Persistent asthma: patient characteristics, courses of asthma, and utility of salmeterol.

Applications of National Asthma and Education and Prevention Program (NAEPP) guidelines for the diagnosis and management of asthma may reduce the morbidity of this disorder. Medical records and questionnaires from a series of 177 outer-city adolescents and adults with persistent asthma were audited according to NAEPP guidelines and for utility of salmeterol (Serevent). Allergic sensitivity and exposure to indoor allergens house-dust mite (66% of patients), fungi (42%), cat (20%) and/or dog (14%) were of dominant importance to persistent asthma. Patients who continued salmeterol over 1 year had reduced severity of disease, improved forced expiratory flow at 25%-75% of vital capacity, and reduced usage of systemic, but not inhaled, corticosteroid.

Montelukast is only partially effective in inhibiting aspirin responses in aspirin-sensitive asthmatics.

BACKGROUND: Leukotrienes have been implicated as major mediators of ASA-induced respiratory reactions. In several prior studies, pretreatment of ASA-sensitive respiratory disease (ASRD) patients with leukotriene modifiers have sometimes allowed subjects to tolerate previously established provoking doses of oral ASA or inhalation ASA-lysine, without respiratory reactions. OBJECTIVE: The purpose of this study was to examine whether ASA-provoked respiratory reactions would be blocked or attenuated by pretreatment with a cystLT1 receptor antagonist, montelukast, particularly if ASA doses were increased above their threshold doses. METHODS: Baseline ASA oral challenges were performed. Eight to 12 days later, following pretreatment with montelukast 10 mg daily, threshold and then escalating doses of ASA were used during repeat oral ASA challenges. The differences in responses between baseline and montelukast protected ASA oral challenges were then compared. RESULTS: Nine of 10 patients, despite pretreatment with montelukast, experienced at least naso-ocular reactions during their second oral ASA challenges. In four of nine patients, asthmatic reactions also occurred. In comparing baseline and montelukast protected ASA challenges, there were no statistically significant differences in their responses. CONCLUSIONS: Pretreatment with montelukast allowed only one patient to proceed through all challenge doses of ASA without any reactions. The remaining nine patients enjoyed only partial protection from respiratory reactions. Montelukast pretreatment was generally not effective in altering upper airway reactions and only partly effective in altering lower airway reactions.

Molecular definition of heterogeneous nuclear ribonucleoprotein R (hnRNP R) using autoimmune antibody: immunological relationship with hnRNP P.

Serum from a patient showing symptoms related to autoimmunity was found to contain autoantibodies to the nuclear mitotic apparatus (NuMA) protein and to several novel nuclear antigens with estimated molecular weights of 40, 43, 72, 74 and 82 kDa. Using this serum for screening a human cDNA expression library a 2.5 kb cDNA clone was isolated which encoded the complete sequence of a protein of 633 amino acids. Sequence analysis revealed a modular structure of the protein: an acidic N-terminal region of approximately 150 amino acids was followed by three adjacent consensus sequence RNA binding domains located in the central part of the protein. In the C-terminal portion a nuclear localization signal and an octapeptide (PPPRMPPP) with similarity to a major B cell epitope of the snRNP core protein B were identified. This was followed by a glycine- and arginine-rich section of approximately 120 amino acids forming another type of RNA binding motif, a RGG box. Interestingly, three copies of a tyrosine-rich decapeptide were found interspersed in the RGG box region. The major in vitro translation product of the cDNA co-migrated in SDS-PAGE with the 82 kDa polypeptide that was recognized by autoantibodies. The structural motifs as well as the immunofluorescence pattern generated by anti-82 kDa antibodies suggested that the antigen was one of the proteins of the heterogeneous nuclear ribonucleoprotein (hnRNP) complex. Subsequently the 82 kDa antigen was identified as hnRNP R protein by its presence in immunoprecipitated hnRNP complexes and co-migration of the recombinant protein with this hitherto uncharacterized hnRNP constituent in two-dimensional gel electrophoresis. The concomitant autoimmune response to a hnRNP component of the pre-mRNA processing machinery and to NuMA, a protein engaged in mitotic events and reported to be associated with mRNA splicing complexes in interphase, may indicate physical and functional association of these antigens. Support for this notion comes from observations that concomitant or coupling of autoantibody responses to proteins which are associated with each other as components of subcellular particles are often found in autoimmune diseases.

Aspirin desensitization treatment of aspirin-sensitive patients with rhinosinusitis-asthma: long-term outcomes.

