polymorphic loci that have a major impact on asthma susceptibility in our population.

6555.  Bennett WD. Effect of beta-adrenergic agonists on mucociliary clearance. J Allergy Clin Immunol. 2002 Dec;110(6 Suppl):S291-7. Review. No abstract

6556.  Cheng NG, Browne GJ, Lam LT, Yeoh R, Oomens M. Spacer compliance after discharge following a mild to moderate asthma attack. Arch Dis Child. 2002 Oct;87(4):302-5.

AIM: To assess MDIS usage in patients discharged from a children's hospital emergency department following a mild to moderate asthma attack. METHODS: Prospective observational study of 73 consecutive patients presenting to a children's hospital emergency department with a mild to moderate asthma attack. Demographic data, whether asthma literature/written MDIS instructions were provided, and who provided MDIS instructions (either a discharge coordinator or other emergency department staff) were noted. Parents of patients were telephoned after the first week following discharge and questioned about patient improvement, MDIS use/reasons for not using MDIS, and unscheduled presentations to their local doctor or hospital. RESULTS: Following discharge, 50/73 (68.5%) patients used MDIS exclusively (compliers), while 23/73 used nebulisers some or all of the time (non-compliers). There was no difference in patient improvement or unscheduled presentations between compliers and non-compliers. Most non-compliers 14/23 (60.9%) changed because of parental preference; ease of nocturnal nebuliser use was a possible factor. Compliance was associated with the age of the patient, spacer usage at hospital, the size of device used at hospital, and whether an information fact sheet was given. CONCLUSIONS: Most children discharged from the emergency department following a mild to moderate asthma attack continue MDIS use exclusively in the first week. MDIS compliance may be associated with knowledge, experience, and ease of spacer usage. The study shows that education for parents is crucial for MDIS compliance.

6557.  Cibella F, Cuttitta G, Bellia V, Bucchieri S, D'Anna S, Guerrera D, Bonsignore G. Lung function decline in bronchial asthma. Chest. 2002 Dec;122(6):1944-8. No abstract

6558.  Dahlen I, Janson C. Anxiety and depression are related to the outcome of emergency treatment in patients with obstructive pulmonary disease. Chest. 2002 Nov;122(5):1633-7.

STUDY OBJECTIVES: To investigate whether psychological factors predict outcome after emergency treatment for obstructive pulmonary disease. SETTING: Emergency department at a university hospital. PATIENTS: Forty-three patients presenting with exacerbation of asthma or COPD. INTERVENTION: The patients received emergency treatment and were followed up for 4 weeks. MEASUREMENT: Spirometry, blood sampling, pulse oximetry, breathing rate, pulse rate, and dyspnea score was measured before and during emergency treatment. The psychological status was assessed using the hospital anxiety and depression (HAD) scale questionnaire at the end of the follow-up period. RESULTS: Anxiety and/or depression was found in 17 patients (40%). Of these patients, nine patients (53%) were admitted to hospital or had a relapse within 1 month, compared with five patients (19%) in  the group without anxiety and/or depression (p < 0.05). Among patients who relapsed within 1 month (n = 14), the HAD total score was 12.4 +/- 5.9 compared with 8.6 +/- 5.1 (mean +/- SD) among the patients without a relapse (p < 0.05). After making adjustments for age, gender, atopic status, treatment, and pack-years, the significant association between treatment failure and anxiety and/or depression still remained. CONCLUSION: Our study indicates that anxiety and depression are related to the outcome of emergency treatment in patients with obstructive pulmonary disease. Further studies should be conducted evaluating the effect of treatment of anxiety and depression in patients with recurrent exacerbations of asthma and COPD.

6559.  Deramo M. Food challenge vs. skin antigen testing. Am Fam Physician 2002 Dec 1;66(11):2048 No abstract

6560.  Diaz-Perales A, Tabar AI, Sanchez-Monge R, Garcia BE, Gomez B, Barber D, Salcedo G.  Characterization of asparagus allergens: a relevant role of lipid transfer proteins. J Allergy Clin Immunol. 2002 Nov;110(5):790-6.

BACKGROUND: No asparagus allergen has been characterized to date. Lipid transfer proteins (LTPs) have an ubiquitous distribution in plant foods and have been identified as relevant allergens in some fruits, seeds, and pollens. OBJECTIVE: We sought to identify asparagus allergens and to evaluate the potential involvement of the panallergen LTP family in asparagus allergy. METHODS: Eighteen patients with asthma, anaphylaxis, and/or contact urticaria after asparagus ingestion or exposure and positive skin prick test (SPT) responses and serum-specific IgE levels to asparagus were selected. Two LTPs were isolated from crude asparagus extract by using chromatographic methods and characterized by means of N-terminal amino acid sequencing. Both isolated proteins were tested by means of immunodetection, CAP inhibition assays, and SPTs. Additional asparagus allergens were located by using immunodetection with a pool of sera from patients allergic to asparagus and with rabbit polyclonal antibodies to sunflower pollen profilin and anti-complex asparagine-linked glycans antibodies. RESULTS: The purified LTPs showed an N-terminal amino acid sequence similar to that of Pru p 3 and a strong reaction to anti-Pru p 3 antibodies. Each isolated protein reached inhibition values of up to 60% in CAP inhibition assays against asparagus extracts and elicited positive SPT responses in 9 of 18 patients with asparagus allergy. Immunodetection assays allowed us to identify profilin and cross-reacting carbohydrate determinants as asparagus IgE-binding components. CONCLUSION: Asparagus LTPs are relevant allergens. In addition, profilin and glycoproteins harboring complex asparagine-linked glycans can also be involved in asparagus allergy.

6561.  Fahy JV. Goblet cell and mucin gene abnormalities in asthma. Chest. 2002 Dec;122(6 Suppl):320S-326S. Review.

Goblet cell hyperplasia (GCH) has been established as a pathologic characteristic of mild, moderate, and severe asthma. Abnormalities in goblet cell number are accompanied by changes in stored and secreted mucin (MUC). The functional consequences of these changes in MUC stores and secretion can contribute to the pathophysiologic mechanisms for multiple clinical abnormalities in patients with asthma, including sputum production, airway narrowing, exacerbations, and accelerated loss in lung function. CD4(+) T cells and their T-helper type-2 cytokine products are important mediators of GCH, and MUC5AC is the dominant MUC gene that is expressed in goblet cells. The mechanism of cytokine-induced GCH, the relationships between MUC gene up-regulation and GCH, and the role of ion channels are all currently being explored. The process of working out the molecular mechanisms of GCH and goblet cell degranulation should provide new targets for novel therapeutic interventions. Such new treatments are urgently needed, because mucus hypersecretion is an important cause of morbidity and mortality in patients with asthma, and no specific treatments are available.

6562.  Foerster M, Haefner D, Kroegel C. Bcl-2-mediated regulation of CD69-induced apoptosis of human eosinophils: identification and characterization of a novel receptor-induced mechanism and relationship to CD95-transduced signalling. Scand J Immunol. 2002 Oct;56(4):417-28.

Elimination of the eosinophils from the airways by selective induction of apoptosis represents a therapeutic approach for asthma. Here we report on a possible target molecule, the surface receptor CD69. To simulate an asthmatic response, segmental allergen challenge in mild asthmatics was performed. Eosinophil numbers increased in bronchoalveolar lavage (BAL) at 18 h. In contrast to blood cells, BAL eosinophils expressed the activation marker CD69. Purified blood eosinophils stimulated with granulocyte/macrophage colony-stimulating factor (GM-CSF) or interferon-gamma (IFN-gamma) expressed CD69 and showed prolonged viability. Only IFN-gamma enhanced constitutive CD95 expression. Coincubation with anti-CD69 or anti-CD95 monoclonal antibody (MoAb) induced apoptosis, as revealed by propidium iodide incorporation, membrane blebbing and nuclear fragmentation. Additionally, both anti-CD69 and anti-CD95 MoAb reduced cytokine-enhanced Bcl-2 expression. In conclusion, CD69 transduces a Bcl-2-dependent death signal when ligated by a specific antibody. As, in contrast to the ubiquitous death-inducer CD95, the function of CD69 appears to be restricted to activated eosinophils, it represents an ideal target for therapeutic intervention in asthma.

6563.  Greenberger PA. Corresponding patterns of rhinitis and asthma during pregnancy. Ann Allergy Asthma Immunol. 2002 Nov;89(5):437-8. No abstract.

6564.  Guthrie CM, Tingen MS. Asthma: a case study, review of pathophysiology, and management strategies. J Am Acad Nurse Pract. 2002 Oct;14(10):457-61; quiz 462-4.

PURPOSE: To review the pathophysiology of asthma, present a case study, and provide management strategies for treating this common, yet complex disorder in children and adults. DATA SOURCES: Selected clinical guidelines, clinical articles, and research studies. CONCLUSIONS: Asthma is a chronic inflammatory airway disorder with acute exacerbations that currently affects approximately 14 million-15 million children and adults in the United States. Costs for asthma are staggering and nurse practitioners (NPs) are frequently presented with management decisions for the acute treatment and chronic management of this disorder. Disparities exist with the occurrence of asthma between race and gender. Additionally, there is an increased incidence in acute exacerbations resulting from poor long-term control and follow-up care among the socioeconomically disadvantaged. IMPLICATIONS FOR PRACTICE: Standards of care, along with new and emerging treatment strategies, guide NPs in providing the most comprehensive care to those affected with this chronic disorder. Knowledge about the pathophysiology of asthma and correlated to the case presentation enhances understanding treatment strategies for NPs who are often faced with providing care for patients with this chronic disorder that may sometimes present in an acute exacerbation.

6565.  Habib GS, Saliba WR, Cohen L. Diabetic ketoacidosis associated with oral salbutamol overdose. Am J Med. 2002 Dec 1;113(8):701-2. No abstract

6566.  Hartert TV, Speroff T, Togias A, Mitchel EF Jr, Snowden MS, Dittus RS, Griffin MR. Risk factors for recurrent asthma hospital visits and death among a population of indigent older adults with asthma. Ann Allergy Asthma Immunol. 2002 Nov;89(5):467-73.

BACKGROUND: Little is known about the morbidity and mortality among older adults with asthma requiring hospital care. OBJECTIVES: To determine whether an initial hospital visit for asthma was associated with an increase in use of inhaled corticosteroids (CCS) at discharge, and to identify risk factors for recurrent asthma hospital visits and death. METHODS: A retrospective cohort analysis identified 93,174 persons 65 years and older enrolled in the Tennessee Medicaid program for at least 1 year and free of asthma hospital visits during that year; 510 survived a single hospital visit for asthma in 1992 and comprised the study population. Main outcome measures included recurrent hospital visit for asthma and all-cause mortality during the year after an asthma hospital visit. RESULTS: Among the 510 study subjects, 10% were on inhaled CCS at admission compared with 11% at discharge. Twenty-three percent of the population had recurrent asthma hospital visits and 12% died during 1-year followup. Asthma severity was the strongest independent risk factor for both a recurrent hospital visit [relative risk for moderate to severe disease 1.92 (1.01 to 3.66), and for near-fatal disease 2.28 (1.01 to 5.13), respectively] and death [relative risk for moderate to severe disease 2.99 (1.07 to 8.32) and for near-fatal disease 4.44 (1.34 to 4.69), respectively]. CONCLUSIONS: In this population, older adults with an exacerbation of asthma requiring hospital care experienced significant morbidity and mortality. An acute hospital visit for an asthma exacerbation did not result in initiation of inhaled CCS therapy. Asthma severity predicted both recurrent hospital visits and all-cause mortality among older adults with asthma requiring hospital care.

 

6567.  Hutchison DC, Cooper D. Alpha-1-antitrypsin deficiency: smoking, decline in lung function and implications for therapeutic trials. Respir Med. 2002 Nov;96(11):872-80.

BACKGROUND: Alpha-1-antitrypsin (AT) deficiency is a hereditary disorder associated with pulmonary emphysema. AT replacement therapy has been available for many years with only one randomised controlled trial, showing no improvement in the rate of decline in lung function. We aimed to obtain further data on the natural history of the disorder and thus to refine the criteria for future clinical trials. METHODS: Homozygotes for Pi type Z were identified among chest clinic patients and close relatives. Clinical and lung function data were obtained by means of a standardised questionnaire administered yearly for a maximum of 15 years. RESULTS: Baseline study: forced expiratory volume in 1 s (FEV1) and vital capacity (VC) were studied in 194 Pi type Z patients at registration. Past or present smoking history had the strongest relationship to reduction in FEV1 (P < 0.001), but among those who had smoked, estimated total lifetime tobacco consumption (kg) was not significantly related to FEV1. No effecton FEV1 was produced by gender, age of starting to smoke, asthma, occupation or intra-family factors in sib pairs concordant for smoking. Follow-up study: In 71 patients, the average number of annual lung function assessments per subject was 8.0 (range 6-13) and average follow-up time 97 years (range 4.2-14.9). FEV1 slope tended to be steeper in current smokers than in ex-smokers (0.05 < P < 0.1) and greatest in patients with initial FEV1 in the range 30-65% predicted. Effects on VC were less severe. Much deterioration takes place before emphysematous patients come to clinical attention. FEV1 slopes calculated using only the first four assessments have a significantly greater variance than when calculated on all assessments (F = 3.79; P < 0.01). FEV1 and VC slopes using post-bronchodilator values are greater than when using pre-bronchodilator values. CONCLUSIONS: Future trials of AT replacement therapy need rigorous standardisation of lung function testing (including bronchodilator protocol) together with an adequate period of assessment. Only randomised controlled trials should be considered valid. Therapy should ideally be started earlier than normally envisaged and before the onset of clinical emphysema.

 

6568.  James AL, Maxwell PS, Pearce-Pinto G, Elliot JG, Carroll NG. The relationship of reticular basement membrane thickness to airway wall remodeling in asthma. Am J Respir Crit Care Med. 2002 Dec 15;166(12 Pt 1):1590-5.

Assessment of airway wall remodeling in asthma is difficult in vivo. The thickness of deposited extracellular matrix proteins below the epithelium, the reticular basement membrane, can be assessed by bronchial biopsy of proximal airways. The aim of this study was to determine the relationship between the thickness of the reticular basement membrane in a sample equivalent to a central airway biopsy and the dimensions of the airway wall measured on transverse sections of both central and peripheral airways. Large and small cartilaginous and membranous airways from persons who had died from asthma (fatal asthma, n = 5) or from nonrespiratory causes with asthma (nonfatal asthma, n = 5) or without asthma (control subjects, n = 5) were studied. Reticular basement membrane thickness correlated with the percentage of smooth muscle, submucosal mucous gland, and inner wall area (p < 0.05) in large cartilaginous airways, and with inner wall area and area of smooth muscle (p < 0.01) in small cartilaginous airways, but was not related to airway wall dimensions in membranous airways. These findings show that reticular basement membrane thickness of central airways, which may be assessed by endobronchial biopsy, is correlated with airway remodeling in cartilaginous airways but not with airway wall dimensions of membranous airways.

6569.  Johnson GL, Lapadat R. Mitogen-activated protein kinase pathways mediated by ERK, JNK, and p38 protein kinases. Science. 2002 Dec 6;298(5600):1911-2. Review.

Multicellular organisms have three well-characterized subfamilies of mitogen-activated protein kinases (MAPKs) that control a vast array of physiological processes. These enzymes are regulated by a characteristic phosphorelay system in which a series of three protein kinases phosphorylate and activate one another. The extracellular signal-regulated kinases (ERKs) function in the control of cell division, and inhibitors of these enzymes are being explored as anticancer agents. The c-Jun amino-terminal kinases (JNKs) are critical regulators of transcription, and JNK inhibitors may be effective in control of rheumatoid arthritis. The p38 MAPKs are activated by inflammatory cytokines and environmental stresses and may contribute to diseases like asthma and autoimmunity.

6570.  Jones AM, Munavvar M, Vail A, Aldridge RE, Hopkinson L, Rayner C, O'Driscoll BR.  Prospective, placebo-controlled trial of 5 vs 10 days of oral prednisolone in acute adult asthma. Respir Med. 2002 Nov;96(11):950-4. No abstract.

6571.  Kanazawa H, Hirata K, Yoshikawa J. Involvement of vascular endothelial growth factor in exercise induced bronchoconstriction in asthmatic patients. Thorax. 2002 Oct;57(10):885-8.

BACKGROUND: There is evidence that the bronchial microcirculation has the potential to contribute to the pathophysiological mechanisms of exercise induced bronchoconstriction (EIB) in asthmatic subjects. Vascular endothelial growth factor (VEGF), which is highly expressed in asthmatic airways, increases vascular permeability. The relationship between VEGF levels in induced sputum and the severity of EIB in asthmatic subjects was studied. METHODS: The concentration of VEGF in induced sputum was examined in 23 asthmatic subjects and 11 normal controls. The asthmatic subjects performed an exercise test and the % maximal fall in forced expiratory volume in 1 second (FEV(1)) was measured. Beclomethasone dipropionate (BDP) 400 micro g twice daily was administered to the asthmatic subjects for 8 weeks and the exercise test and sputum induction were repeated. RESULTS: The concentration of VEGF in induced sputum was significantly higher in asthmatic subjects than in normal controls. There was a significant correlation between the concentration of VEGF and the % maximal fall in FEV(1) (r=0.826, p=0.0001) and between the concentration of VEGF and airway vascular permeability index (r=0.621, p=0.0037). After treatment with inhaled BDP there was a significant decrease in the concentration of VEGF in the asthmatic subjects (before treatment: 7051 (2361) pg/ml, after treatment: 4498 (2135) pg/ml, p<0.0001). The change in the concentration of VEGF was significantly correlated with the change in the % maximal fall in FEV(1) (r=0.463, p=0.031). CONCLUSIONS: Excessive production of VEGF in asthmatic airways may contribute to the pathogenesis of EIB via increased airway vascular permeability.

6572.  Ketchell RI, Jensen MW, Lumley P, Wright AM, Allenby MI, O'connor BJ. Rapid effect of inhaled fluticasone propionate on airway responsiveness to adenosine 5'-monophosphate in mild asthma. J Allergy Clin Immunol. 2002 Oct;110(4):603-6.

Inhaled adenosine 5'-monophosphate (AMP) has an "indirect" bronchoconstrictive effect through mast cell degranulation and mediator release, whereas inhaled histamine has a "direct" effect on smooth muscle. Prolonged treatment with inhaled glucocorticosteroids attenuates airway responsiveness (AR) to AMP and histamine. We investigated the early effects of inhaled fluticasone propionate (FP) therapy on AR in 3 consecutive double-blind, randomized, placebo-controlled crossover studies in steroid-naive subjects with mild asthma. In one study, each of 12 subjects received FP 1000 microg or matched placebo for 7 inhalations at 12 hourly intervals; AR to AMP and FEV(1) were measured 2 hours after the 3^rd and 7th inhalations. In a second study, each of 12 subjects received FP 100, 250, or 1000 microg or matched placebo for 3 inhalations at 12 hourly intervals; AR to AMP and FEV(1) were measured 2 hours after the 1st and 3rd inhalations. In a third study, each of 8 subjects received a single inhalation of FP 1000 microg or matched placebo; AR to histamine was measured 2 hours later. In the first study, FP 1000 microg significantly attenuated AR to AMP by 2.7 and 2.5 doubling doses after 3 and 7 inhalations, respectively (P < or =.0001). In the second study, FP 100, 250, and 1000 microg significantly attenuated AR to AMP by 1.9, 2.2, and 2.7 doubling doses, respectively, after 1 inhalation and by 2.4, 2.2, and 3.2 doubling doses, respectively, after 3 inhalations (P < or =.0001); a small but significant increase in FEV(1) (>0.15 L) was observed after 3 inhalations but not after 1 inhalation of FP irrespective of dose (P < or =.05). In the third study, a single inhalation of FP 1000 microg had no effect on AR to histamine. We have demonstrated a reduction in AR to AMP but not AR to histamine within 2 hours of a single inhalation of FP. This reflects a rapid, topical anti-inflammatory action of inhaled FP by a mechanism of action that remains unknown.

6573.  Kobayashi S, Inokuma S, Setoguchi K, Kono H, Abe K. Incidence of peripheral blood eosinophilia and the threshold eosinophile count for indicating hypereosinophilia-associated diseases. Allergy. 2002 Oct;57(10):950-6.

BACKGROUND: A definite threshold of the peripheral blood eosinophile count that indicates the presence of hypereosinophilia-associated diseases has not yet been determined. METHODS: The threshold eosinophile count at which cases of  hypereosinophilia-associated diseases (n = 25) can be differentiated from those of bronchial asthma (n = 101) was determined. Then, the incidences of eosinophile counts greater than 1.0 x 10(9)/l or the threshold level, were studied by analysis of 43,805 samples sent to the laboratory, and the diseases associated with the increased counts were determined. RESULTS: The eosinophile count in cases of hypereosinophilia-associated diseases and in those of bronchial asthma were 10.967 +/- 1.680 x 10(9)/l and 0.574 +/- 0.045 x 10(9)/l, respectively (P < 0.001); the threshold was 2.052 x 10(9)/l. The percentages of samples with an eosinophile count of more than 1.0 x 10(9)/l and 2.052 x 10(9)/l were 0.6% and 0.1%, respectively; the latter comprised of 41 samples from 24 patients including eight with hypereosinophilia-associated diseases. The patients with hypereosinophilia-associated diseases had a significantly higher count, and a higher incidence of counts of more than 2.052 x 10(9)/l, than others, including patients with malignancies and symptoms conventionally referred as "atopic diseases". CONCLUSION: Hypereosinophilia-associated diseases are associated with a very high eosinophile count of more than 2.052 x 10(9)/l, which was observed rarely.

6574.  Koh YY, Park Y, Kim CK. Maximal airway response in adolescents with long-term asthma remission and persisting airway hypersensitivity: its profile and the effect of inhaled corticosteroids. Chest. 2002 Oct;122(4):1214-21.

BACKGROUND: Many children with asthma go into long-term clinical remission at adolescence, but bronchial hyperresponsiveness (BHR) persists in some of these subjects. BHR in asthma is characterized by an increase in sensitivity and in maximal airway response to bronchoconstrictor stimuli. OBJECTIVE: The aims of this study were to compare the profiles of maximal airway response between adolescents with asthma remission and adolescents with symptomatic asthma to a similar degree of airway hypersensitivity, and to determine whether maximal airway response in adolescents with asthma remission is reduced by prolonged treatment with inhaled corticosteroids. METHODS: A high-dose methacholine inhalation test was performed in 46 adolescents with long-term asthma remission (remission group) and 44 adolescents with symptomatic asthma (symptomatic group). Subjects exhibiting a maximal response plateau in the remission group were administered inhaled budesonide (400 microg bid, budesonide/remission group, n = 15) or identical placebo (placebo/remission group, n = 15) for 6 months, and the subjects in the symptomatic group were administered the same regimen of budesonide (budesonide/symptomatic group, n = 17). The plateau level was measured after 3 months and 6 months of treatment. RESULTS: Thirty-four subjects (73.9%) in the remission group featured a maximal response plateau on the dose-response curve to methacholine, whereas 19 subjects (43.2%) in the symptomatic group had a plateau (p = 0.003). In neither the placebo/remission group nor the budesonide/remission group did the plateau level change significantly over the 6-month period, whereas budesonide markedly decreased the level in the budesonide/symptomatic group. CONCLUSION: The difference in frequency of detection of a plateau between the remission group and the symptomatic group, as well as the difference in its response to treatment with budesonide between the two groups, suggests that inflammatory changes impact the maximal airway response in symptomatic asthmatic adolescents but not in adolescents with asthma remission.

6575.  Laske N, Volk HD, Liebenthalb C, Gr uber C, Sommerfeld C, Nickel R, Wahn U.  Infantile natural immunization to herpes group viruses is unrelated to the development of asthma and atopic phenotypes in childhood. J Allergy Clin Immunol. 2002 Nov;110(5):811-3. No abstract.

6576.  Laube BL, Curbow BA, Costello RW, Fitzgerald ST. A pilot study examining the relationship between stress and serum cortisol concentrations in women with asthma. Respiir Med. 2002 Oct;96(10):823-8

The mechanism (s) by which stress exacerbates asthma is unknown. One explanation could be a reduction in endogenous serum cortisol concentrations as a result of stress. Our objective was to determine if a reduction in morning serum cortisol concentrations is associated with higher levels of stress in women with asthma. In this pilot study, seven women with a history of allergic-asthma were prospectively assigned to either low, moderate, or high stress groups based on a combination of their level of current stress and their resources to cope with the stress. After stress group assignment, women donated a morning blood sample, which was analyzed for serum cortisol concentration by an independent laboratory whose personnel were blinded to the subjects' stress status. Three women were assigned to the low stress group, two to the moderate stress group and two to the high stress group. Serum cortisol concentrations ranged from 8 to 23 microg/dl, averaging 14 +/- 6 microg/dl. A Spearman rank correlation indicated that serum cortisol concentrations were significantly inversely related to the stress groupings (r(s) = -0.915; P = 0.025). These results suggest that a reduction in morning serum cortisol concentration may be associated with higher levels of stress and lower resources to cope with the stress in women with allergic-asthma.

6577.  Lewith GT, Hyland ME, Shaw S. Do attitudes toward and beliefs about complementary medicine affect treatment outcomes? Am J Public Health. 2002 Oct;92(10):1604-6. No abstract.

6578.  Litonjua AA, Milton DK, Celedon JC, Ryan L, Weiss ST, Gold DR. A longitudinal analysis of wheezing in young children: the independent effects of early life exposure to house dust endotoxin, allergens, and pets. J Allergy Clin Immunol. 2002 Nov;110(5):736-42.

