Diagnosis, Diagnostics, Immunodiagnosis & Immunodiagnostics:



Back To Reference


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.



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.


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.





5972.<span style="font-style: normal; font-v