Preventive pharmacologic therapy among asthmatics: five years after publication of guidelines.

BACKGROUND: Guidelines from the National Heart, Lung, and Blood Institute first published in 1991 have recommended anti-inflammatory (AI) agents as a first-line therapy and the bronchodilator as an acute reliever of symptoms. OBJECTIVE: To examine the current usage of anti-inflammatory steroids (inhaled corticosteroids, Cromolyn, systemic steroids) and bronchodilators and compare them with the national guidelines. The relationship between preventive AI usage and the characteristics of the asthma patients and their providers was also examined. METHODS: Cross-sectional survey data linked with 6-month pharmacy claims of asthmatic members at an HMO in California. RESULTS: AI usage increased with current severity (mild, 36.9%; moderate, 47.3%; and severe, 56.8%), though a large percentage are not receiving this emphasized treatment. Bronchodilators were used at a higher rate and 24% of asthmatics relied solely on bronchodilators. Use of bronchodilators without AI (BWAI) was present at all severity levels (mild, 19.5%; moderate, 24.6%; and severe, 24.7%). Advancing age, increasing severity, care by an asthma specialist, and not smoking increased the likelihood of using AIs. Increasing severity, longer duration of asthma, smoking, younger age group, care by a generalist, and no chronic bronchitis increased the likelihood of BWAI. CONCLUSIONS: These results suggest that there is a low level of AI usage despite emphasis in guidelines. Current asthma management in a community-based setting depicts a significant underutilization of long-term control agents and, conversely, an overutilization of symptom relief agents compared with guidelines published 5 years ago. Actively involving patients in the guideline dissemination process, rather than just the medical community, may increase preventive medication usage.

Steroid-resistant chronic urticaria associated with anti-thyroid microsomal antibodies in a nine-year-old boy.

The case of a 9-year-old boy with severe chronic urticaria of 6 months' duration is described. The urticaria was associated with intractable bronchospasm and abdominal cramping and was unresponsive to antihistamines and high doses of corticosteroids. Even though the child was euthyroid, he was treated with thyroid hormone after the presence of anti-thyroid microsomal antibodies was documented. Within 1 month the patient demonstrated full remission. He remained free of symptoms for 9 months after discontinuation of treatment. After a relapse he again responded to thyroid hormone therapy. Children with chronic, intractable urticaria and documented evidence of anti-thyroid microsomal antibodies may benefit from treatment with thyroid hormone.

Resolution of chronic urticaria in patients with thyroid autoimmunity.

BACKGROUND: Autoimmune disease has been implicated as a cause of chronic urticaria, and anti-thyroid antibodies have been found in patients with chronic urticaria. Because some patients with chronic urticaria and autoimmune hypothyroidism have had clinical resolution with thyroid hormone replacement, we investigated the effect of thyroid hormone in euthyroid patients with chronic urticaria and thyroid autoimmunity. METHODS: Ten euthyroid patients with refractory hives were treated with thyroxine. Seven patients had elevated anti-thyroid antibodies at baseline. Thyroid function and anti-microsomal and anti-thyroglobulin antibody levels were monitored during treatment. If a clinical response was achieved, thyroxine was discontinued and restarted if symptoms recurred. RESULTS: Seven patients with elevated anti-thyroid antibodies reported resolution of symptoms within 4 weeks. Three patients without elevated anti-thyroid antibodies did not respond. Five patients had a recurrence of symptoms after treatment was stopped, which resolved after treatment was restarted. Thyroid-stimulating hormone levels decreased in all patients with a clinical response. No correlation between clinical resolution and anti-thyroid antibody levels was seen. CONCLUSION: Thyroid autoimmunity in euthyroid patients may be associated with chronic urticaria, and treatment with thyroid suppression can result in clinical remission.

Anaphylaxis. A preventable emergency.

Anaphylaxis is a life-threatening reaction that may be caused by a variety of agents. Diagnosis depends on the presence of a constellation of symptoms (eg, laryngeal edema, bronchospasm, hypotension, urticaria). The goal of therapy is maintenance of an effective airway, respiratory function, and circulation. Subcutaneous epinephrine, H1 and H2 antihistamines, and a prolonged period of observation (at least 8 hours) should be used in all patients. After the acute attack has been managed, a thorough investigation of possible causes should be made and the patient referred to a specialist, if indicated. Desensitization therapy, premedication before high-risk exposures, and careful avoidance of known causative agents are effective preventive measures. Direction in self-administration of epinephrine is critical in these patients and may prove lifesaving.