BACKGROUND: It has been postulated that exposure to bacterial endotoxins and animals early in life might confer protection against the development of asthma and allergies. OBJECTIVE: We investigated the longitudinal effects of exposure to house dust endotoxin (HDE), allergen levels, and the presence of a dog in the home on wheezing in young children over a 4-year period. METHODS: Two hundred twenty-six children younger than 5 years were followed for 4 years. Endotoxin and allergen levels were measured from house dust collected at baseline. Longitudinal associations were investigated by using a proportional hazards technique that allowed for multiple outcomes per subject. RESULTS: Exposure to high concentrations of HDE of greater than the median level was associated with an increased risk for wheezing over the period of observation (multivariate relative risk, 1.52; 95 % CI, 1.07-2.14), but this risk rapidly decreased over time (P for trend =.005). Exposure to cockroach allergen was associated with increased risk for wheezing, whereas exposure to cat allergen and the presence of a dog in the home were both associated with decreased risk for wheezing. The risks associated with cockroach allergen, cat allergen, and dog did not change over the period of observation. CONCLUSION: The negative associations between exposures to dogs and cat allergen and wheeze appear to be independent of the effects of endotoxin and suggest that separate mechanisms might mediate the effects of HDE exposure and pet exposure on the developing immune system.

 

6579.  Liu LY, Sedgwick JB, Bates ME, Vrtis RF, Gern JE, Kita H, Jarjour NN, Busse WW, Kelly EA.  Decreased expression of membrane IL-5 receptor alpha on human eosinophils: I. Loss of membrane IL-5 receptor alpha on airway eosinophils and increased soluble IL-5 receptor alpha in the airway after allergen challenge. J Immunol. 2002 Dec 1;169(11):6452-8.

IL-5 is a key cytokine for eosinophil maturation, recruitment, activation, and possibly the development of inflammation in asthma. High concentrations of IL-5 are present in the airway after Ag challenge, but the responsiveness of airway eosinophils to IL-5 is not well characterized. The objectives of this study were to establish, following airway Ag challenge: 1) the expression of membrane (m)IL-5Ralpha on bronchoalveolar lavage (BAL) eosinophils; 2) the responsiveness of these cells to exogenous IL-5; and 3) the presence of soluble (s)IL-5Ralpha in BAL fluid. To accomplish these goals, blood and BAL eosinophils were obtained from atopic subjects 48 h after segmental bronchoprovocation with Ag. There was a striking reduction in mIL-5Ralpha on airway eosinophils compared with circulating cells. Furthermore, sIL-5Ralpha concentrations were elevated in BAL fluid, but steady state levels of sIL-5Ralpha mRNA were not increased in BAL compared with blood eosinophils. Finally, BAL eosinophils were refractory to IL-5 for ex vivo degranulation, suggesting that the reduction in mIL-5Ralpha on BAL eosinophils may regulate IL-5-mediated eosinophil functions. Together, the loss of mIL-5Ralpha, the presence of sIL-5Ralpha, and the blunted functional response (degranulation) of eosinophils to IL-5 suggest that when eosinophils are recruited to the airway, regulation of their functions becomes IL-5 independent. These observations provide a potential explanation for the inability of anti-IL-5 therapy to suppress airway hyperresponsiveness to inhaled Ag, despite a reduction in eosinophil recruitment.

6580.  Louis R, Sele J, Henket M, Cataldo D, Bettiol J, Seiden L, Bartsch P. Sputum eosinophil count in a large population of patients with mild to moderate steroid-naive asthma: distribution and relationship with methacholine bronchial hyperresponsiveness. Allergy. 2002 Oct;57(10):907-12.

BACKGROUND: Although airway eosinophilia is seen as a cardinal feature of asthma, data eosinophilia are still lacking on the proportion of the asthma group exhibiting raised airway eosinophilia. This study aimed to assess the distribution of sputum eosinophil count and its relationship with methacholine bronchial hyperresponsiveness in mild to moderate steroid-naive asthmatic people. METHODS: Sputum was induced by inhalation of hypertonic saline (NaCl 4.5%) in 118 mild to moderate steroid-naive asthmatic people consecutively recruited from our outpatient clinic, and in 44 healthy people. The asthma group was selected on the basis of an forced expiratory volume in 1 s (FEV(1)) of > or = 70% predicted, and a provocative methacholine concentration causing a fall of 20% in FEV(1) (PC20 methacholine; PC(20)M) < or = 16 mg/ml. RESULTS: In the asthma group, the median (range) of the percentage and the absolute values of sputum eosinophils were 4.8% (0-75) and 38 10(3)/g (0-14,191), respectively, vs 0% (0-2.3) (P < 0.001) and 0 10(3)/g (0-53) (P < 0.001) in healthy participants. Based on the 95% percentile for normal values calculated from our healthy group, 69% of the asthma group had significantly raised sputum eosinophil count (that is > 2%). In the asthma group, multiple regression analysis followed by a stepwise procedure revealed that sputum eosinophil count was significantly and inversely associated with PC(20)M accounting for 16% of its total variance (P < 0.001) while neutrophil counts positively related to PC(20)M accounting for 4% of total variance (P < 0.05). By contrast, no significant relationship was found between either eosinophil or neutrophil counts and the slope of forced vital capacity (FVC) vs FEV(1) from the methacholine challenge. CONCLUSIONS: We conclude that two-thirds of people in the mild to moderate asthma group had increased sputum eosinophilia, which plays a limited role in determining the degree of methacholine airway hyperresponsiveness.

6581.  Mander A, Langton-Hewer S, Bernhard W, Warner JO, Postle AD. Altered phospholipid composition and aggregate structure of lung surfactant is associated with impaired lung function in young children with respiratory infections. Am J Respir Cell Mol Biol. 2002 Dec;27(6):714-21.

Alterations to pulmonary surfactant structure, composition, and function contribute to the severity of respiratory infections. Analysis of bronchoalveolar lavage fluid (BALF) from children undergoing diagnostic bronchoscopy for structural abnormalities (control group, n = 24), asthma (n = 18), lung infection (n = 30), and cystic fibrosis (CF, n = 15) showed that BALF phospholipid concentration decreased with age for the control group and was elevated in  all disease groups. The fractional concentration of the major surface active component, dipalmitoyl phosphatidylcholine (PC16:0/16:0), correlated (r(2) = 0.608, P < 0.01) with airway resistance (FEV(1%) predicted), and decreased PC16:0/16:0 was accompanied by increased concentrations of phospholipid components characteristic of cell membranes (PC16:0/18:1 and PI18:0/20:4). Median minimal surface tension, measured by pulsating bubble surfactometer, was elevated (P < 0.01) in both infection (17.5 mN/m) and CF (17.1 mN/m) compared with the control group (1.5 mN/m). Centrifugation (60,000 x g, 40 min) of BALF indicated that infection was accompanied by accumulation of large aggregate forms of surfactant, in contrast to previous reports of increased conversion to inactive small aggregate surfactant particles in ventilated patients with respiratory failure. This accumulation of surface-inactive, large aggregate forms of surfactant, possibly due to mixing with membrane material from inflammatory cells, may contribute to severity of lung disease in children with respiratory infections.

6582.  McKenzie SA, Bush A. Difficult asthma in children. Thorax. 2002 Oct;57(10):915-6. Asthmatic children on high dose corticosteroids need to be fully assessed to ensure that such dosages are really necessary. Further work needs to be undertaken to find the best approach to poor treatment adherence and false claims for financial support. The benefits of particular components of specialist assessment need to be evaluated prospectively and multicentre collaboration is needed to evaluate phenotype specific treatment and new treatments for truly difficult asthma.

6583.  Medeiros M Jr, Figueiredo JP, Almeida MC, Atta AM, Taketomi EA, Silva DA, Terra SA, Amorim WW, Pinho RS, Araujo MI, Carvalho EM.  Association between mite allergen (Der p 1, Der f 1, Blo t 5) levels and microscopic identification of mites or skin prick test results in asthmatic subjects. Int Arch Allergy Immunol. 2002 Nov;129(3):237-41.

BACKGROUND: Mite allergens have been involved in airway sensitization and allergic diseases. Immunoassays for the identification and quantifiction of house dust mite (HDM) allergens are useful to improve the knowledge of regional mite fauna and the remediation of mite allergens in allergic diseases. The present study analyzed the association between levels of HDM allergen and results of mite identification or skin prick test (SPT) in two different areas of Bahia, Brazil. METHODS: Forty-two asthmatic subjects from a rural area (group I; n = 21) and a slum (group II; n = 21) were evaluated through SPT with HDM allergens and had dust samples collected at their homes for mite identification and allergen measurements. RESULTS: Positive SPT to Dermatophagoides pteronyssinus, Dermatophagoides farinae and Blomia tropicalis allergens were observed in 42.9, 38.0 and 42.9% subjects from group I and in 47.6, 19.0 and 33.3% subjects from group II, respectively. D. pteronyssinus and B. tropicalis were identified in approximately 76 and 50% of samples from both groups, respectively. D. farinae was identified in 38.0 and 9.5% of samples from groups I and II, respectively (p < 0.005). Der p 1, Der f 1 and Blo t 5 detection were associated with mite identification (p < 0.05). Association between HDM allergen levels over 2 microg/g of dust and positive SPT occurred only with D. pteronyssinus (p < 0.0001). CONCLUSIONS: D. pteronyssinus was the most prevalent  mite species in this study followed by B. tropicalis and D. farinae. Immunoassays done to measure mite allergens were associated with mite-species identification. We conclude that these three mite species must be included on panels for the diagnosis of allergic airway diseases in subjects living in such regions. Copyright 2002 S. Karger AG, Basel

6584.  Meyer PA, Mannino DM, Redd SC, Olson DR. Characteristics of adults dying with COPD. CChest. 2002 Dec;122(6):2003-8

STUDY OBJECTIVE: To describe factors associated with COPD deaths in the United States. DESIGN: Cross-sectional survey. PARTICIPANTS: A total of 12,803 decedents in the National Mortality Followback Survey, a nationally representative sample of US deaths in 1993. METHODS: We compared the characteristics of adults > or = 35 years of age who died with COPD (bronchitis, emphysema, chronic airway obstruction) with those dying without COPD listed on their death certificates. RESULTS: Of the estimated 225,400 adults who died with COPD in 1993, 16.7% had never smoked. People dying with COPD were more likely than those dying without COPD to be current smokers (odds ratio [OR], 6.5; 95% confidence interval [CI], 4.3 to 9.9) or former smokers (OR, 3.7; 95% CI, 2.5 to 5.3), have a history of asthma (OR, 5.0; 95% CI, 3.2 to 7.8), be underweight (OR, 4.5; 95% CI, 2.8 to 7.2), and be of the white race (OR, 3.1; 95% CI, 2.4 to 4.0), after controlling for age group and sex. CONCLUSIONS: A significant proportion of COPD-related deaths occurs in never-smokers. Factors such as a history of asthma and being underweight are associated with COPD mortality and may provide additional opportunities for intervention.

6585.  Moneret-Vautrin DA. Optimal management of atopic dermatitis in infancy. Allerg Immunol (Paris). 2002 Nov;34(9):325-9.

The necessity to optimise the management of atopic dermatitis of infants needs knowledge of three components: increase of prevalence, extreme frequency of food allergy and increase in the frequency of the syndrome of multiple allergies, that frequently develops into asthmatic disease. Management of DA in infancy (first year of life) is based on the global strategy of understanding the physiological Th2 polarisation at birth, that does not allow a re-equilibration of the Th1-Th2 balance that progresses in the first six months of life (in normal infants) making in this period a window of opportunity for sensitizations. Prevention in high-risk children (familial history of atopy) covers the non-exposure to in door pollutants (tobacco and volatile organic compounds), breast-feeding or a hypoallergenic formula for a hydrolysate of pork and soya proteins or better an extensive hydrolysate of casein. Four situations require moving to an amino acid substitute: failure to thrive, severe atopic dermatitis, a syndrome of multiple food allergies, allergy to hydrolysates. Reintroduction of foods should be considered with the least delay so as to induce digestive tolerance. It should take into account the clinical development, the intensity of the sensitisation and eventually depend on a realistic test of introduction. Management of DA searches for recovery of generalized eczema, failure to immediate improvement of quality of life prevention of immediate complications (local sepsis) acceleration of return to food tolerance. Prevention of ulterior development of asthma by immediately introducing measures to diminish respiratory exposure to allergens and tobacco is hoped for.

6586.  Namazy JA, Simon RA. Sensitivity to nonsteroidal anti-inflammatory drugs.  Ann Allergy Asthma Immunol. 2002 Dec;89(6):542-50; quiz 550, 605.

BACKGROUND: Aspirin can provoke reactions ranging from respiratory to cutaneous in susceptible individuals. There has been particular attention looking at the role of cyclo-oxygenase enzymes 1 and 2 and their role in aspirin-exacerbated respiratory disease. OBJECTIVE: Patients who present with a spectrum of allergic and pseudoallergic reactions to aspirin pose a special challenge for the physician. This article discusses proposed classification system, clinical manifestations, pathogenesis of disease, and current treatment options of aspirin-related disease. DATA SOURCES: Relevant articles in the medical literature were derived from searching the MEDLINE database with key terms aspirin-sensitive asthma, cyclo-oxygenase enzymes 1 and 2. Sources also include review articles, randomized control trials, and standard textbooks of allergy and immunology. RESULTS: Aspirin-exacerbated respiratory disease remains a complex, heterogenous disease with varied clinical presentations. There have been many advances in trying to elucidate the pathogenesis of this disease. The classification system presented will provide greater ease when reading the literature and communicating with one another. Oral aspirin challenge remains the diagnostic test of choice for both respiratory and cutaneous reactions. Aspirin desensitization is an option for those with refractory respiratory disease or who require aspirin for other medical conditions. CONCLUSIONS: This review discusses the challenges in classification, diagnosis, and treatment of those patients with a sensitivity to aspirin. Special attention is made to the possible mechanisms mediating disease progression and how specific therapies, such as leukotriene modifiers, may be helpful.

6587.  O'Sullivan S, Cormican L, Murphy M, Poulter LW, Burke CM. Effects of varying doses of fluticasone propionate on the physiology and bronchial wall immunopathology in mild-to-moderate asthma. Chest. 2002 Dec;122(6):1966-72.

OBJECTIVES: Inhaled corticosteroids (ICS) are typically associated with a flat dose-response curve when traditional efficacy values are examined (eg, FEV(1)). The aim of the present study was to investigate if a dose-response relationship exists for lung function and inflammatory cell numbers in bronchial biopsy specimens. METHODS: Bronchial biopsy specimens were obtained from 36 patients randomized to receive 100 micro g, 500 microg, or 2,000 microg/d of fluticasone propionate (FP). Lung physiology and bronchial biopsies were performed at baseline and after 2 weeks of treatment. RESULTS: Improvement in lung function and suppression of airway inflammation were optimal at a dose of 500 microg/d of FP. Significant changes from baseline following treatment were documented in FEV(1) (p = 0.02), forced expiratory flow (p = 0.002), FEV(1)/FVC (p = 0.007), provocative concentration of histamine causing a 20% fall in FEV(1) (PC(20)) [p = 0.02], T-cell numbers (p = 0.0005), activated eosinophils (p = 0.01), and numbers of macrophages (p = 0.01) in the group treated with 500 microg/d of FP. Comparison between groups administered different doses of FP failed to demonstrate a dose-response relationship for change from baseline in PC(20) (p = 0.43), any of the lung function parameters, T-cell numbers (p = 0.64), activated T cells (p = 0.46), eosinophils (p = 0.53), activated eosinophils (p = 0.48), or macrophage numbers (p = 0.68). CONCLUSION: The apparent lack of a dose-response for ICS treatment in patients with asthma further validates the preferential use of add-on therapy over increasing the dose of ICS.

6588.  Osur SL. Viral respiratory infections in association with asthma and sinusitis: a review. Ann Allergy Asthma Immunol. 2002 Dec;89(6):553-60. Review.

OBJECTIVE: Viral respiratory infections (VRIs) commonly precede asthma exacerbations in both children and adults. Likewise, VRIs may affect the paranasal sinuses, predisposing infected individuals to the development of subsequent acute bacterial sinusitis. This article discusses the role that viruses play in both the development of asthma and in acute asthma exacerbations. Mechanisms by which viral infections provoke asthma exacerbations are reviewed, and treatment of such episodes is discussed. The pathogenesis of sinusitis and association with VRIs is reviewed along with treatment recommendations. DATA SOURCES: Relevant articles in the medical literature were reviewed with sources including randomized, controlled clinical trials, review articles, epidemiologic studies, and standard textbooks in allergy and immunology. CONCLUSIONS: This review highlights the prominent role that viral pathogens (especially rhinovirus) play in exacerbation of asthma and in the development of sinus disease. The specific mechanisms whereby viral infection leads to an acute asthma exacerbation or to subsequent bacterial sinusitis are described. Treatment options are outlined including the potential future application of antiviral compounds.

6589.  Palmer GW, Claman HN. Pregnancy and immunology: selected aspects. Ann Allergy Asthma Immunol. 2002 Oct;89(4):350-9; quiz 359-60, 428. Review.

LEARNING OBJECTIVES: This article reviews current concepts of the immunology of pregnancy and of the diagnosis and management of certain allergic conditions in the pregnant woman: asthma, rhinitis, immunotherapy, and hereditary angioedema (HAE). DATA SOURCES: Current texts, reviews, and individual studies were picked from the National Library of Medicine database. RESULTS AND CONCLUSIONS: Knowledge concerning the immunologic paradox of pregnancy continues to evolve. Although the answer is not definitive, attention is being paid to the role of a Th-2 shift in the pregnant uterus. Extensive studies, both epidemiologic and therapeutic, are clarifying the influence of pregnancy on asthma and rhinitis (and vice versa) and the best methods for treatment of these conditions in the pregnant woman. A brief guideline to the handling of hereditary angioedema in pregnancy is presented.

6590.  Piette V, Bourret E, Bousquet J, Demoly P. Prick tests to aeroallergens: is it possible simply to wipe the device between tests? Allergy. 2002 Oct;57(10):940-2.

BACKGROUND: Improperly performed skin prick tests (SPT) can lead to wrong allergy diagnosis and incorrect treatment. To overcome false-positive results it is recommended to change the puncture device between each test, although very few studies have examined the real drawbacks (false-positives) and advantages (time and cost savings) of using only one device. METHODS: Two groups of 20 patients with rhinitis or asthma, sensitized to either house-dust mites or grass pollens, had successive serial SPT to 9% codeine phosphate and the relevant allergen using the same needle or lancet, wiped between each test. RESULTS: With both the needle and the lancet, there were 12.5-67.5% false-positive results using the house-dust mite or grass pollen allergen extracts, respectively. There were no false-positive results with the 9% codeine phosphate. CONCLUSIONS: Our study shows that this technique is not reliable as it provoked an unacceptable number of false-positive results.

6591.  Prikk K, Maisi P, Pirila E, Reintam MA, Salo T, Sorsa T, Sepper R. Airway obstruction correlates with collagenase-2 (MMP-8) expression and activation in bronchial asthma. Lab Invest. 2002 Nov;82(11):1535-45.

Matrix metalloproteinases (MMPs) contribute to extracellular matrix and basement membrane degradation in asthma. The present study analyzed molecular forms and degree of activation and expression of MMP-8 in bronchoalveolar lavage fluid (BALF), BALF cells, and bronchial tissue specimens from 14 steroid-naive asthma patients, 13 uncontrolled severe asthma patients, 13 controlled asthma patients, and 14 healthy subjects by Western immunoblotting, immunohistochemistry, and in situ hybridization. Immunohistochemistry and in situ hybridization revealed a prominent MMP-8 immunoreactivity in submucosal inflammatory, glandular, and shed, but not in intact bronchial epithelial cells of asthma patients. In BALF cytospins, both MMP-8 protein and mRNA expression were observed in epithelial cells, macrophages, and polymorphonuclear leukocytes (PMNs). MMP-8 was present in BALFs asthma patients in complex, pro- and active PMN-type, and pro- and active non-PMN-type forms. BALF MMP-8 was significantly converted to active form only in BALFs from steroid-naive and uncontrolled severe asthma patients, but not in BALFs from well-controlled asthma patients or healthy controls. A significant inverse correlation between BALF MMP-8 levels and FEV1 (r = -0.283, p = 0.04), and BALF activated MMP-8 forms and FEV1 (r = -0.427, p = 0.001) was detected. Overall, these data suggest that MMP-8 and its activation has an important role in the airway destruction, healing, remodeling, and treatment response in asthma.

6592.  Prosperini G, Rajakulasingam K, Cacciola RR, Spicuzza L, Rorke S, Holgate ST, Di Maria GU, Polosa R.  Changes in sputum counts and airway hyperresponsiveness after budesonide: monitoring anti-inflammatory response on the basis of surrogate markers of airway inflammation. J Allergy Clin Immunol. 2002 Dec;110(6):855-61.

BACKGROUND: Airway hyperresponsiveness (AHR) to pharmacologic stimuli and sputum eosinophils might be useful in the individual adjustment of long-term asthma management. However, it is not clear whether inhaled glucocorticosteroids (GCSs) provide greater protection against specific surrogate markers of airways inflammation than other means. In addition, detailed longitudinal assessment of changes in airway response with inhaled GCSs has never been carried out. OBJECTIVES: We compared changes in AHR to inhaled methacholine and adenosine 5'-monophosphate (AMP) after budesonide treatment in a randomized, double-blind, placebo-controlled, crossover study of patients with mild-to-moderate asthma. Subsequently, we undertook a separate study to examine the time course of the changes in AHR in more detail and the changes in sputum cell counts in relation to budesonide treatment. METHODS: In the phase 1 of the study, patients undertook bronchial provocation studies with increasing doubling concentrations of metha choline (0.06 to 16 mg/mL) and AMP (3.125 to 800 mg/mL) before and after budesonide 0.8 mg/daily for 3 weeks. The bronchial responses to the inhaled agonists were expressed as the provocative concentration causing a 20% decline in FEV(1) (PC(20)). In phase 2 of the study, patients attended the laboratory on 12 separate occasions to investigate changes in PC(20) methacholine, PC(20) AMP, and sputum cell counts before, during, and after withdrawal of therapy with inhaled budesonide 0.8 mg/daily for 6 weeks. RESULTS: Budesonide treatment for 3 weeks significantly attenuated the constrictor response by 0.8 +/- 0.3 doubling doses for methacholine and by 2.6 +/- 0.5 doubling doses for AMP. These changes were significantly different from each other (P =.003). Significant variation in PC(20) methacholine (P <.05) value, PC(20) AMP (P <.001) value, percentage of sputum eosinophils (P <.001), and percentage of sputum epithelial cells (P <.001) were observed throughout the longitudinal assessment of changes in airway response to budesonide. Compared with the other surrogate markers, PC(20) AMP appears to be useful in promptly detecting early inflammatory changes of the asthmatic airways; a significant change of 1.6 +/- 0.3, 2.2 +/- 0.3, and 2.8 +/- 0.3 doubling doses of PC(20) AMP was observed at 1, 4, and 6 weeks, respectively, in the course of budesonide treatment. CONCLUSIONS: The present findings underline the exquisite selectivity of diverse surrogate markers of airway inflammation in response to inhaled budesonide. When compared with that to the other markers, AHR to inhaled AMP is an early and sensitive indicator of the beneficial anti-inflammatory effects of topical GCSs.

6593.  Reichenbach J, Jarisch A, Khan S, Homberg M, Bez C, Zielen S. Serum ECP levels and methacholine challenge in infants with recurrent wheezing. Ann Allergy Asthma Immunol. 2002 Nov;89(5):498-502.

BACKGROUND: High levels of serum eosinophil cationic protein (sECP) as a marker of eosinophilic airway inflammation have been described as a predictor of childhood asthma. Bronchial hyperreactivity (BHR) appears to be secondary to the release of inflammatory mediators. OBJECTIVE: We investigated the possible correlation between eosinophilic inflammation and BHR in 72 infants with recurrent wheezing. METHODS: To determine bronchial reactivity, lung function measurements with methacholine challenge were performed in 72 infants, aged 12 to 30 months, and the degree of BHR to methacholine was compared with sECP values. Patients were grouped according to low (group 1, <10 microg/L, n = 22), medium (group 2, 10 to 20 microg/L, n = 23), and high (group 3, >20 microg/L, n = 27) sECP values. RESULTS: In group 1, sECP levels ranged from 3.1 to 9.9 microg/L, mean 6.6 microg/L +/- standard deviation [SD] 2.3, in group 2, from 10.3 to 19.8 microg/L, mean 14.3 microg/L +/- SD 2.8, and in group 3 from 23.0 to 66.7 microg/L, mean 34.5 microg/L +/- SD 9.5. Distribution of provocative methacholine concentration among groups was as follows: group 1, 30 to 976 microg, mean 350.9 microg +/- SD 258.3; group 2, 36 to 752 microg, mean 340.7 microg +/- SD 226.3; group 3, 41 to 848 microg, mean 301.3 microg +/- SD 189.8 methacholine. CONCLUSION: There was no significant correlation between sECP levels and bronchial reactivity in all groups (r = -0.076, P = 0.6), indicating that these parameters reflect two independent pathogenic mechanisms in the etiology of childhood asthma.

