Jerry Dolovich

Asthma and increases in nonallergic bronchial responsiveness from seasonal pollen exposure

Serial measurements of symptoms, peak flow rates, methacholine bronchial responsiveness, and ragweed-specific IgE antibodies were made before and during the ragweed pollen season in 13 sensitized subjects. Allergen inhalation tests were carried out with aerosols of pollen extract out of season in nine subjects; isolated early asthmatic responses were provoked in four, and dual responses (early followed by late) were provoked in five. During the pollen season all subjects developed hay fever and eight had symptoms of asthma. There was a real increase in methacholine responsiveness during the ragweed season. This increase appeared before or after the occurrence of asthma symptoms and changes in flow rates and was greater in subjects with symptoms in the pollen season, dual responses after allergen inhalation tests, and higher levels of ragweed-specific IgE antibodies. The results confirm the occurrence of seasonal asthma and increases in nonallergic (nonspecific) bronchial responsiveness to methacholine from seasonal pollen exposure. They suggest that the occurrence of symptoms is closely linked to the allergic inflammatory reaction and the induction of increased nonallergic responsiveness.

The assessment and treatment of asthma: A conference report

The article published below is the result of the thoughtful workshop deliberations of many investigators interested in and very experienced in the assessment and treatment of asthma. As noted by them, the article is not intended to be a set of authoritative guidelines, but rather a presentation of the opinions of the interested individuals. Committees of the American Academy of Allergy and immunology are also currently addressing some of the points discussed here. I believe that our readers will be very interested in reading these thoughts about areas in which we all still have much to learn-Button Zweiman, MD, Editor.

Assessment of quality of life in adolescents with allergic rhinoconjunctivitis: Development and testing of a questionnaire for clinical trials

BACKGROUND The objectives of the study were to evaluate impairment in quality of life in 12- to 17-year-old patients with seasonal allergic rhinoconjunctivitis and to develop and test a questionnaire suitable for evaluating change in quality of life during clinical trials. METHODS Patients were asked to identify physical and emotional impairments associated with allergic rhinoconjunctivitis. The resultant questionnaire was tested for responsiveness and validity in a clinical trial in which fluticasone nasal spray and loratadine were compared for treatment of ragweed pollen-induced rhinoconjunctivitis. Eighty-three patients, 12 to 17 years of age, with grass- or ragweed-induced hayfever participated in the instrument development phase. They were recruited for the study from an allergy clinic and local schools and recreational organizations. Two hundred forty patients with ragweed hayfever participated in the clinical trial and provided quality of life data. RESULTS The survey showed that in addition to local symptoms, patients experienced impairment of quality of life because of systemic symptoms, activity limitations, and emotional and practical problems. The resultant questionnaire has 25 items in six domains. In the clinical trial responsiveness was demonstrated by the questionnaires ability to detect change over time and differences between treatments. Construct validity was demonstrated by moderate to strong relationships between changes in diary symptom scores and quality of life. CONCLUSIONS The items identified by 12- to 17-year-old patients were not identical to those previously identified by adults. This suggests that impairment of quality of life may not be the same in the two groups and that it is appropriate to have a questionnaire specifically designed for adolescent rhinoconjunctivitis clinical trials.

Late asthmatic responses induced by ragweed pollen allergen

Abstract Allergen inhalation tests with ragweed pollen extract were performed in 15 ragweed-allergic asthmatic subjects. Isolated early asthmatic responses were induced in 6 subjects, dual (early and late) responses in 8 subjects, and predominantly or isolated late responses in 1 subject. The frequency and magnitude of late asthmatic responses (LAR) indicate that they are important in the disease. LAR occurred in the more sensitive subjects; in general, these subjects required smaller doses of inhaled ragweed pollen extracts, exhibited larger skin test responses, and had higher serum levels of IgE antibodies to ragweed antigen E. Intradermal tests with ragweed pollen extract elicited early (wheal and flare) or dual (early followed by late) cutaneous allergic responses. With relatively large concentrations of injected ragweed allergen, dual responses could be elicited in virtually all subjects.