Lymphocytotoxic antibodies and intermediate immune complexes in hypergammaglobulinemic purpura of Waldenström.

Immune complexes, lymphopenia, and lymphocytotoxic antibodies were detected in two patients with hypergammaglobulinemic purpura of Waldenström. These abnormalities were further characterized in one patient. Ultracentrifugation analysis of this patient's serum showed an intermediate peak likely representing medium sized immune complexes. Circulating IgG-containing immune complexes (2-ME resistant Clq binding material) and IgM rheumatoid factor (2-ME sensitive) were also detected. A sequential study of cold reactive IgM lymphocytotoxic antibodies revealed a significant inverse correlation between antibody levels and peripheral lymphocyte counts. The possible implications of these findings in the pathogenesis of hypergammaglobulinemic purpura are discussed.

Delayed pressure urticaria histologically resembles cutaneous late-phase reactions.

In a recent study, all patients with delayed pressure urticaria (DPU) developed late cutaneous reaction (LCR) after intradermal injection of compound 48/80 and after skin testing with certain food antigens. In the present study, we analyzed the histologic changes in the pressure lesions and compared them with those found in normal skin injected with diluent and in LCR to 48/80. The study included five patients with DPU associated with chronic urticaria (CU) and four patients with CU but without DPU. Six to eight hours after pressure challenge and intradermal skin testing with 48/80 and diluent, skin biopsy specimens were obtained from the pressure lesions, the LCRs, and normal skin (diluent injection). Specimens were assessed by Giemsa staining of 1-micron sections and immunofluorescence of frozen sections. Total cells were counted in each specimen. Interstitial deposits of fibrin were observed by immunofluorescence in LCR and pressure lesions. The total numbers of infiltrating cells in the dermis among LCR sites and pressure lesions were not significantly different, while both LCR sites and pressure lesions contained significantly more infiltrating cells than did normal skin injected with saline diluent. The differential counts in LCR and DPU were mostly mononuclear cells. Infiltrates in the DPU and LCR were mostly perivascular. No histopathologic changes were seen at skin sites challenged with pressure in the control patients with CU without clinical manifestations of DPU. We conclude that lesions seen in DPU are morphologically similar to classic LCR.

Possible role of diet in delayed pressure urticaria--preliminary report.

Late cutaneous reactions preceded by an immediate wheal-and-flare reaction have been described after allergen skin testing, intradermal 48/80 injection, and skin testing with heterologous antihuman IgE. We report the finding of delayed cutaneous reactions after prick food skin testing in a subgroup of five patients with delayed pressure urticaria. This subgroup is also defined by symptomatic clearing after fasting. We demonstrate a correlation of food challenge with skin test response in this same subgroup. Some patients who had previously required prednisone for control of urticaria were able to be managed without it while they were receiving the exclusion diet. In addition, their pressure symptoms and challenge disappeared while they were receiving the restricted diet. These findings suggest that an underlying food sensitivity may be an important precipitating factor in some patients with delayed pressure urticaria.

Late cutaneous reactions in patients with delayed pressure urticaria.

Late cutaneous reactions ( LCRs ) have been described in patients after allergen skin testing, skin testing with heterologous anti-human IgE, autologous skin-blister fluid, and, variably, after 48/80 injection. We report our results of skin testing patients with delayed pressure urticaria ( DPU ), chronic urticaria, and normal volunteers with histamine and 48/80. All patients with DPU had LCRs after 48/80. No patients in either of the other groups developed LCRs . This may be a clue to pathogenic mechanisms involved in DPU .

The hypocomplementemic urticarial-vasculitis syndrome: therapeutic response to hydroxychloroquine.

We report a patient with hypocomplementemic urticarial-vasculitis syndrome. This case illustrates the continuum between urticaria and purpura characteristic of hypocomplementemic urticarial-vasculitis syndrome. Clq precipitin was demonstrated in the patient's serum and in the diethylaminoethylcellulose-ion exchange fraction containing only IgG. A skin biopsy specimen of urticarial and purpuric lesions demonstrated leukocytoclastic vasculitis and granular deposition of C3 and Clq in the basement membrane with IgA, IgM, C3, and Clq in postcapillary venules. Serial total hemolytic complement activity and Clq determinations were performed, and the response to several treatment regimens is presented. Symptomatic and serologic improvement was observed only with hydroxychloroquine.

Inhibition of compound 48/80 induced mediator release following oral administration of tiaramide hydrochloride in normal subjects.