6594.  Roth M, Johnson PR, Rudiger JJ, King GG, Ge Q, Burgess JK, Anderson G, Tamm M, Black JL. Interaction between glucocorticoids and beta2 agonists on bronchial airway smooth muscle cells through synchronised cellular signalling. Lancet.  2002 Oct 26;360(9342):1293-9

BACKGROUND: Increased airway smooth muscle bulk is a pathological feature of asthma. Asthma is well controlled by the combined inhalation of glucocorticoids and beta2-adrenoceptor agonists. The basic molecular mechanism of the interaction of the two drugs on proliferation of airway smooth muscle cells is yet to be identified. Our aim was to elucidate how glucocorticoids and beta2 agonists affect the growth of human bronchial airway smooth muscle cells. METHODS: We assessed the effect of formoterol and budesonide on the activation and function of transcription factors by immunohistochemistry, western blottin g, DNA mobility shift assay, and a luciferase reporter gene assay. The effect of the drugs and the involvement of specific transcription factors on cell proliferation was ascertained by direct cell count and confirmed by thymidine incorporation. FINDINGS: Both classes of drugs (10(-8) mol/L) activated C/EBP-alpha and the glucocorticoid receptor with different kinetic profiles, and inhibited proliferation. The combination of lower doses of drugs (10(-12) to 10(-9) mol/L) resulted in a synchronised activation of the transcription factors and an enhanced antiproliferative effect. The action of the drugs alone or in combination on transcription-factor activity and proliferation was suppressed by either depletion of C/EBP-alpha or in the presence of a glucocorticoid-receptor blocker. INTERPRETATION: Our findings could provide one explanation for the nteraction of beta2 agonists and glucocorticoids at a molecular level, and indicate that the concentration of inhaled glucocorticoids can be reduced when combined with beta2 agonists, minimising the side-effects of the drugs.

6595.  Schmidlin F, Amadesi S, Dabbagh K, Lewis DE, Knott P, Bunnett NW, Gater PR, Geppetti P, Bertrand C, Stevens ME. Protease-activated receptor 2 mediates eosinophil infiltration and hyperreactivity in allergic inflammation of the airway. J Immunol. 2002 Nov 1;169(9):5315-21.

Trypsin and mast cell tryptase can signal to epithelial cells, myocytes, and nerve fibers of the respiratory tract by cleaving proteinase-activated receptor 2 (PAR2). Since tryptase inhibitors are under development to treat asthma, a precise understanding of the contribution of PAR2 to airway inflammation is required. We examined the role of PAR2 in allergic inflammation of the airway by comparing OVA-sensitized and -challenged mice lacking or overexpressing PAR2. In wild-type mice, immunoreactive PAR2 was detected in airway epithelial cells and myocytes, and intranasal administration of a PAR2 agonist stimulated macrophage infiltration into bronchoalveolar lavage fluid. OVA challenge of immunized wild-type mice stimulated infiltration of leukocytes into bronchoalveolar lavage and induced airway hyperreactivity to inhaled methacholine. Compared with wild-type animals, eosinophil infiltration was inhibited by 73% in mice lacking PAR2 and increased by 88% in mice overexpressing PAR2. Similarly, compared with wild-type animals, airway hyperreactivity to inhaled methacholine (40 micro g/ml) was diminished 38% in mice lacking PAR2 and increased by 52% in mice overexpressing PAR2. PAR2 deletion also reduced IgE levels to OVA sensitization by 4-fold compared with those of wild-type animals. Thus, PAR2 contributes to the development of immunity and to allergic inflammation of the airway. Our results support the proposal that tryptase inhibitors and PAR2 antagonists may be useful therapies for inflammatory airway disease.

 

6596.  Self TH, Redmond AM, Nguyen WT. Reassessment of theophylline use for severe asthma exacerbation: is it justified in critically ill hospitalized patients? J Asthma. 2002 Dec;39(8):677-86.

In the 1990s, numerous double-blind, randomized, placebo-controlled trials revealed that theophylline therapy offered no benefit to inhaled beta2 agonists and systemic corticosteroids in the treatment of patients hospitalized for asthma exacerbations. Routine use of theophylline in patients hospitalized for asthma is no longer advocated due to the potential for serious adverse effects and lack of benefit. However, the question remains whether this drug adds any benefits in critically ill patients who are being admitted to an intensive care unit. Two recent pediatric studies suggest that theophylline therapy may have a role in the management of patients with impending respiratory failure who have failed aggressive treatment with inhaled beta2 agonists, systemic corticosteroids, and inhaled ipratropium. If a patient has failed to respond adequately to high-dose routine therapies, theophylline should be initiated by a clinician who is competent in dosing, monitoring serum concentrations, and assessing factors that modify clearance of this high-risk drug. Further clinical research is needed to verify the value of theophylline in adults and children with severe asthma exacerbations and impending respiratory failure.

 

6597.  Shiba K, Kasahara K, Nakajima H, Adachi M. Structural changes of the airway wall impair respiratory function, even in mild asthma. Chest. 2002 Nov;122(5):1622-6.

STUDY OBJECTIVES: To clarify whether structural changes of the airway wall impair respiratory function in patients with mild asthma, and to determine whether mild asthma should be treated with inhaled steroids. SETTING: Showa University Hospital in Tokyo. PATIENTS: Thirteen healthy nonatopic volunteers (control subjects), 26 patients with mild asthma treated with a bronchodilator alone without oral or inhaled corticosteroids or antiallergic agents, and 10 patients with mild-to-moderate asthma treated with inhaled corticosteroids. MEASUREMENTS: We measured the thickness of the epithelial reticular basement membrane (Rbm) of the airway wall in bronchial biopsy specimens from patients with asthma and from healthy control subjects. We also performed spirometry and histamine challenge tests to evaluate airflow obstruction and airway hyperresponsiveness. RESULTS: The thickness of the Rbm in patients with mild asthma was significantly greater than that in healthy control subjects and was negatively correlated with the FEV(1) as a percentage of FVC and the provocative concentration of histamine that caused a 20% decrease in FEV(1) from the post-saline solution baseline value. Moreover, the Rbm was thicker in patients with mild asthma not treated with inhaled steroids than in patients with mild-to-moderate asthma treated with inhaled steroids. CONCLUSIONS: The thickness of the Rbm is increased even in mild asthma and is correlated with airway obstruction and hyperresponsiveness. Our results suggests that anti-inflammatory treatment with inhaled steroids should be started in the early stage of bronchial asthma to prevent structural changes from occurring in the airway wall.

6598.  Sousa AR, Parikh A, Scadding G, Corrigan CJ, Lee TH. Leukotriene-receptor expression on nasal mucosal inflammatory cells in aspirin-sensitive rhinosinusitis. N Engl J Med. 2002 Nov 7;347(19):1493-9.

BACKGROUND: Patients with asthma who have aspirin sensitivity have greater cysteinyl leukotriene production and greater airway hyperresponsiveness to the effects of inhaled cysteinyl leukotrienes than their aspirin-tolerant counterparts. We hypothesized that the latter effect reflects elevated expression of the cysteinyl leukotriene receptor CysLT1 on inflammatory cells in the target organ and that its expression is down-regulated by aspirin desensitization. METHODS: We obtained nasal-biopsy specimens from 22 aspirin-sensitive and 12 non-aspirin-sensitive patients with chronic rhinosinusitis and nasal polyps. Additional specimens were then obtained from subgroups of the aspirin-sensitive patients after intranasal application of lysine aspirin or placebo for two weeks (five and four patients, respectively) or for six months (five and four patients, respectively). The numbers of leukocytes expressing the CysLT1 and leukotriene B4 (LTB4) receptors per unit area of sections of the nasal submucosa were determined by immunohistochemistry. RESULTS: The absolute number of cells expressing the CysLT1 receptor was significantly higher in the aspirin-sensitive patients than in thenon-aspirin-s ensitive patients (median, 542 cells per square millimeter [range, 148 to 1390] vs. 116 cells per square millimeter [range, 40 to 259]; P<0.001). The percentage of CD45+ leukocytes expressing the CysLT1 receptor was also higher in the aspirin-sensitive subjects (25 percent of CD45+ leukocytes [range, 4 to 50] vs. 5 percent of CD45+ leukocytes [range, 2 to 11]; P<0.001); the percentage of CD45+ leukocytes expressing the LTB4 receptor did not differ significantly between these two groups. Desensitization was associated with a decrease in the numbers of inflammatory cells expressing CysLT1. CONCLUSIONS: The elevated numbers of nasal inflammatory leukocytes expressing the CysLT1 receptor in aspirin-sensitive patients with chronic rhinosinusitis as compared with their non-aspirin-sensitive counterparts and the down-regulation of receptor expression after desensitization to aspirin are probably fundamental in the pathogenesis of aspirin sensitivity and in the mechanism of aspirin desensitization. Copyright 2002 Massachusetts Medical Society

6599.  Tategaki A, Kawamoto S, Okuda T, Aki T, Yasueda H, Suzuki O, Ono K, Shigeta S.  A high-molecular-weight mite antigen (HM1) fraction aggravates airway hyperresponsiveness of allergic mice to house dusts and whole mite cultures. Int Arch Allergy Immunol. 2002 Nov;129(3):204-11.

BACKGROUND: The house dust mite Dermatophagoides farinae is the most common aeroallergen causing human allergic asthma. Previously, we demonstrated that a high-molecular-weight allergenic fraction (HM1), which was abundant in D. farinae extracts, induced a proliferative response of T cells from healthy donors. The induction was mediated through the activation of macrophages without MHC class II restriction. In this study, we investigate whether HM1 influences the development of airway inflammation in murine models of asthma. METHODS: BALB/c mice were injected twice intraperitoneally with D. farinae fecal extract (Dff) at an interval of 5 days. They were exposed daily to aerosolized antigen (group 1: Dff, group 2: HM1, group 3: HM1-depleted Dff and group 4: PBS) for 10 days. The effect of HM1 on their airway inflammation was evaluated by measuring acetylcholine-induced airway hyperresponsiveness and inflammatory cell infiltration in lung tissue. RESULTS: The inhalation of the whole fecal extract or the HM1 fraction induced airway hyperresponsiveness which was detectable after 24 h and was maintained for as long as 120 h. The inhalation of extract depleted of the HM1 fraction induced hyperresponsiveness measured at 24 h but this was not maintained for 120 h. Macrophage infiltration was significantly prolonged in mice inhaling the whole extract and the HM1 fraction compared to the HM1-depleted extract. CONCLUSION: The inhalation of the  high-molecular-weight HM1 fraction of D. farinae prolonged airway hyperresponsiveness and macrophage inflammation in a mouse model of hypersensitivity. The results indicate that the HM1 fraction which can induce T cell proliferation through macrophage activation may play a role in the duration of airway responsiveness. Copyright 2002 S. Karger AG, Basel

6600.  Thomson F, Masters IB, Chang AB.  Persistent cough in children and the overuse of medications. J Paediatr Child Health. 2002 Dec;38(6):578-81.

OBJECTIVE: Children referred for persistent cough were evaluated for the referring and final diagnosis, and the extent of the use of medications prior to referral and the side effects encountered. METHODS: Data on children seen by respiratory paediatricians for persistent cough (> or =4 weeks) in a tertiary respiratory setting were collected prospectively over 12 months. RESULTS: Of the 49 children, 61.2% were diagnosed with asthma at referral, with similar referral rates from general practitioners and paediatricians. Children with isolated cough were just as likely to have been diagnosed with asthma as children with cough and wheeze. Medication use (asthma, gastro-oesophageal reflux and antibiotics) prior to referral was high, asthma medications were most common, and of these 12.9% had significant steroid side effects. The most common

abnormality found (46.9%) was a bronchoscopically defined airway lesion, and in 56.5% of these children, another diagnosis (aspiration, achalasia, gastro-oesophageal reflux) existed. No children had a sole final diagnosis of asthma and pre-referral medications were weaned in all children. CONCLUSION: Over diagnosis of asthma and the overuse of asthma treatments with significant side effects is common in children with persistent cough referred to a tertiary respiratory clinic. Children with persistent cough deserve careful evaluation to minimize the use of unnecessary medications and, if medications are used, assessment of response to treatment is important.

6601.  Westergren-Thorsson G, Chakir J, Lafreniere-Allard MJ, Boulet LP, Tremblay GM.  Correlation between airway responsiveness and proteoglycan production by bronchial fibroblasts from normal and asthmatic subjects. Int J Biochem Cell Biol. 2002 Oct;34(10):1256-67.

Asthma is characterized by an airway remodeling process involving altered extracellular matrix deposition such as collagen, fibronectin and proteoglycans. Proteoglycans determine tissue mechanical properties and are involved in many important biological aspects. Not surprisingly, it has been suggested that proteoglycan deposition may alter airway properties in asthma including airway hyperresponsiveness. In chronically inflamed airway tissues, fibroblasts likely represent an activated fibrotic phenotype that contributes to the excessive deposition of different extracellular matrix components. To investigate whether this was the case for proteoglycans, the production of hyaluronan, perlecan, versican, small heparan sulphate proteoglycans (HSPGs), decorin and biglycan was quantified in the culture medium of primary bronchial fibroblast cultures, established from four normal and six asthmatic subjects. Values were further correlated to the airway responsiveness (PC(20) methacholine) of donor subjects. Fibroblasts from subjects with the most hyperresponsive airways produced up to four times more total proteoglycans than cells from subjects with less hyperresponsive or normoresponsive airways. We observed a significant negative correlation between the PC(20) and perlecan, small HSPGs and biglycan, while such correlation was absent for decorin and close to significant for hyaluronan and versican. Altered proteoglycan metabolism by bronchial fibroblasts may contribute to the increased proteoglycan deposition in the bronchial mucosa and to airway hyperresponsiveness characterizing asthma. Copyright 2002 Elsevier Science Ltd.

Pathogenesis:

6602.  Arm JP, Austen KF. Leukotriene receptors and aspirin sensitivity. N Engl J Med. 2002 Nov 7;347(19):1524-6. No abstract.

6603.  Asai K, Kanazawa H, Otani K, Shiraishi S, Hirata K, Yoshikawa J. Imbalance between vascular endothelial growth factor and endostatin levels in induced sputum from asthmatic subjects. J Allergy Clin Immunol. 2002 Oct;110(4):571-5.No abstract.

BACKGROUND: Angiogenesis has recently attracted considerable attention as a component of airway remodeling in bronchial asthma. Vascular endothelial growth factor (VEGF) is highly expressed in asthmatic airways, and its contribution to airway remodeling has been reported. Although angiogenesis is regulated by a balance of angiogenic and antiangiogenic factors, the relative levels of antiangiogenic factors in asthmatic airways have not been evaluated. OBJECTIVE: We sought to determine whether an imbalance between angiogenic and antiangiogenic factors exists in asthmatic airways. METHODS: We simultaneously measured VEGF and endostatin levels and evaluated their correlation and balance in induced sputum from 18 steroid-naive asthmatic subjects and 11 healthy control subjects. After initial sputum induction, asthmatic subjects underwent 8 weeks of inhaled beclomethasone dipropionate (BDP; 800 microg/d) therapy, and sputum induction was then repeated. RESULTS: VEGF and endostatin levels in induced sputum were significantly higher in asthmatic subjects than in control subjects (P <.001). There was a significant correlation between VEGF and endostatin levels in both control subjects (r = 0.995, P <.001) and asthmatic subjects (r = 0.923, P <.001). Moreover, the VEGF/endostatin level ratio in asthmatic subjects was significantly higher than that in control subjects (P <.0001). After 8 weeks of inhaled BDP therapy, the VEGF level in induced sputum in asthmatic subjects was significantly decreased (P <.001), whereas the endostatin level was not. A correlation between VEGF and endostatin levels existed even after BDP therapy (r = 0.861, P <.001). Moreover, the VEGF/endostatin level ratio was significantly decreased to the same level as in the control subjects after BDP therapy (P <.0001). CONCLUSION: There was an imbalance between VEGF and endostatin levels in induced sputum from asthmatic subjects. This imbalance might play an important role in the pathogenesis of bronchial asthma through its effects on angiogenesis.

6604.  Dang B, Wiehler S, Patel KD. Increased PSGL-1 expression on granulocytes from allergic-asthmatic subjects results in enhanced leukocyte recruitment under flow conditions. J Leukoc Biol. 2002 Oct;72(4):702-10.

Allergic asthma is increasing in incidence and severity in many industrial countries. Leukocyte recruitment into the airways of affected individuals contributes to the severity of the disease. In this study, whole blood from normal, allergic, asthmatic, or allergic-asthmatic subjects was perfused over immobilized adhesion molecules using an in vitro flow chamber system to determine if there were differences in leukocyte recruitment in these patient populations. Leukocytes from allergic-asthmatic subjects showed a threefold increase in recruitment o n P-selectin as compared with normal controls. In both patient populations, the accumulated cells were exclusively neutrophils and eosinophils. Increased granulocyte recruitment was specific for P-selectin, as neither purified E-selectin nor vascular cell adhesion molecule-1 (VCAM-1) supported enhanced leukocyte recruitment from allergic-asthmatics. Leukocyte accumulation on P-selectin was completely blocked by an anti-P-selectin or anti-P-selectin glycoprotein ligand-1 (PSGL-1) monoclonal antibody. Flow cytometry revealed that neutrophils and eosinophils from allergic-asthmatic subjects had increased expression of PSGL-1, whereas expression of another adhesion molecule, L-selectin, was unchanged. PSGL-1 expression on peripheral blood mononuclear cells of allergic-asthmatic patients was unaffected. The increased PSGL-1 expression on granulocytes from allergic-asthmatic patients also led to enhanced leukocyte recruitment on interleukin-4-stimulated human umbilical vein endothelial cells, which express P-selectin and VCAM-1. Thus, increased PSGL-1 expression on granulocytes from allergic-asthmatic subjects resulted in increased leukocyte recruitment on P-selectin under flow conditions.

 

6605.  Dent G, Hosking LA, Lordan JL, Steel MD, Cruikshank WW, Center DM, Ellis JH, Holgate ST, Davies DE, Djukanovic R. Differential roles of IL-16 and CD28/B7 costimulation in the generation of T-lymphocyte chemotactic activity in the bronchial mucosa of mild and moderate asthmatic individuals. J Allergy Clin Immunol. 2002 Dec;110(6):906-14.

BACKGROUND: IL-16 is an important T-cell chemotactic cytokine in asthmatic airways; its release from allergen-stimulated bronchial mucosa in mild asthma  has been shown to be dependent on CD28/B7 costimulation. OBJECTIVE: We have extended our previous studies to investigate the role of IL-16 and CD28/B7 costimulation in T-lymphocyte chemotactic activity (TLCA) released from the bronchial mucosa in more severe asthma. METHODS: TLCA was determined in the supernatants of induced sputum and allergen-stimulated bronchial mucosal explants from healthy volunteers and volunteers with mild and moderately severe asthma by means of a Boyden chamber technique. The contribution of IL-16 to the activity was evaluated through use of a neutralizing monoclonal antibody; the contribution of CD28/B7 costimulation to allergen-induced release of TLCA was determined through use of CTLA4-Ig fusion protein and neutralizing monoclonal antibodies to CD80 (B7.1) and CD86 (B7.2). RESULTS: Induced sputum and unstimulated explants from asthmatic subjects generated significant spontaneous TLCA (P <.05). Both mild and moderate asthmatic explants showed significantly elevated Dermatophagoides pteronyssinus -induced release of TLCA, but only in mild asthma could sputum and allergen-stimulated explant TLCA be inhibited by anti-IL-16 (median inhibition, 39% and 59%; P <.05). In addition, allergen released significant quantities of IL-16 from mild asthmatic explants (P <.05) but not from moderate asthmatic explants. Antibodies to the CD28 counter-ligands CD80 and CD86 inhibited allergen-induced release of TLCA in mild asthmatic explants by 94% (P <.05) and 62%, but TLCA release from moderate asthmatic explants was unaffected by CTLA4-Ig. CONCLUSION: These results show that TLCA release in moderate asthmatic airways, in contrast to mild asthmatic airways, is not dependent on CD28/B7 costimulation and does not involve IL-16.

6606.  Doshi V; Salat P; Parikh V. Cytokine modulators in asthma: clinical perspectives. Indian Journal of Pharmacology. 2002 Feb; 34(1): 16-25

ABSTRACT: Asthma is a chronic inflammatory disease of the airways characterized by fibrosis of the airways, hyperplasia and hypertrophy of smooth muscle cells and mucous secreting cells due to infiltration of activated eosinophils and activation of resident mast cells and lymphocytes. These chronic inflammatory changes are mediated by secretion of cytokines from inflammatory cells. Cytokines play integral role in the coordination and persistence and inflammatory process in chronic inflammation of the airways. Based on the recent understanding of pathogenesis of asthma, cytokines are classified as a) Lymphokines, b) Proinflammatory cytokines, c) AntiInflammatory cytokines and d) Chemokines. The biology of cytokines seem to be complex and may not confine to inflammatory reactions as some of them do possess anti-inflammatory properties. Current therapies for asthma provide only symptomatic relief to patients and do not control inflammation. Modern treatment of asthma is directed towards lessening inflammation thereby reducing airway reactivity and asthma severity. Development of cytokine modulators which inhibits inflammatory cytokine or potentiates anti- inflammatory cytokine as drugs may provide an emerging trend for more beneficial antiasthmatic treatment.

 

6607.  Heijink IH, Vellenga E, Borger P, Postma DS, de Monchy JG, Kauffman HF. Interleukin-6 promotes the production of interleukin-4 and interleukin-5 by interleukin-2-dependent and -independent mechanisms in freshly isolated human T cells. Immunology. 2002 Nov;107(3):316-24.

T helper 2 (Th2) cytokines [interleukin (IL)-4 and IL-5] play a central role in the development of allergic immune responses. After allergen provocation, the expression of Th2 cytokines is rapidly up-regulated in atopy and asthma. IL-6 is a multifunctional cytokine that is able to direct Th2 immune responses and is secreted by multiple tissue cell types. This study shows that IL-6 induces up-regulation of IL-4 and IL-5 after short (5 min) preincubation periods in freshly isolated, alpha-CD3/alpha-CD28-stimulated T cells. After longer preincubation periods with IL-6 (12 and 24 hr), the priming effect on IL-4 production gradually disappears, whereas the effect on IL-5 becomes more pronounced. In contrast, a small but significant inhibitory effect is found on the production of the Th1 cytokine interferon-gamma. Additional experiments indicate that the long-term priming effect of IL-6 on IL-5 production is dependent on IL-2 signalling. This is not the case for the short-term IL-6 effect on IL-5 secretion, where the p38 mitogen-activated protein kinase-dependent induction of activator protein-1 DNA-binding activity is involved, independent of signal transducer and activator of transcription 3 phosphorylation. In summary, these data demonstrate that the short-term and long-term priming effects of IL-6 on Th2 cytokine production are regulated by different mechanisms.

6608.  Higashi N, Taniguchi M, Mita H, Higashi A, Akiyama K. Aspirin-induced urticaria and angioedema, but not bronchoconstriction, associated with cysteinyl leukotriene overproduction in 2 patients with asthma. J Allergy Clin Immunol. 2002 Oct;110(4):666-7. No abstract.

6609.  Jousilahti P, Salomaa V, Hakala K, Rasi V, Vahtera E, Palosuo T. The association of sensitive systemic inflammation markers with bronchial asthma. Ann Allergy Asthma Immunol. 2002 Oct;89(4):381-5.

BACKGROUND: Airway inflammation is a characteristic feature of bronchial asthma. Previous studies have shown an increased local inflammatory activity in the airway mucosa of asthma patients. OBJECTIVES: To analyze the association of asthma with three sensitive markers of systemic inflammation, C-reactive protein, serum amyloid-A (SAA), and plasma fibrinogen. METHODS: A cross-sectional, population-based study including 1,513 Finnish men aged 45 to 74 years, who participated in a chronic disease risk factor survey in 1997. Of the participating men, 97 were classified as asthma patients. The odds ratios of asthma were analyzed by quartile of each inflammation marker. RESULTS: In logistic regression models the age-adjusted odds ratios (second, third, and fourth quartile  as compared with the first quartile) of asthma increased gradually with increasing quartile of C-reactive protein (1.28, 1.19, 1.96, P for trend = 0.039), SAA (1.20, 3.00, 3.49, P for trend < 0.001), and fibrinogen (1.22, 1.79, 3.16, P for trend < 0.001). The associations were independent of smoking. Further adjustment for waist-to-hip ratio, a marker of central obesity, and symptoms of chronic bronchitis weakened the observed association, but the increasing trend in the association of SAA and fibrinogen with asthma remained highly significant. CONCLUSIONS: Sensitive markers of systemic inflammation, particularly SAA and fibrinogen, were positively and significantly associated with asthma prevalence. These findings support the hypothesis that not only local, but also systemic, inflammation exist in bronchial asthma.

6610.  Lacroix-Desmazes S, Misra N, Bayry J, Villard S, Kazatchkine MD, Kaveri SV. Antibodies with hydrolytic activity towards factor VIII in patients with hemophilia A. J Immunol Methods. 2002 Nov 1;269(1-2):251-6. Review.

Antibodies endowed with hydrolytic properties have been described in humans for over a decade in a variety of pathological conditions such as systemic lupus erythematosus (SLE), autoimmune thyroiditis, asthma, and Bence Jones disease. Although the identified target substrate molecules have always been autoantigens (i.e., DNA, thyroglobulin, vasoactive intestinal peptide), a direct role of hydrolysis of the autoantigen in pathology of the disease has not been clearly documented. We have described in multitransfused patients with hemophilia A the presence of anti-factor VIII (FVIII) IgG antibodies that hydrolyze FVIII. The estimated kinetic parameters derived for FVIII cleavage by anti-FVIII antibodies are in line with the previously described catalytic antibodies. The identified cleavage sites are evenly spread throughout the FVIII molecule and are located

after an arginine or a lysine in most cases. We have recently shown that the catalytic antibodies are highly prevalent among hemophilia A patients with FVIII inhibitors. Catalytic antibodies to FVIII are the first example where the hydrolysis of the target molecule by hydrolytic antibodies may be directly relevant to the etiology of the disease. The characterization of FVIII inhibitors as site-specific proteases may provide novel strategies in the design of therapy against FVIII inhibitors in patients with hemophilia A.