Measuring airway inflammation in asthma: Eosinophils and eosinophilic cationic protein in induced sputum compared with peripheral blood

BACKGROUND Airway eosinophilic inflammation is a characteristic feature of asthma. This can be assessed directly by measurement of eosinophils and eosinophilic cationic protein (ECP) in sputum or indirectly by measurement of the same markers in blood. We investigated the performance of these markers of airway eosinophilic inflammation in a population of patients with asthma compared with control subjects and the extent to which the markers differed. METHODS In a cross-sectional study, subject characteristics were documented on day 1 and induced sputum and blood samples were obtained on day 2. Nineteen patients with asthma and 20 control subjects (10 healthy subjects and 10 smokers with nonobstructive bronchitis) were consecutively enrolled in the study. Sputum (selected from saliva) and blood samples were processed by persons blind to the clinical details. Results are presented as median values (minimum-maximum); differences were measured by Mann-Whitney U test. The accuracy of the tests (sensitivity and specificity) was measured by plotting the data in receiver-operating characteristic (ROC) curves and comparing the areas under the curve for each marker. RESULTS Patients with asthma in comparison with control subjects had a higher proportion of sputum eosinophils (5.2% [0.2% to 93%] vs 0.3% [0% to 1.7%], p < 0.001), higher numbers of blood eosinophils (350.0 x 10(6)/L [144.0 to 1520.0 x 10(6)/L] vs 155.0 x 10(6)/L [34.0 to 426.0 x 10(6)/L], p = 0.003), and higher levels of ECP in sputum (1040.0 micrograms/L [76.8 to 32,000.0 micrograms/L] vs 455.3 micrograms/L [54.4 to 1280.0 micrograms/L], p = 0.001) but not in serum (25.0 micrograms/L [5.6 to 52.4 micrograms/L] vs 16.5 micrograms/L [3.3 to 36.0 micrograms/L], p = 0.08). Markers of airway inflammation in induced sputum and blood samples were correlated with clinical and physiologic variables. The area under the ROC curve showed that eosinophils in sputum (0.90) are significantly more accurate markers than blood eosinophils (0.72) and serum ECP (0.67) (p = 0.02). Although the area under the ROC curve for sputum ECP was greater than those for blood eosinophils and serum ECP, the differences could have occurred by chance (p > or = 0.1). CONCLUSION We conclude that the proportion of eosinophils in sputum is a more accurate marker of asthmatic airway inflammation than the proportions of blood eosinophils or serum ECP.

Eosinophils in chronically inflamed human upper airway tissues express transforming growth factor beta 1 gene (TGF beta 1).

Transforming growth factor beta (TGF beta) is a multifunctional protein which has been suggested to play a central role in the pathogenesis of chronic inflammation and fibrosis. Nasal polyposis is a condition affecting the upper airways characterized by the presence of chronic inflammation and varying degrees of fibrosis. To examine the potential role of TGF beta in the pathogenesis of this condition, we investigated gene expression and cytokine production in nasal polyp tissues as well as in the normal nasal mucosa. By Northern blot analysis using a porcine TGF beta 1 cDNA probe, we detected TGF beta 1-specific mRNA in nasal polyp tissues, as well as in the tissue from a patient with allergic rhinitis, but not in the normal nasal mucosa. By the combination of tissue section staining with chromotrope 2R with in situ hybridization using the same TGF beta 1 probe, we found that approximately 50% of the eosinophils infiltrating the polyp tissue express the TGF beta 1 gene. In addition, immunohistochemical localization of TGF beta 1 was detected associated with extracellular matrix as well as in cells in the stroma. These results suggest that in nasal polyposis where eosinophils are the most prevalent inflammatory cell, TGF beta 1 synthesized by these cells may contribute to the structural abnormalities such as stromal fibrosis and basement membrane thickening which characterize this disease.

The origin of airway hyperresponsiveness

Consideration of the origin of airway hyperresponsiveness appears central to understanding the origin of asthma. Subjects with and without asthma differ both in the ease with which airway narrowing is produced by inhalation of histamine or methacholine and in the ability to demonstrate a maximal response to these agents. The latter appears, on present evidence, to be due to an added mechanism in asthma rather than the absence of a potent inhibitory process. Airway hyperresponsiveness is probably acquired during life as a result of airway reactions to various stimuli, although genetic factors such as atopy are likely to predispose the person to develop hyperresponsiveness. Environmental stimuli include inhaled allergens, chemical sensitizers, airway infections, immunization, and ozone. Allergen-induced airway hyperresponsiveness occurs in association with late-phase asthmatic responses. This and ozone-induced hyperresponsiveness have been demonstrated to be associated with release of chemical mediators and the cellular phase of inflammation. Their effect does not appear to be accounted for by increase in airway epithelial permeability, decrease in airway caliber, reflex bronchoconstriction, or beta-adrenoceptor blockade. The mechanism(s) responsible for the induced hyperresponsiveness are unknown but may involve airway epithelial damage, edema in and around the airway walls, stimulation of the noncholinergic excitatory or inhibition of the nonadrenergic inhibitory systems, or a change in function of airway smooth muscle. Airway hyperresponsiveness can be transient or persistent. Transient increases in responsiveness are almost certainly associated with mediator release and inflammation. It is not known whether persistent hyperresponsiveness is due to the same process, fired, for example, by leaky mediator-releasing cells and/or to some persisting change in neurogenic or smooth muscle function.