The ability of tiaramide hydrochloride (RHC 2592) to inhibit cutaneous reactivity was studied using 11 normal volunteers. After repeated administration tiaramide hydrochloride inhibited cutaneous mast cell mediator release induced by compound 48/80 while not affecting histamine-induced cutaneous reactivity. This is the first demonstration in man of an oral agent with such an effect.

Acquired immunodeficiency syndrome in a patient with hemophilia.

A patient with hemophilia A developed T-cell deficiency characterized by infection with several opportunistic pathogens. Immunologic investigation showed cutaneous anergy, lymphocyte unresponsiveness to mitogens and antigens, an abnormal ratio of T-helper and T-suppressor cells with absolute lymphopenia and elevated IgA. The clinical and immunologic characteristics of this patient fit the recently described syndrome of opportunistic infections or Kaposi's sarcoma in patients with acquired T-cell deficiency; however, this patient does not have any of the associated underlying risk factors such as homosexuality, intravenous drug or amyl nitrite use, or positive serologic tests for syphilis. We conclude that the patient's acquired T-cell deficiency can be explained by exposure to a virus or other transmissible agent during factor VIII transfusions.

Delayed pressure urticaria.

Delayed pressure urticaria (DPU) is a poorly understood syndrome. We describe 17 patients with DPU. Chronic urticaria was present in 94%. All had negative challenges for immediate demographism and cold urticaria. DPU was induced with a pressure challenge on the shoulder of 15 pounds for 15 min. Average onset of pressure lesions after challenge was 6.5. Lesions were painful, not pruritic, peaked at 9 hr, and disappeared by 24 to 48 hr. Fever, chills, and/or arthralgias occurred in 78%. Positive laboratory abnormalities included leukocytosis in 20% and elevated erythrocyte sedimentation rate in 37.5%. Skin biopsies of lesions showed perivascular round cell infiltrates and negative immunofluorescence. Urticaria responded to antihistamines, but not aspirin, in 100% of patients, while pressure lesions improved with nonsteroidal anti-inflammatory drugs (NSAID), but not antihistamines, in 80% of patients. Both urticaria and DPU were controlled with prednisone, which was necessary in 87.5% of patients. A severe nonremitting course was noted in 7%, 40% had a moderate remitting course requiring intermittent prednisone, and 53% had a mild remitting disease requiring no medication or antihistamines and/or NSAID only. We conclude that DPU is more common than previously appreciated and likely involves mediators other than histamine, possibly the prostaglandin system.

Humoral immunity in stage I mycosis fungoides: an increased incidence of lymphocytotoxic antibodies.

Thirteen patients with stage I mycosis fungoides (MF) were studied for the presence of circulating autoantibodies including cold-reactive lymphocytotoxic antibodies (LCA), antinuclear antibodies and rheumatoid factor antibodies to common food antigens, bovine gamma globulin and casein; and immune complexes as measured by cryoglobulins and I125 Clq binding. A significantly increased incidence (11/13) of LCA was found in the MF patients, and this may be related to the alterations in subpopulations of T cells seen in these patients. No significant increase in any other test was noted. there was no evidence of a diffuse hyperactivity of the humoral immune system as seen in systemic lupus erythematosus, which has a similar imbalance of T cell subpopulations.

Evaluation of skin test response using two techniques of measurement.

This study shows that lodoxamide ethyl has no significant effect on 48/80 or histamine skin tests using a double-blind protocol in 10 normal subjects. Direct measurement of area by planimetry is also demonstrated to be less variable than diameters in quantitating skin test results.

Evaluation of a patient with both aquagenic and cholinergic urticaria.

An 11-yr-old girl presented with a history of urticaria induced by warm or cool showers, exercise, and emotional stimuli. During evaluation she repeatedly developed generalized punctate urticaria, pruritus, palpitations, and headaches after warm baths or exercise, and she had a positive methacholine skin test. She developed similar lesions and pruritus after local application of sterile water, tap water, ethanol, normal saline, or 3% saline. The diagnosis of combined aquagenic and cholinergic urticaria was made and presented a unique opportunity to study and compare mediator release and clinical symptoms in both conditions. The patient was submerged in bath water at either 37 degree or 41 degree C to induce either aquagenic or cholinergic urticaria, respectively. Histamine was released into the systemic circulation in both conditions in a similar time course; however, systemic symptoms occurred only after the 41 degree C bath. After failure to induce tolerance to the 41 degree C bath water, hydroxyzine therapy was instituted. One week later she was rechallenged; few symptoms appeared, and a rise in serum histamine was not detected as had been shown in previous challenges. The data suggest that in our patient, hydroxyzine may have contributed to the inhibition of both histamine release and the appearance of symptoms during hot bath challenging.