6611.  Littlejohn MD, Taylor DR, Miller AL, Kennedy MA. Determination of beta2-adrenergic receptor (ADRB2) haplotypes by a multiplexed polymerase chain reaction assay. Hum Mutat. 2002 Dec;20(6):479.

The beta2-adrenergic receptor (B2AR or ADRB2) is the target of beta2-agonist drugs used for bronchodilation in asthma and other respiratory diseases. The gene for this receptor (ADRB2) contains numerous single nucleotide polymorphisms (SNPs) some of which may be of pharmacogenetic relevance, although a consistent picture of genotype-phenotype relationships has yet to emerge. Recently, 12 distinct haplotypes of ADRB2were described along with preliminary evidence that certain haplotypes, rather than specific SNPs, determine differential response to the beta-agonist drug albuterol. In order to further evaluate the role of ADRB2haplotypes as pharmacogenetic determinants, simple and accurate methods for haplotyping clinical samples are required. To this end we have developed a multiplexed, allele-specific PCR assay that interrogates six ADRB2 SNPs in a manner that permits rapid and accurate assignment of ADRB2 haplotype pairs. This assay will facilitate studies of ADRB2haplotypes in phenotypes such as patient responses to beta2-agonists, bronchial hyper-responsiveness, and cardiovascular conditions. Copyright 2002 Wiley-Liss, Inc.

 

6612.  Ostergaard MS, Stauning JA, Andersen JS, Jorgensen M. The PAT study's methods, asthma classification, and results are questionable. J Allergy Clin Immunol. 2002 Oct;110(4):671; No abstract

6613.  Rudwaleit M, Andermann B, Alten R, Sorensen H, Listing J, Zink A, Sieper J, Braun J. Atopic disorders in ankylosing spondylitis and rheumatoid arthritis. Ann Rheum Dis. 2002 Nov;61(11):968-74.

BACKGROUND: The prevalence of atopic disorders in ankylosing spondylitis (AS) is unknown. AS and rheumatoid arthritis (RA) exhibit divergent T helper (Th) cell cytokine patterns. OBJECTIVE: To test the hypothesis that Th2 polarised atopic disorders may be decreased in Th1 polarised RA but increased in AS, which is characterised by an impaired Th1 cytokine pattern, by assessing the prevalence of atopic disorders in AS and RA. METHODS: 2008 subjects (380 patients with AS, 728 patients with RA, 900 controls) from Berlin, Germany, were considered in this cross sectional study. A questionnaire incorporating questions from the European Community Respiratory Health Service (ECRHS) and the International Study of Asthma and Allergies in Childhood (ISAAC) protocol was mailed to all subjects. Disease severity was assessed by the modified Health Assessment Questionnaire (mHAQ). RESULTS: 1271 (63.3%) people responded to the questionnaire. The prevalence of any atopic disorder was 24.6% (61/248) in patients with AS, 20.7% (111/536) in controls, and 13.1% (64/487) in patients with RA (p=0.0009 for AS v RA; p=0.001 for controls v RA). Hay fever was reported by 40/248 (16.1%) patients with AS, 82/536 (15.3%) controls, and 42/487 (8.6%) patients with RA (p=0.002 for AS v RA; p=0.001 for controls v RA). Atopic dermatitis was reported by 19/248 (7.7%) patients with AS, 26/536 (4.9%) controls, and 14/487 (2.9%) patients with RA (p=0.003 for AS v RA), and asthma by 18/248 (7.3%) patients with AS, 35/536 (6.5%) controls, and 21/487 (4.3%) patients with RA. The differences were related neither to age nor to drugs. Disease severity was less in atopic patients with RA who had the atopic disorder before the onset of RA (median mHAQ 0.75) than in patients in whom RA preceded the atopic disorder (median mHAQ 1.75; p=0.027). CONCLUSIONS: Atopic disorders are decreased in RA but only slightly and non-significantly increased in AS. This may imply that atopy confers some protection from RA but only little if any susceptibility to AS. It may further indicate that the cytokine deviation towards an impaired Th1 pattern in AS is less strong than the cytokine deviation towards Th1 in RA, a finding which may affect future therapeutic approaches.

6614.  Silverman ES, Baron RM, Palmer LJ, Le L, Hallock A, Subramaniam V, Riese RJ, McKenna MD, Gu X, Libermann TA, Tugores A, Haley KJ, Shore S, Drazen JM, Weiss ST.  Constitutive and cytokine-induced expression of the ETS transcription factor ESE-3 in the lung. Am J Respir Cell Mol Biol. 2002 Dec;27(6):697-704.

Family studies of asthma suggest that the genes ESE-2 and ESE-3 contain polymorphisms that contribute to disease susceptibility. Each gene codes for an ETS transcription factor that is characterized by epithelium-restricted constitutive expression and may function as a context-dependent activator or repressor of transcription; however, nothing is known about the role of these genes in lung homeostasis or the pathogenesis of airway disease. In this study, we show that ESE-3 mRNA and protein are constitutively expressed in bronchial and mucous gland epithelial cells. Consistent with these findings, ESE-3 mRNA is constitutively expressed in human bronchial epithelial cells grown in tissue culture. In contrast, ESE-2 mRNA could not be detected in the lung or cultured human bronchial epithelial cells. Human bronchial smooth muscle cells and fibroblasts do not constitutively express ESE-3; however, after stimulation with interleukin-1beta or tumor necrosis factor-alpha, levels of ESE-3 mRNA and protein increase dramatically by 24 h. This cytokine induction is dose-dependent and abrogated by specific inhibitors of the MEK1/2 (U0126) and p38 (SB03580) signal transduction pathways. Overexpression of ESE-3 protein in 3T3 cells and human bronchial smooth muscle cells inhibits MMP-1 promoter activity, suggesting that ESE-3 may function as a transcriptional repressor.

6615.  Terashima T, Amakawa K, Matsumaru A, Yamaguchi K. Correlation between cysteinyl leukotriene release from leukocytes and clinical response to a leukotriene inhibitor. Chest. 2002 Nov;122(5):1566-70.

STUDY OBJECTIVES: Antileukotriene drugs are widely used in patients with bronchial asthma, but not all patients show significant clinical improvements, and no factors have been identified that are correlated with the clinical response to these drugs. This study was designed to examine the factors correlated with a response to a leukotriene receptor antagonist, pranlukast, in patients with asthma. DESIGN: WBC counts, IgE, and ex vivo leukotriene release from leukocytes were measured, and 31 patients with asthma were treated with pranlukast, a leukotriene receptor antagonist, for 4 weeks. MEASUREMENTS: Outcome measurements included twice-daily peak expiratory flow rate (PEFR), daytime and nocturnal symptoms, and frequency of beta(2)-agonist use. Subjects with a reduction of > 20% in symptom scores or beta(2)-agonist use, or an improvement of PEFR of > 10% were designated as responders; others were designated as nonresponders. Logistic regression analysis assessed the efficacy of models using various allergic markers correlated with the response to pranlukast. RESULTS: There were 16 responders and 15 nonresponders. The release of cysteinyl leukotrienes from the leukocytes of the responders was higher than that of the nonresponders (p < 0.05). There was a significant correlation between the clinical response and the release of cysteinyl leukotrienes, but not demographic features, WBC counts, percentage of eosinophils, or serum IgE levels (p < 0.05). Subjects with a release of cysteinyl leukotrienes of > 3,500 pg/mL were 11.0 times more likely to respond to pranlukast than those with < 3,500 pg/mL (95% confidence interval, 2.0 to 60.5). CONCLUSION: Cysteinyl leukotriene release from leukocytes is correlated with leukotriene receptor antagonist response.

6616.  Wagner CW. The ongoing evaluation of the impact of depression on asthma. Ann Allergy Asthma Immunol. 2002 Dec;89(6):540-1. No abstract.

                      Therapy:

6617.  Bajel AR; Jadhav DL; Moulick ND. Magnesium in health and disease  Indian Practitioner. 2002 Apr; 55(4): 238-42

ABSTRACT: Magnesium, the second most abundant cation, plays a crucial role in human physiology. This article reviews magnesium balance, its metabolism and predisposing factors for magnesium deficiency-a relatively common condition. Magnesium has been reported as an effective therapy in an expanding array of conditions-ischaemic heart disease, cardiac arrhythmias, asthma and seizures. However in some of these conditions, it has been uncertain whether magnesium administration serves the purpose of merely correcting the underlying deficiency state or of utilizing a specific pharmacological affect of magnesium. This article reviews current status of magnesium therapy and presents guidelines for parenteral administration.

6618.  Chatmongkolchart S, Schettino GP, Dillman C, Kacmarek RM, Hess DR. In vitro evaluation of aerosol bronchodilator delivery during noninvasive positive pressure ventilation: effect of ventilator settings and nebulizer position. Crit Care Med. 2002 Nov;30(11):2515-9.

OBJECTIVE: Respiratory failure due to exacerbation of obstructive lung disease has been successfully treated with noninvasive positive pressure ventilation (NPPV). However, there have been no reports of factors affecting aerosol delivery during NPPV. Our objective was to determine the effect of ventilator settings and nebulizer position on albuterol delivery during NPPV. DESIGN: Bench model study. SETTING: University laboratory. SUBJECTS: None. INTERVENTIONS: A Respironics BiPAP S/T-D30 with a standard circuit was attached to a lung model simulating spontaneous breathing. Inspiratory/expiratory pressures of 10/5, 15/5, 20/5, 15/10, 20/10, and 25/10 cm H2O were tested at respiratory rates of 10 and 20/min. A nebulizer was filled with 5 mg of albuterol in 4 mL of solution, driven with 8 L/min oxygen, and placed at either a proximal (ventilator outlet) or distal (between leak port and lung model connection) position. Albuterol delivery was estimated by measuring the amount of the albuterol collected on a filter placed at the inlet of the lung model. MEASUREMENT AND MAIN RESULTS: Albuterol delivery varied from 5.2 +/- 0.4% to 24.5 +/- 1.3% of the nominal dose and was significantly affected by the position of the nebulizer, respiratory rate, and BiPAP settings (p <.001 in each case). The greatest albuterol delivery was observed with the nebulizer operating at the distal position and a respiratory rate of 20/min. At this respiratory rate and nebulizer placement, albuterol delivery increased with increasing inspiratory pressure levels and decreased as expiratory pressure levels were increased. Nebulizer flow did not affect function of the ventilator. CONCLUSIONS: At optimum nebulizer position (between the leak port and patient connection) and ventilator settings (high inspiratory pressure and low expiratory pressure), as much as 25% of the nominal albuterol dose may be delivered during NPPV.

6619.  Escoubet-Lozach L, Glass CK, Wasserman SI. The role of transcription factors in allergic inflammation. J Allergy Clin Immunol. 2002 Oct;110(4):553-64.

The induction of allergic inflammation and the expression of allergic disorders are dependent on the coordinated regulation of numerous genes. The products of these genes determine lymphocyte phenotype, immunologic responsiveness, eosinophil and mast cell development, activation, migration and life span, adhesion molecule expression, cytokine synthesis, cell-surface receptor display, and processes governing fibrosis and tissue repair. Although the expression of gene products involved in these processes is regulated at multiple levels (eg, transcription, mRNA processing, translation, phosphorylation, and degradation), transcription represents an essential and often the most important determinant of their contribution to cellular function. Signal-dependent and cell type-specific regulation of gene expression is generally achieved by means of combinatorial interactions between sequence-specific transcription factors that recruit chromatin remodeling machinery and general transcription factors to promoter and enhancer regions of RNA polymerase II-dependent genes. As targets of signal-transduction pathways, transcription factors integrate the response of the cell to the myriad of inputs it receives. This integration can be accomplished by the effect of signaling cascades on the activation status or subcellular locus of transcription factors or by transcription factor dimerization induced by means of ligand binding. This review will identify the major families of transcription factors important in allergic mechanisms and discuss their interactions, their mechanisms of action, and their interrelated and competitive actions, as well as implications for therapy of allergic disorders.

6620.  Hegde SC; Shah PB; Mahashur AA. Awareness regarding occupational asthma amongst general practitioners-a critical evaluation.  Indian Journal of Occupational and Environmental Medicine. 2002 Jan-Mar; 6(1): 16-0

ABSTRACT: The original study presented herewith highlights some of the policies of general practitioners, who are considered to be the first point of contact of a patient with occupational asthma, with the health services, Besides bringing out the flaws existing in current treatment strategies, the article also discusses ideal management protocols for therapy of occupational asthma.

6621.  Knox AJ, Pang L. Glucocorticoid and beta-adrenoceptor agonist interactions in asthma. Lancet. 2002 Oct 26;360(9342):1265-6. No abstract

6622.  Lim KG. Management of persistent symptoms in patients with asthma. Mayo Clin Proc. 2002 Dec;77(12):1333-8; quiz 1339.

The main goals of asthma therapy are to control symptoms, prevent acute attacks, and maintain lung function as close to normal as possible. Customizing the regimen to relieve the patient's symptoms and control airway inflammation is important. If asthma is not well controlled, an initial inhaled corticosteroid boost will treat the underlying heightened airway inflammation, and the addition of a long-acting beta2-adrenergic agonist or leukotriene receptor antagonist will rapidly control symptoms. Most patients do not require prolonged treatment with expensive combination or additive agents. Exercise-induced bronchoconstriction is a common source of symptoms. Treatments for scheduled and unscheduled exercises differ. Inhaled corticosteroids prevent frequent and severe asthma exacerbations. When patients have persistent symptoms despite a pharmacological regimen, environmental factors and nonpharmacological interventions must be considered before medication is increased. When an inhaled corticosteroid is being considered, issues of compliance, drug delivery device, and proper inhaler techniques are as important as issues of potency, clinical efficacy, and adverse effects. The new hydrofluoroalkane preparations offer more lung deposition and may be important in treating inflammation of the small airways in patients with asthma.

 

6623.  Mahakalkar SM; Tibdewal S; Khobragade BP.. Cardio-pulmonary effects of various anti-asthmatic agents in patients of acute bronchial asthma. Indian Practitioner. 2002 Feb; 55(2): 79-85

ABSTRACT: Aims and Objectives: The cardio-pulmonary effects of beta-agonist are known to be aggravated by addition of steroids in patients of acute bronchial asthma therefore, this study was planned to assess the cardio- pulmonary effects of various bronchodilators alone and in combination with steroids by different modes of delivery. Material and Methods: Two hundred and fifty nine patients of acute bronchial asthma (age 1-65 years) were randomised to one of the nine (sc-Adr, sc-Ter, Neb-S, MDI-S, MDI-S S*, MDI- S+B, MDI-S+B S*, DPI-Salb, DPI-Salm) treatment groups. Heart rate, respiratory rate, blood pressure, wheezing, retraction and PEER was repeated one hour after therapy. For analysis patients were pooled into two groups- group A (age20 years) and group B (age-20 years). Results and Discussion: The mean wheezing scores and retraction scores improved significantly in all the treatment groups. A significant (p0.05) fall in respiratory rate was observed in all the treatment groups. Tachycardia was seen with subcutaneous adrenaline only and no significant changes were observed in blood pressure. The improvement in per cent predicted PEFR was better with adrenaline compared to terbutaline and was maximum (93.89 percent) with nebulised salbutamol amongst aerosol therapy. Conclusion: our study revealed tachycardia with conventional subcutaneous adrenaline only with no effects on blood pressure and the improvement in pulmonary status was better with aerosol therapy with improved PEFR, in particular.

6624.  Panigrahi L; Ghosal SK. Formulation and evaluation of pseudolatex transdermal drug delivery system of terbutaline sulphate  Indian Journal of Pharmaceutical Sciences. 2002 Jan-Feb; 64(1): 79-82

ABSTRACT: Since oral bioavailability of terbutaline sulphate is poor, pseudolatex transdermal patches incorporating terbutaline sulphate were prepared as an effective mode of therapy for nocturnal asthma in particular. The pseudolatex patches were formulated using combinations of Eudragit RS 100 and R L 100 and Eudraflex as plasticizer. The physicochemical characterization of the films were evaluated for suitability and drug release profile from the films as well as skin permeation aspects were evaluated for therapeutic efficacy. The resulted medicated patches were of average thickness (95-155 mium), and content uniformity of the drug varied from 94.5 to 99.1 percent. The formulation F3 showed least and F7 showed highest percentage of elongation. The percentage of moisture absorption varied from 2.91 to 3.65 at 63 percent relative humidity. The release profiles from the patches followed apparent zero order pattern up to a period 12 h, after which it leaves off. The cumulative amount of drug permeated over a period of 24 h was found to be 4.8 mg/cm square, which was about 50 percent of the loaded dose. The skin permeation took place at a steady rate over a period of 12 h after which the rate was reduced.

6625.  Polosa R. Can immunotherapy prevent progression to asthma in allergic individuals? J Allergy Clin Immunol. 2002 Oct;110(4):672-3. No abstract

6626.  Shaikh GP; Pednekar S; Paidhungat AJ; Nabar ST. Steroids in bronchial asthma: potentiating effect of beta2 agonist. Indian Practitioner. 2002 Feb; 55(2): 92-6

ABSTRACT: Asthma is a chronic inflammatory disorder of the airways in which many cells play a role, in particular mast cells, eosinophils and 'T' lymphocytes. Steroids and beta2 agonist are the main stay of treatment. Patients on chronic steroid therapy can be controlled on a smaller beta2 agonist dose during acute attack. This study showed that patients on chronic steroid maintenance dose had better improvement in PFT than those without.

6627.  Singh N; Syed Sadiq A; Singh V; Singh A  Adaptogens anti stress agents a study focusing Indian plants. Antiseptic. 2002 Jun; 99(6): 198-201

ABSTRACT: This article has been presented with a view to acquaint the readers about plant adaptogens/antistress agent. Although relation of stress has been recognized in genesis of diseases long back, a scientific database is still missing. The pharmaco-clinical studies carried out in this regard are a new venture in Stress-Pharmacology. It is meant to provide new research awareness in the field regarding the fact about stress, Stress-disease and their prevention and treatment. This is more important in view of the fact that there are no drugs for such stress-related diseases in the armamentarium of modern drug therapy. Simple animal models like swimming endurance, immobilization induced gastric ulcers, adrenal function during stress, CCI4 hepatotoxicity, anoxia tolerance test, brain neurotransmitters and enzyme and CNS receptors levels of neurohumorals after swimming immobilization and gravitational stress, milk induced leucocytosis, lipid peroxidase assessment for prevention of cell damage through anti-oxidant activity were carried out to evaluate the adaptogenic activity of these plants in rats and mice. Clinical trial in diseases related to stress like bronchial asthma, hypertension, cellular immunity, viral encephalitis, chronic fatigue syndrome were carried out in man.

6628.  Singh V, Sinha HV, Gupta R. Barriers in the management of asthma and attitudes towards complementary medicine. Respir Med. 2002 Oct;96(10):835-40.

BACKGROUND: Undertreatment is said to be an important problem for those with asthma. Misconceptions regarding the nature and treatment of asthma may contribute to this. This study was planned to evaluate the perception of those with asthma about various aspects of their condition. METHODS: A total of 1012 patients with asthma volunteered to complete the questionnaire. Questions included those regarding severity, nature, regularity of use of medicine and attitudes towards trying complementary medicine. Forced expiratory volume in 1 s (FEV1) was measured to assess the severity of airway obstruction. RESULTS: Only 9% of patients took treatment for asthma according to the advice of the doctor. The remainder reported stopping treatment when they became free of symptoms or were able to tolerate their symptoms. A majority of the patients had moderately severe airway obstruction as determined by spirometer and reported being unable to assess the severity of their disease with only 11.9% reporting that they could perceive the warning symptoms of an acute attack. Seventy-nine percent of the patients had used complementary medicine. Home remedies, such as tea, hot water, walking, ginger and turmeric, were perceived to provide relief in asthma. CONCLUSION: Patients with asthma have many barriers in the way of optimal treatment. These include a failure to recognize warning symptoms, belief in a permanent cure; not continuing treatment for as long as needed; and, an inclination to seek complimentary medicines.

6629.  Tam A. Western medicine in the Eastern mind: a need for integration. Arch Dis Child. 2002 Oct;87(4):287-90. No abstract.

6630.  Yamamoto N, Shichijo M, Kokubo T. Establishment of the superoxide production assay with human monocytic cell line, U937, for the evaluation of Syk kinase inhibitors. J Immunol Methods. 2002 Oct 15;268(2):123-30.

Protein tyrosine kinase Syk is known to play critical roles in the signal transduction from receptors for Fc portion of immunoglobulins (FcRs) and B cell receptor complex (BCR). Its importance was well studied in Fc varepsilon RI-induced activation of mast cells; therefore, Syk inhibitors are expected to have anti-allergic effects and to be novel therapy for allergic diseases, such as asthma, allergic rhinitis and atopic dermatitis. We previously developed an enzyme assay of recombinant human Syk kinase for the high throughput screening. In order to evaluate the Syk kinase inhibitors in a human cell system, we have developed an assay with human monocytic cell line, U937, to monitor FcgammaRI-mediated superoxide production. We treated cells with IFN-gamma to enhance the expression of FcgammaRI and to obtain enough production of superoxide. Engagement of FcgammaRI stimulated superoxide production, which was accompanied with Syk phosphorylation. PMA, an activator of protein kinase C, also evoked superoxide production, but Syk was not phosphorylated. Moreover, the treatment of cells with antisense oligonucleotide against syk attenuated Syk protein expression and suppressed superoxide production induced by FcgammaRI-engagement, but not by PMA. These results confirm that Syk is involved in the signal transduction from FcgammaRI upstream of PKC in U937 cells and we can evaluate the efficacy and the selectivity of Syk inhibitors with this assay system.

July 2003

7100.      Adams R J, Fuhlbrigge A, Finkelestein J A, Lazano P, Livingstone J M, Weiss K B, Weiss S T. Impact of inhaled antiinflammatory therapy on hospitalization  and emergency  department visits for children with asthma. Paediatrics, Indian Edn 2001, 13(4), 193-8 (19631, Vol 38 No 19 1 Oct 2002)

7101.      Atkinson JJ, Senior RM. Matrix metalloproteinase-9 in lung remodeling. Am J Respir Cell Mol Biol. 2003 Jan;28(1):12-24.

Matrix metalloproteinase (MMP)-9 (Gelatinase B, 92-kD type IV collagenase, EC 3.4.24.35) is an MMP that is present in low quantities in the healthy adult lung, but much more abundant in several lung diseases, including asthma, idiopathic pulmonary fibrosis (IPF), and chronic obstructive pulmonary disease (COPD). Despite numerous reports of MMP-9 in these and other lung diseases, whether MMP-9 is causal in lung remodeling or part of the inflammatory and reparative response remains to be determined. Many intrinsic lung cells can be stimulated to produce MMP-9, but much of the information regarding MMP-9 in the lung deals with MMP-9 from inflammatory cells. The multiple locations and cell types producing MMP-9 are consistent with multiple functions in different microenvironments. In addition to digestion of structural proteins and antiproteases, MMP-9 can modify cellular function by regulation of cytokines and matrix-bound growth factors. Determining the role of MMP-9 in health and disease will be important, because broad spectrum and specific inhibitors will soon be available to enable conversion of the bench knowledge to bedside practice. This review addresses the current understanding of MMP-9 in human asthma, IPF, and COPD, and in animal models of these conditions. 

7102.      Burgess JK, Johnson PR, Ge Q, Au WW, Poniris MH, McParland BE, King G, Roth M, Black JL. Expression of connective tissue growth factor in asthmatic airway smooth muscle cells. Am J Respir Crit Care Med. 2003 Jan 1;167(1):71-7.

There is strong evidence to implicate transforming growth factor-beta in the remodeling that occurs in asthma, as levels are increased in bronchial lavage fluid and gene expression is increased in bronchial tissue. Transforming growth factor-beta is also known to increase the release of collagen from airway smooth muscle. Here we identify for the first time a possible mechanism for the effects of transforming growth factor-beta. Transforming growth factor-beta specifically induces mRNA and protein for connective tissue growth factor in airway smooth muscle, and moreover, we report that the connective tissue growth factor response is greater in airway smooth muscle cultured from patients with asthma compared with patients without asthma. This occurs at both the level of mRNA (37.53 +/- 11.62- and 13.59 +/- 3.12-fold increase at 24 hours compared with time 0, respectively, p < 0.02) and protein production (67.57 +/- 27.80- and 3.58 +/- 0.6-fold increase at 24 hours compared with time 0, respectively, p < 0.03). The differential connective tissue growth factor response to transforming growth factor-beta in asthmatic airway smooth muscle identifies a potential role for connective tissue growth factor in the remodeling that is characteristic of  severe persistent asthma.

7103.      Chmura K, Lutz RD, Chiba H, Numata MS, Choi HJ, Fantuzzi G, Voelker DR, Chan ED.  Mycoplasma pneumoniae antigens stimulate interleukin-8. Chest. 2003 Mar;123(3 Suppl):425S. Review. No abstract Available.

7104.      Dupont LJ, Demedts MG, Verleden GM. Prospective evaluation of the validity of exhaled nitric oxide for the diagnosis of asthma. Chest. 2003 Mar;123(3):751-6.