BACKGROUND: Aspirin-sensitive patients with asthma experience continuous inflammation of their nasal and sinus tissues, complicated by recurrent sinusitis, which frequently leads to asthma attacks. Systemic corticosteroid therapy and sinus or polyp surgery are currently required to control underlying rhinosinusitis, and bursts of corticosteroids are used for asthma control. OBJECTIVE: After aspirin desensitization therapy, objective measures of respiratory disease activity, linked to the need for systemic corticosteroids and sinus surgery, were studied to determine whether any changes occurred. METHODS: Sixty-five aspirin-sensitive patients with asthma underwent aspirin challenge, followed by aspirin desensitization and daily treatment with aspirin over 1 to 6 years (mean, 3.1 years). Clinical outcome measurements before aspirin desensitization treatment and during follow-up were analyzed for the larger group of 65 patients and subgroups (29 patients receiving therapy for 1 to 3 years and 36 patients receiving therapy for 3 to 6 years). RESULTS: In the larger group of 65 patients, there were significant reductions in numbers of sinus infections per year (median, 6 to 2), hospitalizations for treatment of asthma per year (median, 0.2 to 0), improvement in olfaction (median, 0 to 2), and reduction in use of systematic corticosteroids (mean, 10.2 to 2.5 mg) with p values less than 0.0001. Numbers of sinus and polyp operations per year were significantly reduced (median, 0.2 to 0; p = 0.004), and doses of nasal corticosteroids (in micrograms) were significantly reduced (mean dose, 139 to 106 micrograms, p = 0.01). Emergency department visits and use of inhaled corticosteroids were unchanged. CONCLUSIONS: The results support a role for aspirin desensitization treatment of aspirin-sensitive patients with rhinosinusitis-asthma.

Prevalence of cross-sensitivity with acetaminophen in aspirin-sensitive asthmatic subjects.

OBJECTIVE: Cross-sensitivity between aspirin and acetaminophen in aspirin-sensitive asthmatic patients has been reported with frequencies ranging from 0% to 29%. The relationship is dose-dependent for acetaminophen challenges, ranging between 300 and 100 mg. METHODS: To determine the prevalence of cross-sensitivity to high-dose acetaminophen, we performed single-blind acetaminophen oral challenges with 1000 mg and 1500 mg in 50 aspirin-sensitive asthmatic patients and in 20 non-aspirin-sensitive asthmatic control subjects. RESULTS: Overall, 17 of 50 (34%) of aspirin-sensitive asthmatic patients reacted to acetaminophen in doses of 1000 to 1500 mg (95% confidence interval: 20% to 49%). By contrast, none of the 20 non-aspirin-sensitive asthmatic patients reacted to acetaminophen (95% confidence interval: 0% to 14%). This difference was highly significant (p = 0.0013), supporting the hypothesis that cross-sensitivity between aspirin and acetaminophen is unique in aspirin-sensitive asthmatic patients. CONCLUSION: Although high-dose ( > 1000 mg) acetaminophen cross-reactions with aspirin were significant with respect to frequency (34%), such reactions included easily reversed bronchospasm in only 22%, and were generally mild. We recommended that high doses of acetaminophen (1000 mg or greater) should be avoided in aspirin-sensitive asthmatic patients.

Prevalence of basidiomycete allergy in the USA and Europe and its relationship to allergic respiratory symptoms.

A total of 701 adults living in the USA or Western Europe who had symptoms of allergic respiratory disease were skin prick tested with extracts prepared from eight basidiomycetes species and four Fungi Imperfecti species. In these subjects, the presence of asthma, rhinitis, or both was determined by questionnaire. Overall, 178/701 (25.4%) of the participants reacted to at least one basidiomycete extract. There was no difference in the prevalence of reactivity detected in the USA and Europe (P < 0.005); however, the prevalence of reactors in individual centers from both areas varied significantly. Psilocybe cubensis was the most potent allergen source in both the USA (12.3% reacted) and Europe (16.0%). Pleurotus ostreatus was second overall (10.6%) and in the USA (10.7%), and third in Europe (10.3%). Pisolithus tinctorius and Coprinus quadrifidus produced the least potent allergens, with only 5.4% of the population reacting. There was a significant relationship (P < 0.005) between basidiospore reactivity and the presence of atopy, asthma, and asthma and rhinitis. Basidiospore reactivity was not associated with the presence of rhinitis alone (P = 0.312). These results suggest that basidiomycetes are important sources of aeroallergens in geographically disparate regions and may be particularly important in patients with asthma.