CD40 expression by human peripheral blood eosinophils.

In this study, we have investigated CD40 expression in human peripheral blood eosinophils and in human chronically inflamed nasal tissues, i.e., nasal polyps. We show by both reverse transcriptase-PCR and Northern blot analysis that eosinophils from allergic subjects express human CD40 mRNA. We also show that constitutive CD40 mRNA expression in eosinophils could be upregulated by exposure to IgA immune complexes and downregulated by IL-10 and the synthetic steroid budesonide. In addition, we demonstrate that eosinophils express CD40 protein by flow cytometry. Such expression is biologically functional as cross-linking CD40 with CD40 mAbs enhances eosinophil survival in a dose-dependent fashion; in addition, CD40 ligation stimulates eosinophils to release GM-CSF. CD40-mediated eosinophil survival was largely inhibited by an anti-GM-CSF neutralizing antibody suggesting GM-CSF involvement in the survival enhancing mechanism. CD40 mRNA was also detected in total RNA extracted from nasal polyp tissues but not in RNA isolated from normal nasal mucosa (inferior turbinate); by immunohistochemistry, we were able to detect immunoreactive CD40 protein in a variety of cell types in the polyp stroma, but primarily in eosinophils. These observations suggest previously unforeseen interactions between eosinophils and cells expressing the CD40 ligand and, thus, novel pathways by which eosinophils may contribute to the regulation of airway inflammation.

Hypersensitivity to natural latex

Rubber hypersensitivity is well described but usually as a contact dermatitis caused by chemicals added during the process of making natural latex or synthetic rubber. IgE-mediated reactions, mainly contact urticaria, have rarely been reported in Europe. We report a case of immediate hypersensitivity to latex. A 34-year-old female operating room nurse developed hand eczema to natural latex. On two occasions, while she was gloving for surgery, she had the following reactions: flushing, tachycardia, urticaria, angioedema, wheezing, and light-headedness. Prick and patch testing to thiuram mix, mercaptobenzothiazole, phenylenediamine mix, and carbamate mix (common rubber additives) were negative. Prick tests to natural latex elicited a 4+ reaction associated with immediate flushing, tachycardia, urticaria, and light-headedness. Five control subjects did not react. IgE antibodies to latex by RAST demonstrated 17.7% binding (control, 4%). This case demonstrates that natural latex can cause IgE-mediated symptoms. The route of exposure was cutaneous absorption of relevant latex allergens. As the use of latex rubber products continues to escalate, more cases are likely to occur.

Increased numbers of circulating basophil progenitors in atopic patients

Recruitment of basophils to sites of homocytotropic antibody-mediated hypersensitivity reactions has been well documented in both experimental and clinical situations. Mechanisms underlying tissue basophil accumulation, however, remain unclear and may involve chemotaxis, cell proliferation, or both. We have recently reported the presence in human blood of circulating basophil/mast cell progenitors on the basis of histamine content of granulocyte colonies grown in methylcellulose. In the current studies we have analyzed the peripheral blood of 30 patients with atopy and 25 comparable control subjects for frequency of basophil/mast cell progenitors by analysis of the histamine content of individual granulocyte colonies. Forty percent of granulocyte colonies in cultures of atopic patients contained histamine in comparison to only 11% in cultures of control subjects (p less than 0.001). Histamine content per colony as well as mean histamine per cell in each colony was higher in granulocyte colonies of atopic subjects and could not be related to colony size or culture conditions. Granulocyte colony growth was enhanced by antigen-stimulated, peripheral blood lymphomononuclear cell--conditioned media of atopic patients. Histamine-positive colonies were found more frequently in active versus quiescent atopic disease (p less than 0.05). These results are consistent with the hypothesis that basophils accumulate at sites of allergic reactions at least in part by recruitment of progenitors from circulation and subsequent differentiation in situ in response to lymphokines. Further studies by use of hemopoietic assays could elucidate the contribution of basophil production to the development of allergic conditions.