STUDY OBJECTIVE: Exhaled nitric oxide (NO) levels are significantly elevated in patients with inflammatory airways disorders such as asthma, and the measurement of exhaled NO has been proposed as a noninvasive marker of airways inflammation. The aim of this study was to assess the accuracy of exhaled NO levels for the diagnosis of asthma. METHODS: Two hundred forty consecutive, nonsmoking, steroid-naive patients, who were referred to our outpatient clinic with symptoms suggestive of obstructive airways disease, were investigated. Asthma was diagnosed in 160 patients on the basis of the presence of significant airways reversibility (DeltaFEV(1) > 12% predicted) and/or airways hyperresponsiveness (provocative concentration of histamine causing a 20% fall in FEV(1) < or = 8 mg/mL). Prior to lung function measurements, exhaled NO was measured during a single-breath exhalation, according to European Respiratory Society and American Thoracic Society guidelines. RESULTS: The measurement of exhaled NO in our study population showed, at a cutoff level of 16 parts per billion, a specificity for the diagnosis of asthma of 90% and a positive predictive value of > 90%. CONCLUSIONS: These findings suggest that the simple and absolutely noninvasive measurement of exhaled NO can be used as an additional diagnostic tool for the screening of patients with a suspected diagnosis of asthma.

7105.      Flood-Page PT, Menzies-Gow AN, Kay AB, Robinson DS. Eosinophil's role remains uncertain as anti-interleukin-5 only partially depletes numbers in asthmatic airway. Am J Respir Crit Care Med. 2003 Jan 15;167(2):199-204.

The role of eosinophils as effector cells in asthma pathogenesis has been questioned since an anti-interleukin (IL)-5 monoclonal antibody (mepolizumab), which depleted blood and sputum eosinophils, failed to inhibit allergen-induced bronchoconstriction and airway hyperresponsiveness. However, the effect of IL-5 blockade on tissue eosinophils was not examined. We sought to determine whether mepolizumab depletes airway tissue eosinophils and their products. Twenty-four patients with mild asthma received three intravenous doses of either 750 mg of mepolizumab or placebo in a randomized, double-blind, parallel-group fashion over 20 weeks. Mepolizumab produced a median decrease from baseline of 55% for airway eosinophils (interquartile range, 29-89%; p = 0.009 versus placebo), 52% for bone marrow eosinophils (45-76%, p = 0.003), and 100% for blood eosinophils (range, 67-100%, p = 0.02). Mepolizumab had no appreciable effect on bronchial mucosal staining of eosinophil major basic protein. There were no significant changes in clinical measures of asthma (airway hyperresponsiveness, FEV1, and peak flow recordings) between the mepolizumab and placebo-treated groups. Anti-IL-5 treatment reduces but does not deplete airway or bone marrow eosinophils. The role of the eosinophil remains uncertain. Further clinical studies in asthma with more effective antieosinophil strategies are required.

7106.      Holzer K, Anderson SD, Chan HK, Douglass J. Mannitol as a challenge test to identify exercise-induced bronchoconstriction in elite athletes. Am J Respir Crit Care Med. 2003 Feb 15;167(4):534-7.

Bronchial provocation tests provide objective criteria for asthma and exercise-induced bronchoconstriction (EIB) and were recommended to justify the use of inhaled beta2-agonists by athletes at the Winter Olympics 2002. Eucapnic voluntary hyperpnea (EVH) was one test recommended to identify EIB. Provocation with EVH requires a special dry gas mixture limiting its availability. Provocation tests with osmotic aerosols require less expensive equipment that is easily portable. We assessed the sensitivity of a challenge with mannitol to identify responsiveness to EVH in 50 elite summer sport athletes who were unselected if they had respiratory symptoms. Asthma was previously diagnosed by a doctor in 27 subjects, and 21 subjects were currently under treatment for EIB or asthma. The mean predicted FEV1 was 103.6 +/- 10.8%, FVC was 99 +/- 13.3%, and mean forced expiratory flow during the middle half of the FVC was 104 +/- 22.7%. A total of 25 subjects were positive to EVH challenge (mean percentage of fall in FEV1 was 25.4 +/- 15% SD), and 26 subjects had a positive mannitol challenge (geometric mean [95% confidence interval] provoking dose causing a 10% fall in forced expiratory volume in one second [PD10] was 202 mg [134, 300], with 24 of the subjects positive to both challenges). Mannitol had a sensitivity of 96% and specificity of 92% to identify a positive response to EVH and, as such, could be used as an alternative to EVH to identify EIB.

7107.      Kaminsky DA, Irvin CG, Moriya HT, Lynn M, Lang S, Bates JH. Peripheral lung responsiveness assessed by forced oscillations through the wedged bronchoscope. Chest. 2003 Mar;123(3 Suppl):363S. Review. No abstract available.

7108.      Marvez E, Weiss SJ, Houry DE, Ernst AA. Predicting adverse outcomes in a diagnosis-based protocol system for rapid sequence intubation. Am J Emerg Med. 2003 Jan;21(1):23-9.

Our ED at Louisiana State University developed a unique approach to airway  anagement by having four diagnosis-based protocols for rapid sequence intubation (RSI). This study examines protocol use and outcome from RSI in an academic ED. The study objective was to identify variables that are predictive of adverse outcomes in patients requiring RSI. This was a 4-year prospective, observational, data-gathering study of all intubations in an academic ED setting with >250,000 patient visits per year. Four protocols were established for 1) children <10 years of age, 2) adults with increased intracranial pressure, 3) adults with chronic obstructive pulmonary disease/asthma, and 4) other adults not fitting B or C. A special continuing quality improvement (CQI) committee was established to examine each case of RSI. Prospective data were collected, including age, race, gender, protocol, diagnostic group, intubation indication, and preintubation oxygen saturation. Diagnostic group was categorized as medical, blunt trauma, or penetrating trauma. Adverse outcome was defined as any case with hemodynamic changes, those requiring surgical or bronchoscopic intervention, and those requiring more than three attempts at intubation. Data were analyzed using univariate analysis, logistic regression, and a binomial regression tree analysis with SPSS 9.0 (Chicago, IL) and Answer Tree (SPSS). A total of 1,320 consecutive intubated patients were included. Protocol A was used in 4%, B in 43%, C in 15%, and D in 38%. Significant differences in number of cases with adverse outcome were based on protocol (P =.03) and final diagnosis (P <.03). Protocol C was less likely to be associated with adverse outcome than protocol D (odds ratio [OR] = 0.2, 95% confidence interval [CI] = 0.1-0.7). Penetrating trauma was more likely to be associated with adverse outcome (OR = 1.8, 95%, CI = 1.1-3.2) than blunt trauma. A regression tree analysis yielded the following, all cases using protocol A or C or medical cases using B had an adverse event in 11 of 458 (2.4%), whereas nonmedical cases using protocols B or D and medical cases using D had adverse outcomes in 73 of 862 cases (8.5%). The decision rules lead to a better classification of cases with adverse outcomes (2.4 vs 8.5%, of = 6.1%, 95% CI = 3.7-8.4). Adult trauma patients who fit the protocols B or D or adult medical patients who fit protocol B were at higher risk for adverse outcomes with RSI. This could alert the physician to a population at higher risk for adverse outcomes. Variables available in a diagnosis-based protocol RSI system can be used to predict adverse outcome among patients requiring RSI. Copyright 2003, Elsevier Science (USA). All rights reserved.)

7109.      Olman MA.  Epithelial cell modulation of airway fibrosis in asthma. Am J Respir Cell Mol Biol. 2003 Feb;28(2):125-8. Review. No abstract available.

7110.      Silkoff P.  Exhaled nitric oxide as a diagnostic tool. Am J Respir Crit Care Med. 2003 Feb 15;167(4):665-6. No abstract available.

7111.      Spina D.  Theophylline and PDE4 inhibitors in asthma. Curr Opin Pulm Med. 2003 Jan;9(1):57-64. Review.

Over the past three decades, beta -adrenoceptor agonists and glucocorticosteroids have formed the mainstay of treatment for patients with asthma; during this time, only one new drug class, leukotriene receptor antagonists, have been introduced. Theophylline has also been used in the treatment of patients with asthma, although there is a perception that this drug does not offer the patient any advantages over conventional therapeutic strategies. However, a number of clinical studies have documented the efficacy of this orally active drug. The mechanism by which theophylline exerts its well recognized antiinflammatory activity remains to be established but, if explained, could lead to newer drug development with greater efficacy. The development of phosphodiesterase (PDE)4 inhibitors is one such approach, and recent studies have demonstrated the potential utility of this new drug class for the treatment of patients with asthma.(2)

7112.      van den Berge M, Kerstjens HA, de Reus DM, Kauffman HF, Koeter GH, Postma DS.  Provocation with adenosine 5'-monophosphate increases sputum eosinophils. Chest. 2003 Mar;123(3 Suppl):417S. No abstract available.

7113.      Vasudev K, Vasudev A, Kohli K. Asthma therapy in the new millennium: achievement and challenges. J Int med Sci Acad 2001, 14(4), 197-203. 24072 Vol 38, No. 23, 1 dec 2002

Pathogenesis:

7114.      Binaei S, Christensen M, Murphy C, Zhang Q, Quasney M. Beta2-adrenergic receptor polymorphisms in children with status asthmaticus. Chest. 2003 Mar;123(3 Suppl):375S. Review. No abstract available.

7115.      El Bahlawan L, Christensen M, Binaei S, Murphy C, Zhang Q, Quasney M.  Lack of association between the tumor necrosis factor-alpha regulatory region genetic polymorphisms associated with elevated tumor necrosis factor-alpha levels and children with asthma. Chest. 2003 Mar;123(3 Suppl):374S-5S. Review. No abstract available

7116.      Erpenbeck VJ, Hohlfeld JM, Discher M, Krentel H, Hagenberg A, Braun A, Krug N. Increased messenger RNA expression of c-maf and GATA-3 after segmental allergen challenge in allergic asthmatics. Chest. 2003 Mar;123(3 Suppl):370S-1S. Review. No abstract available

7117.      Hakansson S, Behrens K, Marko-Varga G, Lindberg H, Pierrou S, Koopmann W. Identification of genes and proteins regulated by interleukin-5 in human eosinophils using microarrays and two-dimensional electrophoresis/mass spectrometry. Chest. 2003 Mar;123(3 Suppl):374S. Review. No abstract available

7118.      Hallsworth MP, Major PJ, Barnes J, Lee TH.  What are the priorities in basic asthma research? A United Kingdom perspective. J Allergy Clin Immunol. 2003 Feb;111(2):251-5.

The National Asthma Campaign (in the United Kingdom) has recently completed a strategic review of priorities for basic asthma research over the next 5 to 10 years. Leading asthma experts and representatives of the main funding agencies were involved in a nationwide consultation. Discussions were carried out in 7 thematic areas: Genetics of asthma, early-life events, environmental influences, immunology and immunotherapy, inflammation and anti-inflammation, airway remodeling, and the interface between academia and industry. Discussions were not restricted by considerations of financial affordability but were driven by vision and science.The consultation highlighted a number of generic issues pertaining to the organization of basic asthma research. Phenotypes of asthma require more robust characterization, particularly for genetic studies. Emphasis on longitudinal studies should be encouraged, and more information can still be gained from existing well-characterized asthma cohorts, though this requires some coordination. Human research is particularly strong and should continue, and the use of human tissue is vital to our understanding of the disease at the cellular and molecular levels. Animal models of asthma remain an important tool with which to dissect disease mechanisms, but they must be improved and refined. The consultation covered a wide range of issues and highlighted the need for collaboration at all levels between research groups and with industry and also between funding agencies. The recommendations made have relevance to everyone involved in basic asthma research. This article describes the recommendations and reviews the specific research issues relating to each of the 7 thematic areas.

7119.      Huovinen E, Kaprio J, Koskenvuo M. Factors associated to lifestyle and risk of adult onset asthma. Respir Med. 2003 Mar;97(3):273-80.

BACKGROUND: Asthma prevalence has been increasing especially in developed countries. The change seems to be associated with changes in lifestyle. We have made a prospective study to assess the effect of lifestyle factors, including smoking, educational level, physical activity and obesity on adult onset asthma. METHODS: A population of 10,597 adult twins, initially free of asthma was followed for 9 years. The main outcome measure was questionnaire-based report of physician diagnosed asthma. Logistic regression was used to estimate the risk of asthma predicted by lifestyle factors, with adjustment for atopy and respiratory symptoms. RESULTS: Obesity at baseline increased asthma risk (multivariable adjusted OR = 3.00, 95% CI: 1.64-5.50 for those with BMI > or = 30 compared to those with normal weight BMI: 20-24.99). Taller height was associated to lower asthma incidence. Leisure time physical activity had a slightly protective effect on asthma risk among men (P for trend = 0.037) while smoking and education did not have significant effects on the risk of adult onset asthma. CONCLUSIONS: Obesity was associated to the risk of adult onset asthma, while short height and low leisure time physical activity can be considered as other potential risk factors.

7120.      Kelly EA, Jarjour NN. Role of matrix metalloproteinases in asthma. Curr Opin Pulm Med. 2003 Jan;9(1):28-33. Review.

Airway inflammation and remodeling are key features of asthma. Matrix metalloproteinases (MMPs) and their inhibitors, tissue inhibitors of metalloproteinases (TIMPs) are thought to contribute to the pathogenesis of asthma via their influence on the function and migration of inflammatory cells as well as matrix deposition and degradation. TIMPs bind MMPs in a 1:1 fashion. Thus, an increase in the molar ratio of MMP/TIMP may favor tissue injury, while the reverse could be associated with increased fibrosis. MMP-9 is the predominant MMP in asthma, and its expression is enhanced when patients have spontaneous exacerbations or in response to local instillation of allergen in the airway. As acute inflammation resolves, MMP-9 levels return toward normal. Interestingly, corticosteroids downregulate MMP and enhance TIMPs. Even though it is clear that enhanced airway inflammation in asthma is associated with increased expression of MMPs, whether specific inhibitors of MMP could reduce airway injury and facilitate orderly healing in asthma is still unknown.

7121.      Kumar R.  The wheezing infant: diagnosis and treatment. Pediatr Ann. 2003 Jan;32(1):30-6. Review. No abstract available.

7122.      Leckie MJ, Jenkins GR, Khan J, Smith SJ, Walker C, Barnes PJ, Hansel TT. Sputum T lymphocytes in asthma, COPD and healthy subjects have the phenotype of activated intraepithelial T cells (CD69+ CD103+). Thorax. 2003 Jan;58(1):23-9.

BACKGROUND: T cells of intraepithelial phenotype have previously been detected in bronchoalveolar lavage (BAL) fluid in a range of lung diseases; these cells express the adhesion molecule alpha(E)beta(7) integrin, CD103, the ligand for epithelial cell E-cadherin. In subjects with asthma CD4+ lymphocytes are the predominant T cell subtype found in bronchial biopsy specimens and in BAL fluid, whereas CD8+ lymphocytes have been shown to predominate in subjects with chronic obstructive pulmonary disease (COPD). The aim of this study was to analyse the expression of CD103, activation markers (CD25 and CD69), and chemokine receptors (CXCR3, CCR5 and CCR3) on CD4+ and CD8+ lymphocytes from sputum and peripheral blood of subjects with asthma, COPD, and healthy controls. METHODS: T cell surface markers were assessed by immunofluorescence labelling and flow cytometry of gated lymphocytes among CD45+ leucocytes in sputum cell suspensions. RESULTS: Sputum lymphocytes expressed higher levels of CD103 and CD69 than blood lymphocytes in all subject groups, with CD103 expressed at higher levels on CD8+ than on CD4+ cells. There were no detectable differences in numbers of CD4+ and CD8+ T cells between subjects with asthma, COPD and controls. The percentage of sputum lymphocytes expressing CXCR3 was lower in subjects with asthma or COPD than in healthy controls; CCR3 was not detectable on sputum or blood lymphocytes. CONCLUSIONS: Sputum T lymphocytes are predominantly of activated intraepithelial phenotype (CD103+ CD69+), and normal numbers of CD4+ and CD8+ T cell populations are found in the sputum of patients with asthma and COPD.

7123.      Maziak W. Endotoxin and asthma. N Engl J Med. 2003 Jan 9;348(2):171-4; author reply 171-4. No abstract available.

7124.      Noguchi E, Iwama A, Takeda K, Takeda T, Kamioka M, Ichikawa K, Akiba T, Arinami T, Shibasaki M. The promoter polymorphism in the eosinophil cationic protein gene and its influence on the serum eosinophil cationic protein level. Am J Respir Crit Care Med. 2003 Jan 15;167(2):180-4.

Asthma is characterized by reversible airway obstruction and airway inflammation. Serum levels of eosinophil cationic protein (ECP) might reflect eosinophilic airway inflammation and asthma activity. However, serum ECP levels are not elevated in some patients with asthma, even when they are symptomatic. In this study, we screened for polymorphisms in the ECP gene and analyzed association between these polymorphisms and asthma and serum ECP levels in 137 Japanese families identified through children with asthma. We identified three polymorphisms (-393C/T, -38C/A, and 124Arg/Thr) in human ECP. We did not find associations between these polymorphisms and asthma by the transmission disequilibrium test. However, we found that serum ECP levels in subjects with the -393T allele were significantly lower than those in subjects with the -393C allele. A reporter construct with the -393T allele showed significantly lower promoter activity than one with the -393C allele. Gel shift assay revealed that C/EBP proteins can bind the -393C/T polymorphic site. These data indicate that C/EBP proteins play an important role in the regulation of ECP and that a significant amount of the variance in baseline serum ECP levels may be explained by the -393C/T polymorphism. Although ECP polymorphisms are not likely to be involved in the development of asthma, measurement of ECP levels for the assessment of asthma activity may be improved when done in combination with genotyping of the -393C/T polymorphism.

7125.      Roche N, Stirling RG, Lim S, Oliver BG, Oates T, Jazrawi E, Caramori G, Chung KF. Effect of acute and chronic inflammatory stimuli on expression of protease-activated receptors 1 and 2 in alveolar macrophages. J Allergy Clin Immunol. 2003 Feb;111(2):367-73.

BACKGROUND: Protease-activated receptors 1 and 2 (PAR-1 and PAR-2) are 7-transmembrane G protein-coupled receptors activated by serine proteases in many cell types, including monocytes-macrophages, leading to the production of pro-inflammatory mediators, cytokines, and growth factors. OBJECTIVE: We determined the influence of chronic smoking and asthma on the expression of PAR-1 and PAR-2 receptors on alveolar macrophages (AMs). METHODS: We used RT-PCR and immunocytochemistry with confocal microscopy to determine mRNA and protein expression of PAR-1 and PAR-2 in AMs obtained from healthy smokers, asthmatic patients, and healthy subjects. In addition, we examined the effect of IL-1beta and LPS. RESULTS: PAR1 mRNA was decreased, whereas PAR2 mRNA was increased in 24-hour cultured AMs from smokers when compared with values in AMs from healthy subjects. Paradoxically, there was a higher degree of PAR-1 protein staining in AMs from smokers, whereas PAR-2 staining was similar in smokers and healthy subjects. PAR-1 and PAR-2 mRNA and protein expression were similar in asthmatic patients and control subjects. IL-1beta and LPS had no effect on PAR1 and PAR2 gene expression by AMs. CONCLUSIONS: There is a dissociation between gene and protein expression of PAR-1 and PAR-2. PAR-1 protein overexpression in AMs from smokers might be important in the pathophysiology of chronic airways disease.

7126.      Sengler C, Haider A, Sommerfeld C, Lau S, Baldini M, Martinez F, Wahn U, Nickel R. Evaluation of the CD14 C-159 T polymorphism in the German Multicenter Allergy Study cohort. Clin Exp Allergy. 2003 Feb;33(2):166-9.

BACKGROUND: Multiple genetic studies have shown linkage of atopy-related phenotypes to chromosome 5q31. In this region several candidate genes for atopy are localized such as the Th2 cytokines IL-4, IL-5 and IL-13, but also CD14, a receptor for LPS. Recently, a functional CD14 promoter polymorphism was related to total and specific IgE responsiveness. OBJECTIVE: The aim of our study was to evaluate the role of this single nucleotide polymorphism (SNP) in a large German birth cohort. METHODS: Atopy-related phenotypes were longitudinally carefully evaluated in over 800 children from birth to the age of 10 years. Yearly visits included standardized interviews, physical examinations and determination of total and specific IgE antibodies. Pulmonary function tests and histamine provocations were performed at the age of seven. Eight-hundred and seventy-two children of the Multicenter Allergy Study (MAS) cohort were genotyped using melting curve and restriction digest analyses. RESULTS: CD14-159 allele frequencies were consistent with previous reports, however, no association of the SNP with asthma, atopic dermatitis, allergic rhinitis, total or specific IgE levels could be observed. CONCLUSION: The CD14-159 SNP might not play a major role in the development of atopy in German children.

7127.      Shankaranarayanan P, Nigam S. IL-4 induces apoptosis in A549 lung adenocarcinoma cells: evidence for the pivotal role of 15-hydroxyeicosatetraenoic acid binding to activated peroxisome proliferator-activated receptor gamma transcription factor. J Immunol. 2003 Jan 15;170(2):887-94.

The proinflammatory cytokine IL-4 is secreted in large amounts during allergic inflammatory response in asthma and plays a pivotal role in the airway inflammation. IL-4 has been shown to up-regulate 15-lipoxygenase and produce 15(S)-hydroxyeicosatetraenoic acid (15(S)-HETE) in A549 cells via the Janus kinase/STAT6 pathway under coactivation of CREB binding protein/p300. IL-4 has also been shown to up-regulate peroxisome proliferator-activated receptor gamma (PPARgamma) nuclear receptors in macrophages and A549 cells. In this study we demonstrate that 15(S)-HETE binds to PPARgamma nuclear receptors and induces apoptosis in A549 cells. Moreover, pretreatment of cells with nordihydroguaiaretic acid, a 15-lipoxygenase inhibitor, prevented PPARgamma activation and apoptosis. The latter was accomplished by the interaction of the 15(S)-HETE/PPARgamma complex with the adapter protein Fas-associating protein with death domain and caspase-8, as shown by transfection of Fas-associating protein with death domain dominant negative vector and cleavage of caspase 8 to active subunits p41/42 and p18. Whereas IL-4 and PPARgamma ligands failed to induce cleavage of Bid and release of cytochrome c from mitochondria, they caused translocation of the proapoptotic protein Bax from cytoplasm to mitochondria with a concomitant decrease in the Bcl-x(L) level. We therefore believe that in unstimulated cells Bcl-x(L) and Bax form a heterodimer, in which Bcl-x(L) dominates and prevents the induction of apoptosis, whereas in IL-4-stimulated cells the 15(S)-HETE/PPARgamma complex down-regulates Bcl-x(L), and the resulting overweight of Bax commits the cell to apoptosis via caspase-3. However, this pathway does not rule out the direct caspase-8-mediated activation of caspase-3. In conclusion, IL-4-induced apoptosis may contribute to severe loss of alveolar structures and infiltration of eosinophils, mononuclear phagocytes, etc., into the lung tissue of chronic asthma patients.

7128.      Smith SJ, Brookes-Fazakerley S, Donnelly LE, Barnes PJ, Barnette MS, Giembycz MA. Ubiquitous expression of phosphodiesterase 7A in human proinflammatory and immune cells. Am J Physiol Lung Cell Mol Physiol. 2003 Feb;284(2):L279-89.

We have determined the expression of phosphodiesterase (PDE) 7A1 and PDE7A2 in human cells that have been implicated in the pathogenesis of chronic obstructive pulmonary disease and asthma. Messenger RNA transcripts were detected by RT-PCR in T lymphocytes, monocytes, neutrophils, airway and vascular smooth muscle cells, lung fibroblasts, epithelial cells, and cardiac myocytes. Human epithelial, T cell, eosinophil, and lung fibroblast cell lines were also positive for PDE7A1 and PDE7A2 mRNA transcripts. By Western immunoblot analyses the amount of PDE7A1 was greatest in T cell lines, peripheral blood T lymphocytes, epithelial cell lines, airway and vascular smooth muscle cells, lung fibroblasts, and eosinophils but was not detected in neutrophils. In contrast, PDE7A2 protein, which was identified in human cardiac myocytes, was not found in any of the other cell types investigated. Immunoconfocal analyses showed that PDE7A was expressed in neutrophils and alveolar macrophages. As the expression of PDE7A mirrors the distribution of PDE4 we speculate that this enzyme could be a target for novel anti-inflammatory drugs.

7129.      Srivastava P, Helms PJ, Stewart D, Main M, Russell G. Association of CCR5Delta32 with reduced risk of childhood but not adult asthma. Thorax. 2003 Mar;58(3):222-6.

BACKGROUND: A number of potential candidate genes have been implicated in the pathogenesis of asthma. A 32 base pair deletion in the CCR5 gene renders this chemokine receptor non-functioning and has been shown to be associated with a reduced prevalence of asthma in childhood. The mechanism may be related to impairment of pathogen entry into cells and modified host inflammatory response. We sought to determine the influence of the CCR5Delta32 mutation on asthma and allergy in the transition from childhood to adulthood. METHODS: 627 individuals first studied as part of a whole population schoolchildren cohort in 1989 when aged 8-12 years were followed up 10 years later for respiratory and allergy symptoms and laboratory markers of atopy. CCR5Delta32 status was also characterised and the association with childhood and adulthood symptoms determined. RESULTS: The follow up sample was representative of the original cohort except for a slightly greater prevalence of symptomatic individuals. As children, none who were homozygous for the CCR5Delta32 mutation had a current physician's diagnosis of asthma. In multivariate analysis and controlling for known confounders, the protective effect of carrying the allele in childhood was highly significant (OR 0.31, 95% CI 0.14 to 0.72, p=0.006). There was no protective association with "current asthma" as classified in adulthood within the same population. Subjective or laboratory markers of atopy in childhood or adulthood were not associated with the CCR5Delta32 mutation. Methacholine bronchial hyperresponsiveness in adulthood was also unrelated to gene carrier status. CONCLUSIONS: In a population with a high allelic frequency for the CCR5Delta32 mutation, a significant protection against childhood asthma is evident which is independent of atopy. This protection is lost in the transition between childhood and early adulthood. The contribution of different genetic candidates to the expression of asthma may change with advancing maturity and confound the interpretation of association and linkage studies unless age is taken into account.