A controlled trial of therapy in chronic urticaria.

Nineteen patients with chronic idiopathic urticaria (duration 2 to 192 mo) referred to our clinic as therapeutic failures were treated sequentially with five regimens. These were administered orally in a double-blind random sequence and included hydroxyzine pamoate (25 mg q.i.d.) plus one of the following: (1) placebo, (2) terbutaline (2.5 mg q.i.d.), (3) cyproheptadine (4 mg q.i.d.), (4) chlorpheniramine (4 mig q.i.d.), (5) cimetidine (300 mg q.i.d.). Therapeutic response was assessed by patient's subjective choice, symptom diary scores, and suppression of wheal response to intradermal injections of histamine and compound 48/80. At least 35% improvement was noted in all patients with an average optimal response of 70%. The hydroxyzine-cimetidine combination was favored by 11 of 19 (58%) patients, in addition to producing the lowest symptom scores and the greatest histamine-48/80 wheal suppression. These results support the efficacy of combination H1 and H2 antihistamines in the management of some patients with difficult chronic urticaria.

A comparison of the actions of H1 and H2 antihistamines on histamine-induced bronchoconstriction and cutaneous wheal response in asthmatic patients.

The effect of an H1 antihistamine, an H2 antihistamine, and the combination of the two drugs on both histamine-induced bronchoconstriction and dermal whealing was examined in five patients with mild asthma. Chlorpheniramine 8 mg, cimetidine 300 mg, the combination of both, and placebo were administered orally to each patient for a single dose and for seven consecutive doses given every 6 hr after a double-blind, randomized protocol. The airway response to inhaled histamine and the wheal size induced by the intradermal injection of histamine were determined in every patient 2 hr after the final drug dose. The results indicate that a single dose of chlorpheniramine produces a significant increase in the threshold of histamine-induced bronchoconstriction as measured by the provocative histamine dose producing 20% decrease in 1-sec forced expiratory volume (PD20-FEV1), and this effect was significantly enhanced after seven doses. Cimetidine caused a significant decrease in the threshold of histamine-induced bronchoconstriction, but this was not augmented by seven doses. Only chlorpheniramine, when given for seven doses, improved the baseline FEV1 and forced expiratory flow during middle half of forced vital capacity (FEF25%-75%). Chlorpheniramine in both single and multiple doses and the combination of chlorpheniramine and cimetidine given for seven doses produced a significant inhibition of histamine-induced dermal wheals, whereas cimetidine alone had no effect. These results confirm our previous observation that both H1 and H2 receptors are present in the airways of asthmatic patients and that they mediate opposite effects. We also demonstrated a cumulative effect with the repeated administration of chlorpheniramine but not with cimetidine. Finally, the results suggest that the role of H1 and H2 receptors differs in the bronchi from that seen in the dermal vessels of asthmatic patients and are in contrast to those of normals. The H2 receptor effect on histamine-induced skin wheals appears deficient, further supporting earlier suggestions of the presence of an H2 receptor defect in asthmatic patients.

Gastrointestinal involvement in leukocytoclastic vasculitis and polyarteritis nodosa.

The records of 106 consecutive patients referred to the University of Colorado Medical Center (UCMC) vasculitis study group during a 5-yr period were evaluated for gastrointestinal (GI) manifestations attributable to vasculitis. There were 3 groups: 18 with leukocytoclastic vasculitis (LCV) on skin biopsy younger than 16 yr of age; 75 with LCV older than 16 yr of age; and 13 with polyarteritis nodosa (PAN). Significant GI manifestations at presentation or exacerbation of vasculitis occurred in 38 of 106 (36%) patients. These were more frequent in LCV patients younger than 16 yr (66%), than older LCV patients (26%) or PAN patients (46%). The commonest complaint was abdominal pain (79%), followed by nausea (63%), vomiting (37%) and diarrhea (23%). GI bleeding was present in 52% and acute abdomen in 21% of patients. No consistent radiologic findings were noted. Duodenal and peritoneal biopsies suggested vasculitis in 6 LCV patients. Seven exploratory laparotomies were performed in 4 LCV and 3 PAN patients. Intestinal infarction was found in 3 patients with PAN, but in one of the LCV patients. Two patients with LCV with an acute abdomen were not explored and responded promptly to iv corticosteroids. Thus, systemic vasculitis frequently involves the GI tract. In patients with LCV, recognition of this association and treatment with corticosteroids can avoid surgery. In our patients with PAN, however, acute abdominal signs indicated infarction requiring surgery and resection.