Safety and possible efficacy of fiberoptic bronchoscopy with lavage in the management of refractory asthma with mucous impaction.

Mucous impaction may be suspected in asthmatic exacerbation when, despite aggressive medical management, patients continue to produce sputum containing mucous plugs and exhibit prominent rhonchi and/or wheezes on chest auscultation. Spirometric measurements in this setting corroborate lack of improvement and reveal significant impairment in indices that may reflect small airways function (FEF25-75). We hypothesized that clearance of inspissated secretions by fiberoptic bronchoscopy with lavage (FOBwL) may promote or hasten the clinical improvement of such patients. Fifty-one therapeutic FOBwL were accomplished in 19 patients during 20 episodes of stabilized yet refractory asthma with mucous impaction. No significant complications were encountered. After FOBwL, spirometric measurements of FEV1, FEF25-75, and FVC increased significantly (P less than .01, paired t test), and correlated with relief of dyspnea and mobilization of secretions with cough. FOBwL can be safely performed in stabilized, refractory asthma, and with apparent efficacy. Further investigation is needed to document the therapeutic utility of FOBwL in refractory asthma.

Long-term effects of aspirin desensitization--treatment for aspirin-sensitive rhinosinusitis-asthma.

One hundred seven known aspirin (ASA)-sensitive patients with rhinosinusitis-asthma were studied from 1975 to 1988. Forty-two of the patients avoided ASA and served as the control group. Thirty-five patients were desensitized to ASA and treated with daily ASA treatment (Rx) for as long as 8 years (mean, 3.75 years) to May 1988 and were designated the continuous group. Thirty patients, initially desensitized to ASA and treated with daily ASA, who stopped Rx permanently after a mean duration of 2 years, were designated the discontinued group. Retrospective analyses of baselines revealed that both continuous and discontinued groups during ASA Rx demonstrated statistically significant reduction in number of hospitalizations per year, emergency room visits per year, outpatient visits per year, upper respiratory infections-sinusitis-antibiotics per year, need for nasal polypectomies and additional sinus operations, and improvement in sense of smell compared to the control group. Simultaneously, the ASA-Rx groups were able to significantly reduce systemic corticosteroid dosage, corticosteroid bursts per year, and, in the continuous group only, significantly reduce inhaled corticosteroids. All three groups maintained control of respiratory symptoms. ASA desensitization followed by long-term daily ASA Rx appears to improve ASA-sensitive rhinosinusitis-asthma and concomitantly allows reduction of systemic corticosteroids.

Precipitating factors in asthma. Aspirin, sulfites, and other drugs and chemicals.

Several types of reactions to drugs and chemicals may precipitate or perpetuate asthmatic relapse. This review focuses on reactions to aspirin and sulfites. Approximately 40 percent of patients with rhinosinusitis, nasal polyps, and asthma and 5 to 10 percent of all asthmatic patients are sensitive to aspirin and aspirin-like nonsteroidal anti-inflammatory drugs at some time in their course. A prudent recommendation to all asthmatics is to substitute acetaminophen for aspirin. When aspirin/aspirin-like drug is essential for treatment of cardiovascular or musculoskeletal disorder, desensitization by cautious oral challenges with graded doses of aspirin can be accomplished. Treatment of the respiratory disorder per se by desensitization followed by daily therapeutic aspirin remains investigational. Sulfur dioxide and sulfites, commonly used as sanitizers and preservatives of foods and pharmaceuticals, may precipitate acute asthma in 5 percent or more of asthmatic patients. When the history suggests sulfite sensitivity, challenges can be used to confirm sensitivity and the patient counseled in avoidance of these chemicals.

Allergic bronchopulmonary candidiasis.

A patient had an illness consistent with allergic bronchopulmonary candidiasis. She had asthma, fleeting pulmonary infiltrate, immediate skin reactivity and precipitating antibody against Candida albicans, elevated total serum IgE concentration, elevated IgE and IgG antibody activity against C albicans, and two positive sputum cultures for C albicans. Serial serologic studies showed a significant decrease of serum IgE levels and IgE antibody activity after corticosteroid treatment.

Aspirin-sensitive rhinosinusitis asthma: a double-blind crossover study of treatment with aspirin.

Twenty-five ASA-sensitive patients with rhinosinusitis asthma underwent oral ASA challenges followed by desensitization to the adverse respiratory effects of ASA. We then compared the efficacy of continuous ASA treatment for their respiratory tract disease to that of a placebo treatment during a double-blind crossover study. For this group of 25 patients, there was significant improvement in nasal symptoms and a reduction in use of nasal beclomethasone during the months when they received ASA treatment. Lower respiratory tract symptoms, values of FEV1, and the use of antiasthmatic medications including prednisone were not significantly changed during ASA treatment. Desensitization to ASA followed by ASA treatment appears to significantly alleviate symptoms of rhinosinusitis. However, only half the patients experienced improvement in their asthma symptoms during ASA treatment.