7130.      Tang L, Morales T, Boroughs KL, Cailles Lo-Keiser K, Sellins K, Stedman K, McCall C, McDermott MJ. Expression and characterization of recombinant canine IL-13 receptor alpha2 protein and its biological activity in vitro. Mol Immunol. 2003 Jan;39(12):719-27.

Our previous study showed that recombinant canine IL-13 (rcaIL-13) stimulated production of allergen-specific IgE in vitro by peripheral blood mononuclear cells (PBMC) from flea allergen-sensitized dogs. This has also been demonstrated using human IL-13 (huIL-13) and PBMC isolated from human allergy patients. The stimulatory activity of rcaIL-13 was specifically inhibited by a fusion protein of the extracellular domain of canine IL-13Ralpha2 and the Fc fragment of canine IgG heavy chain (rcaIL-13Ralpha2-Fc). In this communication, we report the construction and expression of a non-fused recombinant extracellular domain of canine IL-13Ralpha2 (rcaIL-13Ralpha2) in an E. coli expression system. The E. coli expressed rcaIL-13Ralpha2 was isolated in inclusion bodies, then solubilized in buffer containing denaturants and reducing agents. After refolding and purification, the biological activity of rcaIL-13Ralpha2 was found in the monomer fraction resulting from gel filtration and ion exchange chromatographies. Biological activity of purified rcaIL-13Ralpha2 was demonstrated by the specific inhibition of rcaIL-13 activity in a TF-1 cell proliferation assay. Additionally, rcaIL-13Ralpha2 was found to be active in neutralizing rcaIL-13 induced upregulation of IgE mRNA levels in PBMCs of "high IgE" dogs, which have been bred to exhibit a predisposition for high IgE production and are used as a model for allergic asthma. The data confirm our previous report that the regulatory effects of IL-13 on IgE production in canine PBMCs are similar to those reported in humans. Thus, allergic dogs, such as the "high IgE" producing dogs, may be excellent models for research on IgE-mediated diseases in humans.

7131.      Zabner J, Winter MC, Shasby S, Ries D, Shasby DM. Histamine decreases E-cadherin-based adhesion to increase permeability of human airway epithelium. Chest. 2003 Mar;123(3 Suppl):385S. Review.No abstract available.

 

Therapy:

7132.      Gupta S; Chauhan DK; Verma A; Misra NP; Trivedi HH; Irani P; Moharana NK.Study of montelukast: a once daily leukotriene receptor antagonist in the management of chronic persistent asthma.Indian Practitioner. 2003 Feb; 56(2): 99-105

ABSTRACT: Today, with growing understanding of its natural history, once considered a disease of airway smooth muscle, asthma is now defined as "a chronic inflammatory disorder of the airways". Therefore, although control of bronchoconstriction remains an important therapeutic objective, the more fundamental goal of asthma therapy is to reduce airway inflammation. Inhaled corticosteroids (ICS) remain the gold standard agents for this purpose (long term preventer therapy), with periodic use of a bita2- agonist bronchodilator agent (as needed therapy) for relief of acute symptoms in patients with persistent asthma. Persistent asthma is characterized by recurrent, chronic inflammation of the lungs, a process in which leukotrienes play a key role. Leukotriene receptor antagonists (LTRAs) are an important new class of non-steroidal anti-asthma therapy, effective over a wide range of asthma severity with a high therapeutic index as well as orally active. Montelukast, the currently available LTRA, has a rapid onset in action which is sustained, allowing for treatment of early-and late-phase symptoms of asthma. Moreover, near maximum effect is obtained with the first dose. Because of its additive effects, montelukast help improve asthma control in patients in whom ICS monotherapy is inadequate. The present study is an effort to garner experience with montelukast in Indian patients with mild, moderate and severe chronic persistent asthma on airway function, asthma symptoms and use of as needed bita2-agonists. The study design is an open, multi-centric and non-comparative study evaluating efficacy and tolerability of montelukast 10 mg once daily administered to patients with chronic persistent asthma for a period of four weeks. The study was designed to enroll a non-homogeneous set of patients (mixture of mild to moderate chronic persistent asthma cases) in order to reflect the real world clinical practice in our country. 51.67 percent of the enrolled patients were on ICS and 27.04 percent patients were on different bronchodilators. The day time asthma symptoms score prior to the drug therapy reported on several days was 10.27+_ 1.92. Whereas, after the drug therapy the same symptoms intensity was reduced significantly (by 56.76 percent), to only 4.44+_ 2.53 (p 0.001). The average number of nocturnal or early morning awakenings in the preceding weeks were 1.68 +_0.89 times which was reduced to 0.56 +_ 0.66 (a reduction of 66.66 percent, p0.001) when treated with montelukast. Asthma attacks in last 4 weeks were 1.12 +_ 1.24, and reduced to 0.30 +_ 0.65 (a reduction by 73.21 percent: p0.001). Significantly fewer patients in the treatment group needed the use of inhaled beta2-agonist after one month of treatment (4.88 to 2.74 puffs per day; p0.05) Patients had a forced expiratory volume in I st second (FEV1) that had at least 21.26 percent improvement in absolute FEV1 after therapy from baseline. PEFR was 215.7L/min at baseline, which increased to 297.3 at the final visit, a 37.83 percent enhancement. Similar observations were reported for the percent predicted values of PEFR and FEV. Physician's Global assessment of Montelukast has shown that 86.15 percent patients felt significantly better, whereas in 11.77 percent patients the baseline parameters did not change. 2.18 percent patients worsened their initial symptoms at the end of the study. The study results clearly demonstrated the role of montelukast as an add-on therapy to patients already on ICS and as mono-therapy in a subset of mild asthmatics. One thousand six hundred and eighty six patients (939 males and 747 females: mean age of 43.14 +_ 15.25) with mild or moderate persistent asthma, with mean duration of asthma of 6.72 +_ 13.12 years were enrolled. Sixty seven patients were associated with hypertension and thirty seven with ischaemic heart disease. These patients were treated simultaneously with co-medications like nitrates, CCBs and ACEIs.

7133.      Talib SH; Sane SD; Gopanpallikar AM; Kumbhakarna NR. Effect of helicobacter pylori eradication therapy in patients of bronchial asthma with gastroesophageal reflex disease (GERD) Journal, Indian Academy of Clinical Medicine. 2003 Jan-Mar; 4(1): 39-49

 

October 2003 

7808.  Adams BK, Cydulka RK.  Asthma evaluation and management. Emerg Med Clin North Am. 2003 May;21(2):315-30.

 

Asthma is a chronic inflammatory illness with acute exacerbations, which often is encountered in the ED setting. Knowledge of the presentation and treatment of asthma is crucial for any physician treating patients with this disease. Beta-agonist, anticholinergic, and corticosteroid therapy continue to be the mainstay of emergency therapy despite advances in newer medications. Proper attention to long-term treatment of asthma and aggressive treatment of acute exacerbations should help reduce morbidity and mortality.

7809.  Addington WR, Stephens RE, Widdicombe JG, Anderson JW, Rekab K.  Effect of tartaric acid-induced cough on pulmonary function in normal and asthmatic humans. Am J Phys Med Rehabil. 2003 May;82(5):374-8.

 

OBJECTIVE: The laryngeal cough reflex and the laryngeal cough expiratory reflex are brainstem reflexes that protect the upper airway from significant aspiration. The purpose of this investigation was to examine the effects of tartaric acid-induced cough on pulmonary function in normal healthy and asthmatic individuals. DESIGN: Twenty healthy and 20 asymptomatic, medicated, asthmatic volunteers engaged in a two-part evaluation of pulmonary function testing. All 40 subjects were nonsmokers. The reflex cough test, a 20% solution of prescription-grade L-tartaric acid dissolved in 0.15 M NaCl solution, initiated the laryngeal cough expiratory reflex/laryngeal cough reflex. The solution was placed in a Bennett Twin nebulizer and inhaled as a microaerosol. Pulmonary function testing was with a Spiromate AS-600. Baseline pulmonary function testing was initially performed, followed by two separate inhalations of the reflex cough test. The pulmonary function testing was repeated 5 min  after the second reflex cough test. RESULTS: Statistically significant changes seen after the reflex cough test included increases in the peak inspiratory flow in normal subjects (P = 0.004) and in the peak expiratory flow in asthmatic subjects (P = 0.014). No respiratory adverse events occurred after the reflex cough test. CONCLUSIONS: Explanations for these findings include the possibility that tartaric acid-induced cough produces central nervous system-mediated bronchodilatation, through the cough itself or by secondary mechanisms.

 

7810.  Anees W.  Use of pulmonary function tests in the diagnosis of occupational asthma. Ann Allergy Asthma Immunol. 2003 May;90(5 Suppl 2):47-51.

 

OBJECTIVE: To discuss the different methods of assessing lung function measurements for the diagnosis of occupational asthma, focusing in particular on serial peak expiratory flow rate (PEFR) monitoring, including details on how PEFR records should be kept, plotted, and analyzed and limitations of the method. DATA SOURCES: Published studies on the use of diagnostic methods in occupational asthma, expert opinion, and recently obtained data from studies performed at a large occupational lung disease clinic. STUDY SOURCES: The expert opinion of the author was used to select the relevant data for review. RESULTS: Objective methods are necessary for the diagnosis of occupational asthma, since clinical history alone is not a satisfactory means of diagnosis. Serial PEFR monitoring has a high diagnostic sensitivity and specificity for occupational asthma and is more useful than evaluation of cross-shift change in forced expiratory volume in 1 second or change in nonspecific bronchial hyperresponsiveness. Interpretation is best performed by expert visual evaluation of plots of maximum, mean, and minimum daily PEFR readings. CONCLUSIONS: Despite some limitations of the method, serial PEFR monitoring is usually the most appropriate first-line investigation in workers suspected of having occupational asthma.

7811.  Arets HG, Brackel HJ, van der Ent CK.  Applicability of interrupter resistance measurements using the MicroRint in daily practice. Respir Med. 2003 Apr;97(4):366-74.

 

This study was performed to evaluate the applicability of a simple device (MicroRint) for measuring airway resistance, to derive normal values and to compare values with maximal expiratory flow volume (MEFV) parameters in asthmatic and healthy children. Repetitive R(int) measurements were performed in 125 healthy children and 107 asthmatic children (age range 0.8-16.8 years). In 42 asthmatic patients R(int) and MEFV values were compared and in 29 asthmatic children bronchodilation testing was performed. Successful R(int) measurements were possible in 91% of the children. The mean coefficient of variation of repeated measurements was 7.1 (+/-6.1)%. R(int) values of healthy children showed a significant curvilinear correlation with age (r=-0.80, P < 0.001) and height (r=-0.81, P < 0.001). In asthmatic and healthy children R(int) values were comparable. A significant inverse correlation was found between R(int) and MEFV values (for FEV1 and R(int) r=-0.80, P < 0.001). After bronchodilation there was a significant increase in FEV1 and decrease in R(int), but changes between the two parameters did not correlate. In conclusion, the interrupter technique is feasible and repeatable in children and has a significant correlation with other parameters of airway caliber. Baseline values do not discriminate healthy from asthmatic children.

7812.  Baraldi E, Carraro S, Alinovi R, Pesci A, Ghiro L, Bodini A, Piacentini G, Zacchello F, Zanconato S.  Cysteinyl leukotrienes and 8-isoprostane in exhaled breath condensate of children with asthma exacerbations. Thorax. 2003 Jun;58(6):505-9.

 

BACKGROUND: Cysteinyl leukotrienes (Cys-LTs) and isoprostanes are inflammatory metabolites derived from arachidonic acid whose levels are increased in the airways of asthmatic patients. Isoprostanes are relatively stable and specific for lipid peroxidation, which makes them potentially reliable biomarkers for oxidative stress. A study was undertaken to evaluate the effect of a course of oral steroids on Cys-LT and 8-isoprostane levels in exhaled breath condensate of children with an asthma exacerbation. METHODS: Exhaled breath condensate was collected and fractional exhaled nitric oxide (FE(NO)) and spirometric parameters were measured before and after a 5 day course of oral prednisone (1 mg/kg/day) in 15 asthmatic children with an asthma exacerbation. Cys-LT and 8-isoprostane concentrations were measured using an enzyme immunoassay. FE(NO) was measured using a chemiluminescence analyser. Exhaled breath condensate was also collected from 10 healthy children. RESULTS: Before prednisone treatment both Cys-LT and 8-isoprostane concentrations were higher in asthmatic subjects (Cys-LTs, 12.7 pg/ml (IQR 5.4-15.6); 8-isoprostane, 12.0 pg/ml (9.4-29.5)) than in healthy children (Cys-LTs, 4.3 pg/ml (2.0-5.7), p=0.002; 8-isoprostane, 2.6 pg/ml (2.1-3.0), p<0.001). After prednisone treatment there was a significant decrease in both Cys-LT (5.2 pg/ml (3.9-8.8), p=0.005) and 8-isoprostane (8.4 pg/ml (5.4-11.6), p=0.04) concentrations, but 8-isoprostane levels remained higher than in controls (p<0.001). FE(NO) levels, which fell significantly after prednisone treatment (p<0.001), did not correlate significantly with either Cys-LT or 8-isoprostane concentrations. CONCLUSION: After a 5 day course of oral prednisone there is a reduction in Cys-LT and 8-isoprostane levels in EBC of children with an asthma exacerbation, although 8-isoprostane levels remain higher than in controls. This finding suggests that corticosteroids may not be fully effective in reducing oxidative stress in children with an exacerbation of asthma.

 

7813.  Barczyk A, Pierzchala W, Sozanska E.  Interleukin-17 in sputum correlates with airway hyperresponsiveness to methacholine. Respir Med. 2003 Jun;97(6):726-33.

 

BACKGROUND: Interleukin-17 (IL-17) is a novel cytokine secreted by activated human memory CD4+ T cells. In vivo IL-17 recruits neutrophils into the airways via the release of CXC chemokines (interleukin-8) from bronchial epithelial cells. Since neutrophils are implicated in pathogenesis of chronic obstructive pulmonary disease (COPD) chronic bronchitis (CB) and asthma, we hypothesized that there would be increased concentration of IL-17 in the airways of these patients. To test this hypothesis, we measured levels of IL-17 in induced sputum of COPD patients, chronic bronchitis and asthmatics and compared them with healthy controls. METHODS: Levels of IL-17 in induced sputum were measured via ELISA method in 19 COPD, 16 CB, 10 asthma and 11 control subjects. Airway responsiveness to methacholine was performed in people with FEV1 higher than 70% of predicted. RESULTS: There were no significant differences in IL-17 levels between control group and the other groups. However, levels of IL-17 in sputum of COPD patients were significantly lower than in asthma (P=0.004) and in CB (P=0.01) groups. Medians and (ranges) were as follows: asthma--37.6 pg/ml (18.8-55.7 pg/ml), CB 293 pg/ml (18.8-49.7 pg/ml) and COPD 24.6 pg/ml (0-34.1 pg/ml). Comparison of healthy control subjects (PC20 > 8 mg/ml) to a group with bronchial hyperreactivity, which consisted of asthmatics and CB patients, whose PC20 was less than 8 mg/ml, revealed that levels of IL-17 were significantly increased in the second group (P=0.02). Also, levels of IL-17 were significantly increased (P=0.02) in the asthmatic patients with bronchial hyperreactivity compared to healthy subjects. Moreover levels of IL-17 in sputum of all studied subjects correlated negatively with PC20 (r=-0.51, P=0.002). CONCLUSIONS: According to our results IL-17 is probably not involved in pathogenesis of stable COPD, but it may play a role in people with airway hyperresponsiveness.

 

7814.  Benayoun L, Druilhe A, Dombret MC, Aubier M, Pretolani M.  Airway structural alterations selectively associated with severe asthma. Am J Respir Crit Care Med. 2003 May 15;167(10):1360-8. Epub 2003 Jan 16.

 

To identify airway pathologic abnormalities selectively associated with severe asthma, we examined 10 control subjects, 10 patients with intermittent asthma, 15 patients with mild-to-moderate persistent asthma, 15 patients with severe persistent asthma, and 10 patients with chronic obstructive pulmonary disease. Bronchial biopsies were assessed for epithelial integrity; subepithelial basement membrane (SBM) thickness; collagen type III deposition; eosinophil, neutrophil, and fibroblast numbers; mucous gland and airway smooth muscle (ASM) areas; SBM-ASM distance; ASM hypertrophy (increased cell size); and the expression of the contractile proteins alpha-actin, smooth muscle myosin heavy-chain isoforms, myosin light-chain kinase, and the phosphorylated form of the regulatory light chain of myosin. Neither mucosal eosinophilia nor neutrophilia, epithelial damage, or SBM thickness reflected asthma severity. In contrast, higher numbers of fibroblasts (p < 0.001), an increase in collagen type III deposition (p < 0.020), larger mucous gland (p < 0.040) and ASM (p < 0.001) areas, augmented ASM cell size (p < 0.001), and myosin light-chain kinase expression (p < 0.005) distinguished patients with severe persistent asthma from patients with milder disease or with chronic obstructive pulmonary disease. Stepwise multivariate regression analysis established that fibroblast numbers and ASM cell size were negatively associated with prebronchodilator and postbronchodilator FEV1 values in patients with asthma. We conclude that fibroblast accumulation and ASM hypertrophy in proximal airways are selective determinants of severe persistent asthma.

7815.  Currie GP, Lee DK, Lipworth BJ.  Asthma exacerbations and sputum eosinophil counts. Lancet. 2003 Apr 12;361(9365):1302-3;  No abstract

7816.  Davies PD.  The challenge of tuberculosis. J R Soc Med. 2003 Jun;96(6):262-5. No abstract

7817.  Di Franco A, Bartoli ML, Carnevali S, Cianchetti S, Bacci E, Dente FL, Giannini D, Taccola M, Vagaggini B, Paggiaro PL.  Analysis of sputum cell counts during spontaneous moderate exacerbations of asthma in comparison to the stable phase. J Asthma. 2003 Apr;40(2):155-62.

 

BACKGROUND: Acute airway inflammation is considered to characterize asthma exacerbations, but its specific cellular pattern has not yet been completely evaluated. AIM: To evaluate the prevalence of sputum eosinophilia during acute asthma exacerbations of moderate severity, compared with a stable phase of the disease, and to assess the concordance between changes in pulmonary function and sputum eosinophilia in the period between exacerbation and post exacerbation. METHODS: We compared sputum and blood inflammatory cell counts in 29 asthmatic subjects during a spontaneous moderate exacerbation of asthma (visit 1) with sputum and blood cell counts measured 4 weeks after the resolution of asthma exacerbation (visit 2). At visit 1, all subjects required an appropriate 1 week treatment with oral corticosteroids. RESULTS: At visit 1, all subjects were able to collect spontaneous sputum, whereas at visit 2 sputum was induced by inhalation of hypertonic saline (NaCl 3, 4, and 5%, 10 minutes each) with beta2-agonist pretreatment. Asthma exacerbation was accompanied by a significant increase in sputum eosinophil percentages compared with levels after exacerbation [25% (1-78) versus 4% (0-23), p<0.05). Only four subjects showed low sputum eosinophil percentages during exacerbation, and these showed no differences in main clinical findings with respect to subjects with sputum eosinophilia. At visit 2, the stability of asthma was assessed on the basis of PEF, FEV1, symptoms, and use of rescue beta2-agonist. Asthma was defined as stable in 21 out of 29 subjects. Sputum eosinophil percentages fell significantly between visit 1 and visit 2 in both stable and unstable patients, but at visit 2 sputum eosinophil percentages were still high in subjects with unstable asthma. In patients who proved to be stable at visit 2, there was a significant correlation between the changes recorded in sputum eosinophil percentages and in FEV1 between the two visits (rho: 0.723, p<0.001). CONCLUSION: Sputum cosinophil but not neutrophil percentages increase in most asthmatic subjects during moderate exacerbation of asthma. Changes in the degree of airway eosinophilic inflammation are related to changes in the severity of airway obstruction during asthma exacerbation.

 

7818.  Erpenbeck VJ, Hohlfeld JM, Volkmann B, Hagenberg A, Geldmacher H, Braun A, Krug N.  Segmental allergen challenge in patients with atopic asthma leads to increased IL-9 expression in bronchoalveolar lavage fluid lymphocytes. J Allergy Clin Immunol. 2003 Jun;111(6):1319-27.

 

BACKGROUND: IL-9 is a T(H)2 cell-derived cytokine that might be involved in the pathophysiology of allergic diseases. Little is known about its expression and release during the allergic response in the human lung. OBJECTIVE: The expression of IL-9 was measured in 10 atopic subjects with mild asthma and 5 nonatopic healthy control subjects at baseline and 24 hours after segmental sham and allergen challenge. METHODS: IL-9 protein was measured in bronchoalveolar lavage (BAL) fluid by means of ELISA and detected within the BAL cells by means of immunocytochemistry. Furthermore, IL9 mRNA expression of BAL cells was detected by means of real-time PCR. RESULTS: Although only low or undetectable amounts of IL9 mRNA and IL-9 protein were present in nonatopic control subjects and atopic asthmatic patients at baseline, there was an increase after segmental allergen challenge in the atopic subjects. Lymphocytes were identified as major cellular sources of IL-9 production by means of immunocytochemistry. Furthermore, IL-9 protein and IL9 mRNA expression correlated with eosinophil numbers in BAL fluid. CONCLUSIONS: These findings demonstrate that IL-9 is specifically upregulated after local allergen challenge in the lungs of atopic asthmatic patients. Lymphocytes are the major cellular source of IL-9. The increased expression and its correlation with eosinophil numbers suggest a potential role for IL-9 in the late phase of the allergic response.

7819.  Han Z, Junxu, Zhong N.  Expression of matrix metalloproteinases MMP-9 within the airways in asthma. Respir Med. 2003 May;97(5):563-7.

 

The matrix metalloproteinase (MMP) enzymes MMP-9, have relevance to chronic structural airway changes in asthma, which can be generated by structural and inflammatory cells, and have the ability to degrade proteoglycans and thus potentially enhance airway fibrosis and smooth muscle proliferation through  their ability to release and activate latent, matrix-bound growth factors.Immunostaining for MMP-9 was undertaken in acetone-fixed and glycolmethacrylate-embedded endobronchial biopsy specimens obtained by fibreoptic bronchoscopy under local anaesthesia. The findings from 30 asthmatic subjects were compared with those from 18 chronic obstructive pulmonary disease (COPD) subjects and 10 healthy controls. Meanwhile, pulmonary function test and airway responsiveness were performed. Immunoreactivity for MMP-9 was assessed by an image analysis system. The biopsy specimens from asthmatic subjects contained significantly more eosinophils (P < 0.001) than those from COPD subjects, and healthy control did not contain eosinophils. MMP-9 immunoreactivity could be identified in endobronchial biopsy specimens from all the asthmatic subjects and 40% ofthe COPD subjects, but could not be identified in healthy controls. Gelatinase B (MMP-9) immunoreactivity was located in bronchial epithelium and extracellular matrix in submucosa, prominent in denuded epithelium. The immunohistochemical score for MMP-9 was significantly correlated with eosinophilic number in bronchial mucosa. FEV1% predicted FEV1/FVC (%) (r = 0.52, 0.41, 0.37, respectively P < 0.01 did not correlate with PD20 FEV1 from asthmatic subjects. MMP-9 is expressed by bronchial epithelium and may be a important factor for eosinophil infiltraed into airway from asthma subjects.

7820.  Huang J, Jiang Y.  Genetic linkage analysis of a dichotomous trait incorporating a tightly linked quantitative trait in affected sib pairs. Am J Hum Genet. 2003 Apr;72(4):949-60. Epub 2003 Mar 17.

 

Many complex diseases are usually considered as dichotomous traits but are also associated with quantitative biological markers or quantitative risk factors. For such dichotomous traits, although their associated quantitative traits may not directly underly the diagnosis of the disease status, if the associated quantitative trait is also linked to the chromosomal regions linked to the dichotomous trait, then joint analysis of dichotomous and quantitative traits should be more efficient than consideration of them separately. Previous studies have focused on the situation when a dichotomous trait can be modeled by a threshold process acting on a single underlying normal liability distribution. However, for many complex disorders, including most psychiatric disorders, diagnosis is generally based on a set of binary or discrete criteria. These traits cannot be modeled on the basis of a threshold process acting on an underlying continuous trait. We propose a likelihood-based method that efficiently combines such a discrete trait and an associated quantitative trait in the analysis, using affected-sib-pair data. Our simulation studies suggest that joint analysis increases the power to detect linkage of dichotomous traits. We also apply the proposed new method to an asthma genome-scan data set and incorporate the total serum immunoglobulin E level in the analysis.

7821.  Kapui Z, Varga M, Urban-Szabo K, Mikus E, Szabo T, Szeredi J, Batori S, Finance O, Aranyi P.  Biochemical and pharmacological characterization of 2-(9-(2-piperidinoethoxy)-4-oxo-4H-pyrido[1,2-a]pyrimidin-2-yloxymethyl)-4-(1-me thylethyl)-6-methoxy-1,2-benzisothiazol-3(2H)-one-1,1-dioxide (SSR69071), a novel, orally active elastase inhibitor. J Pharmacol Exp Ther. 2003 May;305(2):451-9. Epub 2003 Feb 11.

 

Human leukocyte elastase (HLE) is a proteinase capable of degrading a variety of proteins. Under normal circumstances, the proteolytic activity of HLE is effectively controlled by its natural inhibitors. However, an imbalance between elastase and its endogenous inhibitors may result in several pathophysiological states such as chronic obstructive pulmonary disease, asthma, emphysema, cystic fibrosis, and chronic inflammatory diseases. It is anticipated that an orally active HLE inhibitor could be useful for the treatment of these diseases. 2-(9-(2-Piperidinoethoxy)-4-oxo-4H-pyrido[1,2-a]pyrimidin-2-yloxymethyl)-4-(1-me thylethyl)-6-methoxy-1,2-benzisothiazol-3(2H)-one-1,1-dioxide (SSR69071) is a potent inhibitor of HLE, with the inhibition constant (K(i)) and the constant for inactivation process (k(on)) being 0.0168 +/- 0.0014 nM and 0.183 +/- 0.013 10(6)/mol sr, respectively. The dissociation rate constant, k(off), was 3.11 + 0.37 10(-6)/s. SSR69071 displays a higher affinity for human elastase than for rat (K(i) = 3 nM), mouse (K(i) = 1.8 nM), and rabbit (K(i) = 58 nM) elastases. Bronchoalveolar lavage fluid from mice orally treated with SSR69071 inhibits HLE (ex vivo), and in this model, SSR69071 has a dose-dependent efficacy with an ED(50) = 10.5 mg/kg p.o. SSR69071 decreases significantly the acute lung hemorrhage induced by HLE (ED(50) = 2.8 mg/kg p.o.) in mice. Furthermore, SSR69071 prevents carrageenan- (ED(30) = 2.2 mg/kg) and HLE-induced (ED(30) = 2.7 mg/kg) paw edema in rats after p.o. administration. In conclusion, SSR69071 is a selective, orally active, and potent inhibitor of HLE with good penetration in respiratory tissues.

7822.  Lee IS.  Effect of bedding control on amount of house dust mite allergens, asthma symptoms, and peak expiratory flow rate. Yonsei Med J. 2003 Apr 30;44(2):313-22.

 

This quasi-experimental study was designed to investigate the effect of bedding control on the amount of house dust mite (HDM) allergens, asthma symptoms, and peak expiratory flow rate (PEFR) in asthmatics sensitive to HDMs. The subjects in the study were drawn from patients receiving treatment at the allergy clinics of three university-affiliated hospitals in Seoul. Forty-two patients without prior practice of the bedding control used in this study were selected. They commonly showed bronchial asthma caused by HDMs, and exhibited strong positive points (more than 3 points) in skin prick test (D. farinae, D. pteronyssinus), and positive response in both fluoro-allergosorbent test (FAST), and PC20 methacholine test. Of the subjects, alternatively, 22 were assigned to the experimental group and 20 to control group. Bedding control consisted of the use of outer cotton covers, boiling them for 10 minutes fortnightly, and disinfecting bedding by sunlight fortnightly. The experimental group was under bedding control for 4 weeks. The data were collected from October 2000 to January 2001. The results were as follows: 1. After bedding control, the total amount of HDM allergens decreased significantly in the experimental group. However there was no significant difference in the decrease of the amount of HDM allergens between the two groups. 2. Of the asthma symptoms, there was significant difference only in the decrease of the frequency of dyspnea, and in the increase of sleeping disturbance between the two groups after bedding control. 3. After bedding control, PEFR increased in the experimental group whereas it decreased in the control group. However, neither change was significant. The above findings indicate that bedding control improved several asthma symptoms in asthmatics sensitive to HDMs. Accordingly, we suggest that bedding control is adopted as a useful nursing intervention in the field.

7823.  Lewis CA, Eaton TE, Fergusson W, Whyte KF, Garrett JE, Kolbe J.  Home overnight pulse oximetry in patients with COPD: more than one recording may be needed. Chest. 2003 Apr;123(4):1127-33.

 

STUDY OBJECTIVES: Home overnight pulse oximetry (OPO) is used to assess nocturnal desaturation in patients with COPD, but the current practice of relying on one recording has not been studied. We assessed the variability of nocturnal desaturation in patients with COPD between nights, as measured by home OPO. DESIGN: Study subjects attended for clinical evaluation, spirometry, and arterial blood gas analysis. OPO was prospectively completed at home on 2 consecutive nights (study night 1 [N1] and study night 2 [N2]) and repeated at 3 weeks (study night 3 [N3]). SETTING: Respiratory Services, Green Lane Hospital, Auckland, New Zealand. PATIENTS: Twenty-six patients with clinically stable COPD (mean age, 69.3 years [SD, 6.9]; FEV(1), 28.6% predicted [SD, 10.6]; PO(2), 71.3 mm Hg [SD, 9.8]). Patients with asthma or clinical evidence of obstructive sleep apnea were excluded. MEASUREMENTS AND RESULTS: Mean nocturnal saturation (MNS) and time spent with saturation below 90% (TB90%) were calculated for N1, N2, and N3. Group mean recording length, MNS, and TB90% were similar for each night. Little variation in MNS was seen between nights (N1 and N2 mean difference, 1.31%; N2 and N3, 1.26%; N1 and N3, 1.25%). Larger variation was seen between nights for TB90% (N1 and N2 mean difference, 17.46%; N2 and N3, 9.95%; N1 and N3, 14.05%). No factors were identified that predicted increased variability of TB90%. Using the current definition of "significant nocturnal desaturation" (TB90% > or = 30% of the night), 9 of 26 patients (34.6%) changed category between "desaturator" and "nondesaturator" from N1 to N2. CONCLUSION: Nocturnal desaturation in patients with COPD exhibits considerable night-to-night variability when measured by home OPO. A single home OPO recording may be insufficient for accurate assessment of nocturnal desaturation.

 

7824.  Lieutier-Colas F, Purohit A, Meyer P, Fabries JF, Kopferschmitt MC, Dessanges JF, Pauli G, de Blay F.  Bronchial challenge tests in patients with asthma sensitized to cats: the importance of large particles in the immediate response. Am J Respir Crit Care Med. 2003 Apr 15;167(8):1077-82.

 

Our aim was to compare bronchial responses to major cat allergen (Fel d 1) in individuals with intermittent asthma sensitized to cats (19 subjects) according to the droplet particle size. We used three nebulizers, which delivered particles with mass median aerodynamic diameters of 1.4, 4.8, and 10.3 microm. A dosimeter nebulizer was used. The cat allergen was diluted to obtain the same amount of Fel d 1 per puff with each nebulizer. Each patient underwent three methacholine bronchial challenge tests (BCT), each followed 24 hours later by a cat allergen BCT, each performed with a different nebulizer (randomly selected each time, with patient and tester always blinded). Subjects did not differ for methacholine responsiveness, FEV1, mean forced expiratory flow during the middle half of the FVC (FEF25-75), PEF, or dyspnea (Borg scale) before any of the three cat BCTs. Cat allergen PD20 was 271 ng of Fel d 1 with the 1.4 microm nebulizer, 46 ng with the 4.8 microm nebulizer, and 13.5 ng with the 10.3 microm nebulizer (p = 0.00001). Inhalation of small particles (1.4 microm) resulted in significantly lower FEF25-75 24 hours after provocation than large particles did. In conclusion, immediate bronchial response appears to be localized in large airways, and the use of large particles is more appropriate for cat allergen BCTs.

7825.  Mortimer KM, Fallot A, Balmes JR, Tager IB.  Evaluating the use of a portable spirometer in a study of pediatric asthma. Chest. 2003 Jun;123(6):1899-907.

 

STUDY OBJECTIVES: Laboratory-based spirometry is the "gold standard" for the assessment of lung function, both in clinical and research protocols. These spirometers, however, are neither practical nor affordable for home-based monitoring or studies that collect data in multiple locations. Traditionally, peak flowmeters have been used, but they have important limitations. DESIGN: Based on data from a cohort of 92 children with asthma, we evaluated the agreement between a portable spirometer and a office-based spirometer, using an in-line technique to evaluate measures from the same effort. We compared a range of pulmonary function parameters collected during office-based tests, and also evaluated whether adequate adherence and data quality could be achieved in a home-based study of children with asthma. RESULTS: The agreement between the devices for the actual values of peak expiratory flow, FEV(1), and forced expiratory flow at 25% of FVC was excellent. The portable device was programmed with customized software to grade each curve using revised American Thoracic Society acceptability and reproducibility criteria. For 74% of the curves, quality grade agreed with a grade assigned by physician review of the curve from the office-based spirometer. During 2 weeks of twice-daily monitoring at home, children completed an average of 23 of 28 possible sessions (83%). Of these, 84% had at least two acceptable and two reproducible curves. Although children >or= 8 years old were not more adherent, they were significantly more likely to achieve acceptable and reproducible curves. CONCLUSIONS: Portable spirometers can provide measurements that are highly comparable to those obtained from "gold standard" laboratory spirometers, and high-quality tracings can be achieved both at home and in the office setting. Visual inspection of the curves by experienced reviewers identified unacceptable curves that were not rejected by the quality control software. Portable spirometers are an important contribution to epidemiologic and clinical studies that require frequent measures of a more broad range of pulmonary function parameters than can be provided by peak flowmeters.

7826.  Ortega AN, McQuaid EL, Canino G, Ramirez R, Fritz GK, Klein RB.  Association of psychiatric disorders and different indicators of asthma in island Puerto Rican children. Soc Psychiatry Psychiatr Epidemiol. 2003 Apr;38(4):220-6.

 

BACKGROUND: We examined the relationship between three different indicators of childhood asthma (asthma diagnosis, ever had an asthma attack, and asthma hospitalization) and having any psychiatric disorder, comorbid disorders, or specific disorders. Three study hypotheses were examined: 1) there will be subject variability in responses to the asthma indicators; 2) there will be different observed associations between the three asthma indicators and psychiatric disorders; and 3) maternal mental health, family income, and maternal education will confound the associations between childhood asthma and psychiatric disorders. METHOD: Data were drawn from a community-based, random sample of 1,891 island Puerto Rican children aged 4-17 years. Information was collected through direct interview with children and adolescents and their primary caretakers. The Diagnostic Interview Schedule for Children (DISC) was used to determine DSM-IV diagnoses. RESULTS: Thirty-two percent of the children had been diagnosed with asthma but only 22 % had  ever experienced an asthma attack. Seventeen percent of the children had been hospitalized for asthma. Having been hospitalized for asthma was not associated with any of the psychiatric disorders, having a diagnosis was associated with some of the disorders, and having experienced an asthma attack was associated with almost all the disorders, after controlling for family income and maternal education and mental health. CONCLUSIONS: Determining and measuring asthma may be difficult because of confusion and differing perceptions of what constitutes asthma or an asthma attack. Future studies should consider the problems in capturing perceptions of asthma and severity in Puerto Rican children and should continue to explore the relationship between asthma and mental illness.

7827.  Ownby DR.  Strategies for distinguishing asymptomatic latex sensitization from trueoccupational allergy or asthma. Ann Allergy Asthma Immunol. 2003 May;90(5 Suppl 2):42-6.

 

OBJECTIVE: To evaluate strategies for distinguishing those individuals with true occupational asthma caused by exposure to natural rubber latex from those individuals with allergic disease related to other allergens. DATA SOURCES: Article published between January 1, 1981, and December 31, 2001, were identified via a MEDLINE search with the following keywords: latex, allergy, asthma, occupation asthma, and adverse reactions. STUDY SELECTION: English-language reports concerning diagnostic methods in latex and other forms of occupational asthma. RESULTS: Many methods have been evaluated for the diagnosis of latex allergy, including medical history, skin prick tests, in vitro tests, and various challenge tests. Skin prick tests with well characterized latex extracts are highly sensitive and specific predictors of latex-specific IgE antibodies; however, direct pulmonary challenge with latex allergen appears to be the only highly reliable method for diagnosis of latex-related occupational asthma. CONCLUSIONS: It is difficult to optimally distinguish between occupational latex asthma and asymptomatic latex sensitization in a person with preexisting asthma using currently available techniques.

7828.  Pajukanta P, Allayee H, Krass KL, Kuraishy A, Soro A, Lilja HE, Mar R, Taskinen MR, Nuotio I, Laakso M, Rotter JI, de Bruin TW, Cantor RM, Lusis AJ, Peltonen L.  Combined analysis of genome scans of dutch and finnish families reveals a susceptibility locus for high-density lipoprotein cholesterol on chromosome 16q. Am J Hum Genet. 2003 Apr;72(4):903-17. Epub 2003 Mar 12.

 

Several genomewide screens have been performed to identify novel loci predisposing to unfavorable serum lipid levels and coronary heart disease (CHD). We hypothesized that the accumulating data of these screens in different study populations could be combined to verify which of the identified loci truly harbor susceptibility genes. The power of this strategy has recently been demonstrated with other complex diseases, such as inflammatory bowel disease and asthma. We assessed the largely unknown genetic background of CHD by investigating the most common dyslipidemia predisposing to CHD, familial combined hyperlipidemia (FCHL), affecting 1%-2% of Western populations and 10%-20% of families with premature CHD. To be able to perform a combined data analysis, we unified the diagnostic criteria for FCHL and its component traits and combined the data from two genomewide scans performed in two populations, the Finns and the Dutch. As a result of our pooled data analysis, we identified three chromosomal regions, on chromosomes 2p25.1, 9p23, and 16q24.1, exceeding the statistical significance level of a LOD score >2.0. The 2p25.1 region was detected for the FCHL trait, and the 9p23 and 16q24.1 regions were detected for the low high-density lipoprotein cholesterol (HDL-C) trait. In addition, the previously recognized 1q21 region also obtained additional support in the other study sample, when the triglyceride trait was used. Analysis of the 16q24.1 region resulted in a statistically significant LOD score of 3.6 when the data from Finnish families with low HDL-C were included in the analysis. To search for the underlying gene in the 16q24.1 region, we investigated a novel functional and positional candidate gene, helix/forkhead transcription factor (FOXC2), by sequencing and by genotyping of two single-nucleotide polymorphisms in the families.

7829.  Persson T, Monsef N, Andersson P, Bjartell A, Malm J, Calafat J, Egesten A.  Expression of the neutrophil-activating CXC chemokine ENA-78/CXCL5 by human eosinophils. Clin Exp Allergy. 2003 Apr;33(4):531-7.

 

BACKGROUND: Eosinophils are seen at sites of inflammation in diseases such as helminthic infestation, asthma, ulcerative colitis and some neoplastic diseases. They are also associated with connective tissue remodelling, for example in longstanding asthma. In the present study, we investigated whether eosinophils express the CXC chemokine epithelial cell-derived neutrophil activating peptide (ENA-78/CXCL5), a chemokine that can activate neutrophils and in addition possesses angiogenic properties. Immunocytochemistry detected CXCL5 in eosinophils and the peptide was localized in the specific granules by immunoelectron microscopy. METHODS AND RESULTS: In eosinophil lysates, 12 +/- 2 pg (mean +/- SEM) of CXCL5 was detected per 106 cells by enzyme-linked immunosorbent assay (ELISA). Weak constitutive expression of CXCL5, as well as the related CXC chemokine IL-8/CXCL8, could be detected in freshly isolated eosinophils by RT-PCR. However, during prolonged incubation of eosinophils, a strong increase in both CXCL5 and IL-8/CXCL8 expression was seen, as detected by RT-PCR, and increasing amounts of CXCL5 peptide with time were detected in the incubation medium by ELISA. Addition of TNF-alpha neutralizing antibodies during prolonged incubation significantly inhibited CXCL5 production, demonstrating involvement of auto- and paracrine effects from TNF-alpha produced by eosinophils themselves. Addition of IFN-gamma showed a strong inhibitory effect on CXCL5 synthesis. CONCLUSION: These findings suggest that, through expression of CXCL5, eosinophils can recruit and activate CXC receptor 2 (CXCR2)-bearing cells such as neutrophils at sites of inflammation. Eosinophils may also promote connective tissue remodelling through release of this peptide.

7830.  Peterson MW.  Accessing the tools for improved asthma management. Am J Med. 2003 Apr 1;114(5):415-6. No abstract

7831.  Samee S, Altes T, Powers P, de Lange EE, Knight-Scott J, Rakes G, Mugler JP 3rd, Ciambotti JM, Alford BA, Brookeman JR, Platts-Mills TA. Imaging the lungs in asthmatic patients by using hyperpolarized helium-3 magnetic resonance: assessment of response to methacholine and exercise challenge. J Allergy Clin Immunol. 2003 Jun;111(6):1205-11.

 

BACKGROUND: Imaging of gas distribution in the lungs of patients with asthma has been restricted because of the lack of a suitable gaseous contrast agent. Hyperpolarized helium-3 (HHe3) provides a new technique for magnetic resonance imaging of lung diseases. OBJECTIVE: We sought to investigate the use of HHe3 gas to image the lungs of patients with moderate or severe asthma and to assess changes in gas distribution after methacholine and exercise challenge. METHODS: Magnetic resonance imaging was performed in asthmatic patients immediately after inhalation of HHe3 gas. In addition, images were obtained before and after methacholine challenge and a standard exercise test. RESULTS: Areas of the lung with no signal or sharply reduced HHe3 signal (ventilation defects) are common in patients with asthma, and the number of defects was inversely related to the percent predicted FEV(1) (r = 0.71, P <.002). After methacholine challenge (n = 3), the number of defects increased. Similarly, imaging of the lungs after exercise (n = 6) showed increased ventilation defects in parallel with decreases in FEV(1). The increase in defects after challenge in these 9 asthmatic patients was significant both for the number (P <.02) and extent (P <.02) of the defects. The variability and speed of changes in ventilation and the complete lack of signal in many areas is in keeping with a model in which the defects result from airway closure. CONCLUSION: HHe3 magnetic resonance provides a new technique for imaging the distribution of inhaled air in the lungs. The technique is suitable for following responses to treatment of asthma and changes after methacholine or exercise challenge.

7832.  Saotome A, Kanai N, Nagai T, Yashiro T, Tokudome S.  Immunohistochemical classification of the localization of laminin in the thickened bronchial epithelial basement membrane of deceased bronchial asthma patients. Respir Med. 2003 Jun;97(6):688-94.

 

To ascertain histological changes in the basal lamina of the bronchial epithelial basement membrane in patients with severe bronchial asthma, an immunohistochemical study was conducted in 43 patients who died of bronchial asthma. Antibodies against laminin, a component of the lamina lucida, were utilized. The results revealed various patterns for immunoreactivity to laminin in the thickened basement membrane layer. We were able to classify these reactivities into four patterns. In Pattern A, laminin reactions branched vertically in relation to the thickened basement membrane layer. In Pattern B, laminin reactions formed lines along the lower margin of the thickened basement membrane layer. In Pattern C, laminin reactions formed lines along the upper margin of the thickened basement membrane layer. Finally, in Pattern D, no laminin reactions were observed. In addition, relationships between immunohistological characteristics of laminin and findings such as epithelial cell shedding, basal cell proliferation and basement membrane layer thickening were investigated. In many Pattern A patients, epithelial cell shedding was observed, but goblet cell hyperplasia and basal cell proliferation were barely detectable. Conversely, in numerous Pattern D patients, epithelial cell shedding was barely seen, but goblet cell hyperplasia and basal cell proliferation were marked. Hence, Patterns A and D were on opposite ends of the spectrum of morphological characteristics associated with severe bronchial asthma. In Patterns B and C, laminin reactions formed lines along the lower and upper margin of the thickened basement membrane layer, respectively. However, no marked differences existed in epithelial cell shedding and basement membrane layer thickening. The present study is thus the first to clarify that laminin reactions in the thickened basement membrane layer vary, and this feature is unique to the bronchi of patients with severe bronchial asthma.

7833.  Stoloff SW, Stempel DA.  Study design is a major determinant of whether equivalence or superiority is demonstrated. J Allergy Clin Immunol. 2003 Jun;111(6):1413;  No abstract

7834.  Tarlo SM, Liss GM.  Occupational asthma: an approach to diagnosis and management. CMAJ. 2003 Apr 1;168(7):867-71. Review. No abstract available. Erratum in: CMAJ. 2003 Apr 15;168(8):966. No abstract

7835.  Tarlo SM.  Laboratory challenge testing for occupational asthma. J Allergy Clin Immunol. 2003 Apr;111(4):692-4. No abstract

7836.  Taube C, Kanniess F, Gronke L, Richter K, Mucke M, Paasch K, Eichler G, Jorres RA, Magnussen H.  Reproducibility of forced inspiratory and expiratory volumes after bronchodilation in patients with COPD or asthma. Respir Med. 2003 May;97(5):568-77.

 

The aim of the present study was to assess the reproducibility of changes in forced inspiratory volumes after bronchodilator inhalation. Thirteen patients with chronic obstructive pulmonary disease (COPD) (FEV1, 32-75%pred) and 10 patients with asthma (FEV1, 43-75%pred) inhaled either 200 microg fenoterol or 200 microg oxitropium bromide or placebo, each of them on three occasions, on nine different days in a randomised, cross-over, double-blind fashion. Forced expiratory (FEV1) and inspiratory (FIV1) volumes were measured before and 30 min after inhalation. In patients with COPD, the increase in FEV1 (coefficient of variation) was 221 ml (43%) after fenoterol and 235 ml (33%) after oxitropium; changes in FIV1 were 301 ml (45%) and 360 ml (29%). In patients with asthma, FEV1 improved by 618 ml (26%) and 482 ml (25%), FIV1 by 553 ml (41%) and 475 ml (23%). In less severe COPD or asthma, the reduction in dyspnoea was associated with the improvements in both FIV1 and FEV1, but in severe COPD with the improvement in FIV1 only. The data demonstrate that, at least in terms of relative changes, the reproducibility of bronchodilator responses in terms of FIV1 is similar to that of FEV1 and they underline the assertion of FIV1 being a sensible parameter particularly in severe COPD.

7837.  Taussig LM, Wright AL, Holberg CJ, Halonen M, Morgan WJ, Martinez FD.  Tucson Children's Respiratory Study: 1980 to present. J Allergy Clin Immunol. 2003 Apr;111(4):661-75; quiz 676.

 

The Tucson Children's Respiratory Study (TCRS), begun in 1980, has followed 1246 subjects from birth together with their family members to delineate the complex interrelationships between a large number of potential risk factors, acute lower respiratory tract illnesses, and chronic lung disorders later in childhood and early adult life, especially asthma. Nine hundred seventy-four (78%) of the original subjects are still being followed. Among its numerous findings, the TCRS has (1) described various wheezing disorders (transient, nonatopic, atopic) and their characteristics; (2) developed an Asthma Predictive Index; (3) delineated the respiratory and atopic outcomes for children who had respiratory syncytial virus-related wheezing illnesses in infancy; and (4) evaluated a large number of risk factors for acute respiratory tract illnesses during the first 3 years of life. Future TCRS studies will focus on (1) factors in infancy and early childhood that relate to persistent asthma and atopy; (2) role of genetic factors in persistent asthma; and (3) determinants of lung function decline in early adult life.

7838.  Vrijhoef HJ, Diederiks JP, Wesseling GJ, van Schayck CP, Spreeuwenberg C.  Undiagnosed patients and patients at risk for COPD in primary health care: early detection with the support of non-physicians. J Clin Nurs. 2003 May;12(3):366-73.

 

Given the increasingly heavy workload in the primary health care sector, the option of allocating activities involving the management of chronic diseases to non-physicians has recently come under scrutiny. The purpose of this study was to assess the feasibility of the support provided by non-physicians to general practitioners (GPs) in the early detection of chronic obstructive pulmonary disease (COPD). A convenience sample consisting of 231 patients [40-70 years; >10 pack years (number of packs of cigarettes smoked per day multiplied by the number of years the individual has smoked)] from eight general practices in the Maastricht region in the southern Netherlands, who consulted their GP for reasons unrelated to respiratory diseases, were assessed for their respiratory function. Prior to the first assessment, patients were interviewed about their medical history and symptoms. By taking the results of the lung function measurement as the starting point, the predictive value of medical history and symptoms in the identification of patients at risk for airflow obstruction or of COPD was assessed and compared with findings in the literature. Seventeen patients (7.4%) were diagnosed with COPD, 11 patients (4.8%) with asthma. In addition to age and moderate smoking history, breathlessness and a history of heavy smoking were identified as risk factors for airflow limitation and COPD. Early detection of COPD in primary health care by non-physicians is feasible and should be considered for middle aged, moderate and heavy smokers experiencing breathlessness.

7839.  Wagers S.  Polarized helium: changing our view of asthma. J Allergy Clin Immunol. 2003 Jun;111(6):1201-2. No abstract

7840.  Warner JO.  The blood lung function test: does it exist for asthma? Am J Respir Crit Care Med. 2003 Jun 1;167(11):1465-6. No abstract

7841.  Yao TC, Kuo ML, See LC, Chen LC, Yan DC, Ou LS, Shaw CK, Huang JL. The RANTES promoter polymorphism: a genetic risk factor for near-fatal asthma in Chinese children. J Allergy Clin Immunol. 2003 Jun;111(6):1285-92.