Aspirin-sensitive rhinosinusitis/asthma: spectrum of adverse reactions to aspirin.

In order to determine the types of respiratory responses observed during aspirin-induced reactions, 50 consecutive asthmatic patients with a history of aspirin sensitivity underwent prospective oral aspirin challenges between 1979 and 1981. Oral aspirin challenges produced 36 asthmatic responses (33 combined with rhinitis and three purely asthmatic) and six acute rhinoconjunctivitis responses (three combined with mild asthma and three purely rhinoconjunctivitis) but failed to stimulate any reaction in eight patients. The results produced by these challenges were then compared with results recorded during additional aspirin challenges in 28 of these patients, performed after the index challenge in 1979-1981 in 26 patients and in the case of two patients before 1979. The type of respiratory response to aspirin varied significantly in 11 (39%) of the 28 patients and included disappearance of aspirin reactivity in four patients.

Aspirin desensitization in aspirin-sensitive asthmatic patients: clinical manifestations and characterization of the refractory period.

Thirty aspirin-sensitive asthmatic patients underwent incremental, oral aspirin challenge until a "positive reaction" (delta FEV1 greater than or equal to 25%) occurred. After this reaction, aspirin was readministered in an attempt to achieve "desensitization." This was defined as the ability of the patient to ingest 650 mg of aspirin without experiencing upper or lower respiratory-tract symptoms or a decrease in lung function. To determine the "refractory period" following aspirin desensitization, patients were rechallenged after various intervals (days) without aspirin until a positive reaction recurred. All 30 aspirin-sensitive asthmatic patients were successfully desensitized to aspirin. Individual patient refractory periods ranged from less than 2 days to greater than 5 days, with most patients gradually returning to sensitivity between 2 to 4 days. Cross-densensitization with indomethacin and other nonsteroidal anti-inflammatory drugs was also demonstrated. These studies show that aspirin desensitization can be safely achieved in aspirin-sensitive asthmatic patients; however, this desensitization will gradually disappear over several days when additional aspirin is withheld.

Immunoglobulin E-rheumatoid factor in the serum of patients with rheumatoid arthritis, asthma, and other diseases.

A solid-phase radioimmunoassay was developed to detect immunoglobulin (Ig)E antibodies that bound to human IgG. IgE-rheumatoid factor activity was found in the serum of 18 of 20 patients with seropositive rheumatoid arthritis, 1 of 4 patients with seronegative rheumatoid arthritis, 3 of 32 patients with seronegative rheumatoid arthritis, 3 of 32 patients with asthma, and in 1 patient with hypocomplementemic vasculitis and iodide sensitivity. Immunopathologic implications of IgE-rheumatoid factor are discussed.

Purification and characterization of two functionally distinct forms of C1 inhibitor from a patient with angioedema.

A minority of patients with hereditary angioedema (HAE) have normal concentrations of a dysfunctional C1 inhibitor protein (C1INH) in their plasmas. We purified C1INH from the plasmas of one such patient before and during treatment with the anabolic steroid stanozolol. Both the pretreatment plasma and plasma obtained during stanozolol treatment contained varying amounts of two extremely similar C1INH proteins that were functionally distinct. The pretreatment plasma contained primarily (94%) dysfunctional C1INH that did not inactivate or complex with either purified C1s, activated Hageman factor, or kallikrein and small amounts (6%) of functionally normal C1INH. Stanozolol treatment increased the plasma concentrations of both of these proteins as well as the proportion (23%) of functional C1INH in the plasma. The purified dysfunctional and functional C1INHs had identical or nearly identical molecular sizes, charges, amino acid compositions, and amino sugar contents, and could not be distinguished physicochemically from each other or from normal C1INH. From these studies of purified C1INH proteins we concluded that HAE associated with dysfunctional C1INH is due to a defect at the structural locus for one C1INH gene and that both the dysfunctional C1INH gene and the normal C1INH gene products are present in the plasma of the affected subject. Treatment with stanozolol comparably increased the synthesis of both C1INH proteins. The disproportionate rise in the level of the normal C1INH protein is consistent with the view that it is more rapidly catabolized as a consequence of its interaction with the proteases it inactivates.