 

BACKGROUND: RANTES promoter polymorphisms were found associated with asthma/atopy in some studies but not others, possibly reflecting the genetic heterogeneity among different ethnicities and different asthma severity. OBJECTIVE: The purpose of this investigation was to test the genetic association between the RANTES -28C/G and -403G/A polymorphisms and asthma/atopy in a cohort of Chinese children, with particular emphasis on those patients who had experienced life-threatening asthma attacks. METHODS: Forty-eight children with near-fatal asthma, 134 children with mild-to-moderate asthma, 69 children with allergic disorders but no asthma, and 107 nonasthmatic nonatopic control children were genotyped through use of a PCR-based assay. RESULTS: No significant difference was demonstrated for frequency of the RANTES -28C/G  polymorphism when the mild-to-moderate asthma, atopic/nonasthmatic, and normal control groups were compared. The RANTES -28G allele was present in a significantly higher proportion of the children with near-fatal asthma compared with the nonasthmatic nonatopic controls (odds ratio, 2.93 [1.41-6.06]; P =.006) and the children with mild-to-moderate asthma (odds ratio, 3.52 [1.73-7.16]; P =.001). The frequency of -28G allele carriage correlated with asthma severity. The RANTES -28G allele was also associated with an increased blood eosinophil count and a higher degree of bronchial hyperresponsiveness. The RANTES -403G/A polymorphism did not influence asthma/atopy susceptibility, blood eosinophil count, or bronchial hyperresponsiveness. Interestingly, a higher frequency of -403A allele carriage was observed in the moderate asthma subgroup compared with the mild asthma analog. CONCLUSIONS: We conclude that the RANTES -28C/G polymorphism exacerbates asthma severity, representing a genetic risk factor for life-threatening asthma attacks in Chinese children. In addition, the linkage disequilibrium between these 2 polymorphisms is a potential confounder that must be considered in the design and interpretation of RANTES gene association studies.

 

7842.  Zaitsu M, Hamasaki Y, Matsuo M, Ichimaru T, Fujita I, Ishii E.  Leukotriene synthesis is increased by transcriptional up-regulation of  5-lipoxygenase, leukotriene A4 hydrolase, and leukotriene C4 synthase in asthmatic children. J Asthma. 2003 Apr;40(2):147-54.

 

Leukotrienes (LTs) are recognized to be important mediators in asthma. Recent studies revealed that LT synthesis is controlled by the regulation of LT-synthesizing enzymes. We determined the synthesis of LTB4 and LTC4 by

specific radioimmunoassay, and the messenger RNA (mRNA) expression of LT-synthesizing enzymes by reverse transcriptase polymerase chain reaction in peripheral polymorphonuclear leukocytes, which were obtained from controls and asthmatic children. The synthesis of LTB4 and LTC4, and the mRNA expression of 5-lipoxygenase, LTA4 hydrolase, and LTC4 synthase were enhanced in the patients. The mRNA expression of LT-synthesizing enzymes was up-regulated, resulting in increased LT synthesis, which may play an important role in the pathogenesis of childhood asthma.

Pathogenesis:

7843.  Colilla S, Nicolae D, Pluzhnikov A, Blumenthal MN, Beaty TH, Bleecker ER, Lange EM, Rich SS, Meyers DA, Ober C, Cox NJ; Collaborative Study for the Genetics of Asthma.   Evidence for gene-environment interactions in a linkage study of asthma and smoking exposure. J Allergy Clin Immunol. 2003 Apr;111(4):840-6.

 

BACKGROUND: Asthma, a common and chronic disease of the airways, has a multifactorial cause involving both genetic and environmental factors. As a result, mapping genes that influence asthma susceptibility has been challenging. OBJECTIVE: This study tests the hypothesis that inclusion of exposure to environmental tobacco smoke (ETS), a potential risk factor for asthma, would improve the ability to map genes for asthma. METHODS: By using 144 white families from the Collaborative Study for the Genetics of Asthma, environmental information about exposure to ETS during infancy was incorporated into a genome-wide multipoint linkage analysis. Statistical significance of observed gene-environment interactions was assessed by means of simulation. RESULTS: Three regions with nominal evidence for linkage when stratified on the basis of ETS exposure were identified (P <.01) and showed a significant increase from the baseline lod score (1p at 97 cM, D1S1669-D1S1665; 5q at 135 cM, D5S1505-D5S816; and 9q at 106 cM, D9S910; all P <.05). In addition, 2 other regions, although not meeting nominal significance after stratification on the basis of ETS exposure, showed a significant increase from baseline lod score when ETS was taken into account (1q at 240 cM, D1S549; 17p at 3 cM, D17S1308; all P <.01). CONCLUSION: These results illustrate how evidence for linkage of asthma can depend on exposure to an environmental factor, such as ETS. Future linkage analyses should include information on suspected environmental factors for asthma to help target new candidate susceptibility genes for asthma.

7844.  Donninger H, Glashoff R, Haitchi HM, Syce JA, Ghildyal R, van Rensburg E, Bardin PG.  Rhinovirus induction of the CXC chemokine epithelial-neutrophil activating peptide-78 in bronchial epithelium. J Infect Dis. 2003 Jun 1;187(11):1809-17.

 

Epithelial-neutrophil activating peptide-78 (ENA-78) induces neutrophil migration, an early response to viral infection. Rhinovirus serotype 16 (RV16) was used to infect primary bronchial epithelial cells and a cell line (BEAS-2B). Release of ENA-78 protein was measured by enzyme-linked immunosorbent assay, ENA-78 mRNA production was quantified by reverse-transcription polymerase chain reaction, and ENA-78 promoter activity was assessed by use of a promoter construct. After infection with RV16, ENA-78 protein and mRNA increased significantly, and RV16 induced 3-fold increases in ENA-78 gene transcription. Nasal ENA-78 measured in patients with asthma with and without RV infection was more elevated in patients with RV infection present. Our study demonstrates that ENA-78 is produced in bronchial epithelial cells in response to RV16 infection. With other chemokines, it may be an important initiator of neutrophil airway inflammation during RV common colds and thus may play a role in the development of virus-associated airway pathologies.

7845.  Elias JA, Lee CG, Zheng T, Shim Y, Zhu Z.  Interleukin-13 and leukotrienes: an intersection of pathogenetic schema. Am J Respir Cell Mol Biol. 2003 Apr;28(4):401-4. No abstract.

7846.  Kabesch M, Peters W, Carr D, Leupold W, Weiland SK, von Mutius E.  Association between polymorphisms in caspase recruitment domain containing protein 15 and allergy in two German populations. J Allergy Clin Immunol. 2003 Apr;111(4):813-7.

 

BACKGROUND: Early exposure to microbial matter such as LPS may influence the development of asthma and allergies by activation of innate immunity pathways as indicated by studies in farming environments. Recently, polymorphisms in caspase recruitment domain containing protein 15 (CARD15), an intracellular LPS receptor protein, have been associated with Crohn's disease. Because these polymorphisms lead to changes in LPS recognition, they may affect the development of asthma and allergies. OBJECTIVE: We genotyped a large population of German schoolchildren (N = 1872) from East and West Germany for 3 functional relevant CARD15 polymorphisms for their role in the development of asthma and allergy. METHODS: By use of parental questionnaires, skin prick testing, pulmonary function tests, bronchial challenge tests, and measurements of serum IgE levels, children were phenotyped for the presence of atopic diseases. Genotyping was performed with PCR-based restriction enzyme assays. To assess associations between atopic phenotypes and genotypes standard statistical procedures were applied. RESULTS: Children with the polymorphic allele C2722 had a more than 3-fold risk to develop allergic rhinitis (P <.001) and an almost 2-fold risk for atopic dermatitis (P <.05). Furthermore, the T2104 allele was associated with an almost 2-fold risk for allergic rhinitis (P <.05). When a C insertion at position 3020 was present, the risk of atopy increased by 50% (P <.05) and serum IgE levels were elevated (P <.01). CONCLUSION: The shared genetic background between Crohn's disease and atopy may indicate that an impaired recognition of microbial exposures results in an insufficient downregulation of excessive immune responses, giving rise to either T(H)2 dominated allergies or T(H)1related Crohn's disease.

 

7847.  Kelly-Welch AE, Hanson EM, Boothby MR, Keegan AD.  Interleukin-4 and interleukin-13 signaling connections maps. Science. 2003 Jun 6;300(5625):1527-8.

 

Cytokines are inflammatory mediators important in responding to pathogens and other foreign challenges. Interleukin-4 (IL-4) and IL-13 are two cytokines produced by T helper type 2 cells, mast cells, and basophils. In addition to their physiological roles, these cytokines are also implicated in pathological conditions such as asthma and allergy. IL-4 can stimulate two receptors, type I and type II, whereas IL-13 signaling is mediated only by the type II receptor (see the STKE Connections Maps). These cytokines activate the Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling cascades, which may contribute to allergic responses. In addition, stimulation of the phosphatidylinositol 3-kinase (PI3K) pathway through recruitment of members of the insulin receptor substrate family may contribute to survival and proliferation.

7848.  Lopuhaa CE, de Riemer MJ, Out TA, Sjamsoedin DH, Aalberse RC, Jansen HM, van der Zee JS.  Comparison of allergen-induced late inflammatory reactions in the nose and in the skin in house dust mite-allergic patients with or without asthma. Int Arch Allergy Immunol. 2003 Apr;130(4):266-74.

 

BACKGROUND: It remains to be established which factors contribute to the occurrence of asthma in allergic individuals. We hypothesized that differences in the late allergic inflammatory reaction to allergen between asthmatic and non-asthmatic house dust mite-allergic individuals might contribute to the difference in the clinical presentation of allergy. AIM: To compare allergen-induced changes in parameters for cellular inflammation during the phase of the late allergic reaction in the skin and nose, in house dust mite-allergic individuals with or without asthma. MATERIAL AND METHODS: Nasal and dermal allergen challenges with house dust mite (Dermatophagoides pteronyssinus) extract were performed in 52 house dust mite-allergic individuals, of whom 26 had mild to moderate persistent asthma and 26 had perennial rhinitis without current or past asthmatic symptoms. Serial nasal lavage samples were analyzed for the presence of inflammatory cells (eosinophils and neutrophils) and soluble markers associated with cellular inflammation [interleukin-5 (IL-5), interleukin-8 (IL-8), eosinophil cationic protein (ECP) and myeloperoxidase (MPO)]. Macroscopic late phase skin reactions were studied after intracutaneous skin tests with house dust mite extract. RESULTS: Fixed dose nasal allergen provocation elicited a similar degree of immediate allergic reaction as judged by plasma protein exudation and histamine concentrations in asthma and non-asthmatic rhinitis. Subsequently, no differences between groups were found during the phase of the late allergic reaction (4-24 h) in inflammatory cell influx, plasma protein leakage, ECP or MPO. Likewise, there were no differences in levels of chemotactic cytokines IL-5 and IL-8. In agreement with the results of nasal challenge, the late skin reaction after dermal challenge with a fixed allergen dose and after an allergen dose 10,000 times above the skin threshold for an early skin reaction did not differ between the groups. CONCLUSION: House dust mite-allergic patients with or without asthma have very similar late allergic inflammatory reactions in the skin and in the nose after allergen challenge. Hence, it is unlikely that the occurrence of pulmonary symptoms in asthma is explained by a general tendency of asthmatics to have an enhanced late allergic cellular inflammatory response. Nasal and dermal allergen provocations are adequate models to study allergen-induced inflammation but probably lack the pivotal link which is essential for the development of asthma. Copyright 2003 S. Karger AG, Basel

7849.  Obase Y, Shimoda T, Kawano T, Saeki S, Tomari SY, Mitsuta-Izaki K, Matsuse H, Kinoshita M, Kohno S.  Polymorphisms in the CYP1A2 gene and theophylline metabolism in patients with asthma. Clin Pharmacol Ther. 2003 May;73(5):468-74.

 

BACKGROUND: Cytochrome p450 (CYP) 1A2 gene polymorphisms are thought to be involved in theophylline metabolism. OBJECTIVE: We analyzed the effect of genetic polymorphisms in the 5'-flanking region to the first intron of the CYP1A2 gene on theophylline metabolism in 75 Japanese patients with asthma and 159 healthy Japanese volunteers. METHODS: Genetic polymorphisms were detected at 4 sites of the CYP1A2 gene, -2964(G/A) and -1569(T/del) in the 5'-flanking region and 155(T/G) and 731(A/C) in the first intron. RESULTS: There were no significant differences in the distribution of gene polymorphisms between the asthmatic and control groups. Among asthmatic patients, theophylline clearance was significantly lower in patients with the polymorphism at site -2964(G/A) whose genotype was G/A (0.029 +/- 0.001 L x h(-1) x kg(-1)) or A/A (0.029 +/- 0.002 L x h(-1) x kg(-1)) than in those whose genotype was G/G (0.034 +/- 0.001 L x h(-1) x kg(-1)) (P <.01 and P <.05, respectively). High theophylline clearance levels significantly correlated with age in the G/G subgroup of site -2964(G/A) (P <.05, r = -0.35) but not in the G/A or A/A subgroup. CONCLUSION: Given its potential side effects, theophylline may need to be used with care in patients with the A allele at site -2964(G/A) in the CYP1A2 gene, because theophylline metabolism levels are lower in such patients, particularly in young asthmatic individuals.

7850.  Pierzchalska M, Szabo Z, Sanak M, Soja J, Szczeklik A.  Deficient prostaglandin E2 production by bronchial fibroblasts of asthmatic patients, with special reference to aspirin-induced asthma. J Allergy Clin Immunol. 2003 May;111(5):1041-8.

 

BACKGROUND: Regulation of prostaglandin synthesis and the activation of human airway fibroblasts associated with the remodeling of the bronchi play an important role in asthma. OBJECTIVE: We sought to assess the cyclooxygenase pathways in airway fibroblasts of patients with bronchial asthma. METHODS: Generation of prostaglandin E(2) (PGE(2)) and pros-taglandin D(2) (PGD(2)) by bronchial fibroblasts was measured by means of mass spectrometry in culture supernatants, and cyclooxgenases expression was estimated by means of RT-PCR and immunoblotting. The cells were isolated from 3 groups of subjects: nonasthmatic patients (n = 10), patients with aspirin-tolerant asthma (ATA, n = 9), and patients with aspirin-intolerant asthma (AIA, n = 7). RESULTS: The cytomix (LPS, 5 square g/mL; IL-1 square, 5 ng/mL; and TNF- square, 10 ng/mL; 18 hours) stimulated the production of prostaglandins. Asthmatic patients were characterized by low capacity to produce PGE(2) after cytomix stimulation. In the nonasthmatic patient group the mean PGE(2) production was 32 +/- 33 ng/mL (35-fold of the basic production), in the ATA group it was 16 +/- 18 ng/mL (16-fold), and in the AIA group it was only 5.3 +/- 3.6 ng/mL (4-fold). The mean concentration of PGD(2) for nonasthmatic patients, patients with ATA, and patients with AIA was 0.18 +/- 0.16 ng/mL (4.7-fold of the basic production), 0.18 +/- 0.14 ng/mL (4.2-fold), and 0.235 +/- 0.19 ng/mL (1.9-fold), respectively. The observed difference was not due to insufficient cyclooxygenase 2 expression because all groups had similar levels of its mRNA and protein. The patients with AIA had low expression levels of cyclooxygenase 1 protein but not of its mRNA. The PGE(2)/PGD(2) concentration ratio increased after cytomix stimulation in all groups but was significantly less in patients with AIA than in patients with ATA. CONCLUSIONS: Our results point to a deficient PGE(2) production under proinflammatory conditions in asthmatic airways. This could weaken local defensive mechanisms and promote cysteinyl leukotrieneoverproduction.

7851.  Reibman J, Hsu Y, Chen LC, Bleck B, Gordon T.  Airway epithelial cells release MIP-3alpha/CCL20 in response to cytokines and ambient particulate matter. Am J Respir Cell Mol Biol. 2003 Jun;28(6):648-54.

 

The initiation and maintenance of airway immune responses in Th2 type allergic diseases such as asthma are dependent on the specific activation of local airway dendritic cells (DCs). The cytokine microenvironment, produced by local cells, influences the recruitment of specific subsets of immature DCs and their subsequent maturation. In the airway, DCs reside in close proximity to airway epithelial cells (AECs). We examined the ability of primary culture human bronchial epithelial cells (HBECs) to synthesize and secrete the recently described CC-chemokine, MIP-3alpha/CCL20. MIP-3alpha/CCL20 is the unique chemokine ligand for CCR6, a receptor with a restricted distribution. MIP-3alpha/CCL20 induces selective migration of DCs because CCR6 is expressed on some immature DCs but not on CD14+ DC precursors or mature DCs. HBECs were stimulated with pro-inflammatory cytokines tumor necrosis factor-alpha and interleukin (IL)-1beta or, because of their critical role in allergic diseases, IL-4 and IL-13. Cells were also exposed to small size-fractions of ambient particulate matter. Each of these stimuli induced MIP-3alpha/CCL20 gene and protein expression. Moreover, these agents upregulated mitogen-activated protein kinase pathways in HBECs. Inhibition of the ERK1/2 pathway or p38 reduced cytokine-induced MIP-3alpha/CCL20 expression. These data suggest a mechanism by which AEC may facilitate recruitment of DC subsets to the airway.

7852.  Silverman ES, Drazen JM.  Immunostimulatory DNA for asthma: better than eating dirt. Am J Respir Cell Mol Biol. 2003 Jun;28(6):645-7. No abstract

7853.  Taha R, Hamid Q, Cameron L, Olivenstein R.  T helper type 2 cytokine receptors and associated transcription factors GATA-3, c-MAF, and signal transducer and activator of transcription factor-6 in induced sputum of atopic asthmatic patients. Chest. 2003 Jun;123(6):2074-82.

 

BACKGROUND: It is well-known that the expression of T helper (Th) type 2

cytokines such as interleukin (IL)-4 and IL-5, and their receptors, is up-regulated within the airways of allergic asthmatic patients. Furthermore, higher numbers of cells producing GATA-3, c-MAF, and signal transducer and activator of transcription factor (STAT)-6, which are transcription factors (TFs) that are implicated in the regulation and signaling of the Th2 cytokines, have been observed in bronchial biopsy specimens from asthmatic patients but not in those of healthy control subjects. METHODS: We examined whether these mediators also can be detected in induced sputum. Immunoreactivity for IL-4Ralpha, IL-5Ralpha, GATA-3, c-MAF, and STAT-6 was investigated in samples of induced sputum from asthmatic patients (n = 8) and healthy control subjects (n = 8). RESULTS: Our results showed that the numbers of cells expressing IL-4 receptor alpha (Ralpha) and IL-5Ralpha were higher in samples from asthmatic patients compared to those of control subjects (p < 0.01). More cells exhibiting GATA-3, c-MAF, and STAT-6 immunoreactivity also were found in asthmatic patients vs those in control subjects (p < 0.005). Furthermore, the expression of STAT-6 and IL-4Ralpha, GATA-3 and IL-5Ralpha, and c-MAF with both IL-4Ralpha and IL-5Ralpha was correlated (p < 0.05). CONCLUSIONS: This study demonstrated that induced sputum provides sufficient sensitivity for examining the pathways of cytokine signaling, cytokine receptor signaling, and intracellular signaling. Furthermore, these data show correlations between the expression of Th2 cytokine receptors and associated TFs in the human lung, which has not been documented previously.

7854.  Tamura K, Suzuki M, Arakawa H, Tokuyama K, Morikawa A.  Linkage and association studies of STAT6 gene polymorphisms and allergic diseases. Int Arch Allergy Immunol. 2003 May;131(1):33-8.

 

BACKGROUND: Signal transducer and activator of transcription 6 (STAT6) is a key transcription factor involved in both interleukin-4 (IL-4) and IL-13-mediated biological responses, such as allergies. Recently, we reported that the polymorphism of the STAT6 gene exon 1 was associated with allergic diseases, while another group studied the G2964A variant of the STAT6 gene's association with atopic asthma. We undertook an association study between these variants of the STAT6 gene and allergic diseases, including atopic dermatitis, bronchial asthma, and food-related anaphylaxis in a Japanese population. METHODS: STAT6 gene polymorphisms were genotyped by polymerase chain reaction (PCR) fragment length polymorphism analysis, and PCR-SSCP analysis in 106 allergic and 66 control subjects. RESULTS: The 2964A variant was in significant linkage disequilibrium with the dinucleotide repeat polymorphism, the 13-GT repeat allele of STAT6 exon 1 (p < 0.0000000003). There was no association between the STAT6 2964A variant and allergic subjects in a Japanese population (p = 0.2724). The genotype of 13/15-GT repeat allele heterozygosity was significantly associated with allergic subjects (p = 0.0006), as previously reported. In one major genotype of the STAT6 exon 1 (15 GT repeat homozygosity), wild-type 2964G allele homozygosity was significantly associated with allergic subjects (p = 0.0382). CONCLUSIONS: Our findings indicate that in combination the dinucleotide repeat polymorphism of the STAT6 exon 1 gene and the 2964A variant may be useful markers for predicting allergic diseases in a Japanese population.

 

Therapy:

7855.  Menzies-Gow A, Flood-Page P, Sehmi R, Burman J, Hamid Q, Robinson DS, Kay AB, Denburg J.  Anti-IL-5 (mepolizumab) therapy induces bone marrow eosinophil maturational arrest and decreases eosinophil progenitors in the bronchial mucosa of atopic asthmatics. J Allergy Clin Immunol. 2003 Apr;111(4):714-9.

 

BACKGROUND: Eosinophils develop from CD34(+) progenitors under the influence of IL-5. Atopic asthmatic individuals have increased numbers of mature eosinophils and eosinophil pro-genitors within their bone marrow and bronchial mucosa. We have previously reported that anti-IL-5 monoclonal antibody treatment decreases total bone marrow and bronchial mucosal eosinophil numbers in asthma. OBJECTIVE: Using an anti-IL-5 monoclonal antibody, we examined the role of IL-5 in eosinophil development within the bone marrow and bronchial mucosa in asthma. METHODS: Blood, bone marrow, and airway mucosal biopsy specimens were examined before and after anti-IL-5 (mepolizumab) treatment of asthmatic individuals in a double-blind, placebo-controlled trial. Numbers of mature and immature eosinophils were measured by histologic stain (bone marrow myelocytes, metamyelocytes, and mature eosinophils), flow cytometry (bone marrow and blood CD34(+)/IL-5Ralpha(+) cells), enumeration of bone marrow-derived eosinophil/basophil colony-forming units in methylcellulose culture, and sequential immunohistochemistry and in situ hybridization (bronchial mucosal CD34(+)/IL-5Ralpha mRNA(+) cells). RESULTS: Mepolizumab decreased mature eosinophil numbers in the bone marrow by 70% (P =.017) in comparison with placebo and decreased numbers of eosinophil myelocytes and metamyelocytes by 37% (P =.006) and 44% (P =.003), respectively. However, mepolizumab had no effect on numbers of blood or bone marrow CD34(+), CD34(+)/IL-5Ralpha(+) cells, or eosinophil/basophil colony-forming units. There was a significant decrease in bronchial mucosal CD34(+)/IL-5Ralpha mRNA(+) cell numbers in the anti-IL-5 treated group (P =.04). CONCLUSION: These data suggest that anti-IL-5 therapy might induce partial maturational arrest of the eosinophil lineage in the bone marrow. The reduction in airway CD34(+)/IL-5 mRNA(+) cell numbers suggests that IL-5 might also be required for local tissue eosinophilopoiesis.

7856.  Selroos O, Ekstrom T, Hultquist C.  The EDICT study. Respir Med. 2003 Apr;97(4):446; No abstract.

7857.  van Strien RT, Koopman LP, Kerkhof M, Oldenwening M, de Jongste JC, Gerritsen J, Neijens HJ, Aalberse RC, Smit HA, Brunekreef B; Prevention and Incidence of Asthma and Mite Allergy Study.   Mattress encasings and mite allergen levels in the Prevention and Incidence of Asthma and Mite Allergy study. Clin Exp Allergy. 2003 Apr;33(4):490-5.

BACKGROUND: Reduction of allergen exposure from birth may reduce sensitization and subsequent allergic disease. OBJECTIVE: To measure the influence of mite allergen-impermeable mattress encasings and cotton placebo encasings on the amount of dust and mite allergen in beds. METHODS: A total of 810 children with allergic mothers took part in the Prevention and Incidence of Asthma and Mite Allergy (PIAMA) study. Allergen-impermeable and placebo mattress encasings were applied to the childrens' and the parents' beds before birth. Dust samples were taken from the beds of children and their parents before birth and 3 and 12 months after birth. Extracts of dust samples were analysed for mite allergens (Der p 1 and Der f 1). RESULTS: Active mattress encasings were significantly more effective in reducing dust and mite allergen levels than placebo encasings. Mite allergen levels were low in general and the treatment effect was modest. Twelve months after birth, mattresses with active mattress encasings had about half the amount of Der 1 (Der p 1 + Der f 1)/m2, compared to mattresses with placebo encasings, for the child's and the parental mattress. CONCLUSION: This study shows that mite-impermeable mattress encasings have a significant but modest effect on dust and mite allergen levels of mattresses with low initial mite allergen levels, compared to placebo.

7858.  Warschburger P, Landgraf JM, Petermann F, Freidel K.  Health-related quality of life in children assessed by their parents: evaluation of the psychometric properties of the CHQ-PF50 in two German clinical samples. Qual Life Res. 2003 May;12(3):291-301.

 

The aim of the study was to evaluate the psychometric properties of the German translation of the Child Health Questionnaire (CHQ). Parents of two clinical samples were asked to rate the quality of life of their children using the German version of the CHQ. Item internal consistency (item-scale correlation) and internal consistency of scales were tested; quartiles and factor analysis were conducted. The results of the German clinical samples were compared with US clinical samples (t-test). The two clinical German sub-groups were compared using multivariate analysis (MANOVA). The psychometric testing of the CHQ showed good results. Internal consistency of the hypothesized scales were all higher than 0.70. The results of the factor analysis confirmed the results of the US norm sample: As expected, the subscales loaded on two factors explaining 57.4% of the total variance. The group comparison supported the discriminative properties of the CHQ. Preliminary psychometric findings support use of the German version of the CHQ. The next step will be the testing of healthy German samples and development of norm scores.

 

 

 

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