Para-aminosalicylic acid (PAS) desensitization review in a case of multidrug-resistant pulmonary tuberculosis.

SETTING: Tertiary care hospital in the Upper Midwest, United States. OBJECTIVE: Rapid desensitization to para-aminosalicylic acid (PAS) in a patient with previous hypersensitivity reaction and a review of published PAS desensitization protocols. DESIGN: Composition and implementation of a short-course PAS desensitization protocol for a 34-year-old woman with multidrug-resistant (MDR) pulmonary tuberculosis, incorporating published experiences of PAS desensitization over the past 50 years. RESULTS: We composed a protocol and successfully desensitized our patient to PAS (Paser granules). By starting with a low dose (50 mg), then doubling the PAS dose on each successive day, our patient was able to tolerate full dose in 1 week. No steroids were required and no adverse reactions were encountered. Previous published PAS desensitization protocols used starting doses of 10-500 mg, desensitization time ranges from 7 to 54 days and commonly used steroids or corticotropin. CONCLUSION: Rapid desensitization to PAS can be successfully conducted within 1 week without the use of steroids or corticotropin. Given the limited number of drugs available for many patients with MDR-TB, desensitization to PAS is a valid alternative to drug discontinuation for patients with hypersensitivity reactions.

Hereditary angioedema: a broad review for clinicians.

Hereditary angioedema (HAE) is an autosomal dominant disease that afflicts 1 in 10,000 to 1 in 150,000 persons; HAE has been reported in all races, and no sex predominance has been found. It manifests as recurrent attacks of intense, massive, localized edema without concomitant pruritus, often resulting from one of several known triggers. However, attacks can occur in the absence of any identifiable initiating event. Historically, 2 types of HAE have been described. However, a variant, possibly X-linked, inherited angioedema has recently been described, and tentatively it has been named "type 3" HAE. Signs and symptoms are identical in all types of HAE. Skin and visceral organs may be involved by the typically massive local edema. The most commonly involved viscera are the respiratory and gastrointestinal systems. Involvement of the upper airways can result in severe life-threatening symptoms, including the risk of asphyxiation, unless appropriate interventions are taken. Quantitative and functional analyses of C1 esterase inhibitor and complement components C4 and C1q should be performed when HAE is suspected. Acute exacerbations of the disease should be treated with intravenous purified C1 esterase inhibitor concentrate, where available. Intravenous administration of fresh frozen plasma is also useful in acute HAE; however, it occasionally exacerbates symptoms. Corticosteroids, antihistamines, and epinephrine can be useful adjuncts but typically are not efficacious in aborting acute attacks. Prophylactic management involves long-term use of attenuated androgens or antifibrinolytic agents. Clinicians should keep this disorder in their differential diagnosis of unexplained, episodic cutaneous angioedema or abdominal pain.

Inhaled mometasone furoate reduces oral prednisone requirements while improving respiratory function and health-related quality of life in patients with severe persistent asthma.

BACKGROUND: Inhaled corticosteroid therapy in severe persistent asthma has been shown to reduce or eliminate oral corticosteroid (OCS) use while retaining effective asthma control. OBJECTIVE: We sought to evaluate the ability of mometasone furoate (MF) delivered by means of dry powder inhaler to reduce daily oral prednisone requirements in OCS-dependent patients with severe persistent asthma. METHODS: We performed a 12-week, double-blind, placebocontrolled trial (21 centers, 132 patients) comparing 2 doses of MF (400 and 800 microg administered twice daily) with placebo, followed by a 9-month open-label phase in which 128 patients received treatment with MF. RESULTS: At the endpoint of the double-blind trial, MF 400 and 800 mg twice daily reduced daily OCS requirements by 46.0% and 23.9%, respectively, whereas placebo increased OCS requirements by 164.4% (P <.01). Oral steroids were eliminated in 40%, 37%, and 0% of patients in the MF 400 and 800 mg twice daily and placebo groups, respectively. Pulmonary function and quality of life significantly increased for MF-treated patients. Further reductions in OCS requirements were achieved with long-term MF treatment in the open-label phase. CONCLUSION: MF inhaled orally as a dry powder is an effective alternative to systemic corticosteroids in patients with severe persistent asthma.

Acquired C1 esterase inhibitor deficiency.

Acquired C1 esterase inhibitor deficiency is a rare condition associated with autoimmune or low-grade lymphoproliferative disorders. Adults or elderly patients are most commonly affected. The diagnosis is suspected when patients present with recurrent angioedema and low serum levels of C4 with normal levels of C3. Low levels of C1q and low C1 esterase inhibitor activity confirm the diagnosis. In this paper, we summarize experience with 22 cases of acquired C1 esterase inhibitor deficiency in the context of a review of the published literature on diagnosis and treatment of this condition.

The diagnosis and incidence of allergic fungal sinusitis.

OBJECTIVE: To reevaluate the current criteria for diagnosing allergic fungal sinusitis (AFS) and determine the incidence of AFS in patients with chronic rhinosinusitis (CRS). METHODS: This prospective study evaluated the incidence of AFS in 210 consecutive patients with CRS with or without polyposis, of whom 101 were treated surgically. Collecting and culturing fungi from nasal mucus require special handling, and novel methods are described. Surgical specimen handling emphasizes histologic examination to visualize fungi and eosinophils in the mucin. The value of allergy testing in the diagnosis of AFS is examined. RESULTS: Fungal cultures of nasal secretions were positive in 202 (96%) of 210 consecutive CRS patients. Allergic mucin was found in 97 (96%) of 101 consecutive surgical cases of CRS. Allergic fungal sinusitis was diagnosed in 94 (93%) of 101 consecutive surgical cases with CRS, based on histopathologic findings and culture results. Immunoglobulin E-mediated hypersensitivity to fungal allergens was not evident in the majority of AFS patients. CONCLUSION: The data presented indicate that the diagnostic criteria for AFS are present in the majority of patients with CRS with or without polyposis. Since the presence of eosinophils in the allergic mucin, and not a type I hypersensitivity, is likely the common denominator in the pathophysiology of AFS, we propose a change in terminology from AFS to eosinophilic fungal rhinosinusitis.

The eosinophilic injury to the mucosa of the airways in the pathogenesis of bronchial asthma.

Eosinophilic bronchitis and desquamation of the bronchial mucosa are the salient features of the pathology of both allergic (extrinsic) and nonallergic (intrinsic) asthma. Because of this association, the possibility of the eosinophil being the cause of the injury to the bronchial mucosa has been investigated during the last decade. In vitro, eosinophil granule major basic protein (MBP) concentrations as low as 10 micrograms.ml-1 cause desquamation and destruction of the epithelium of the airways which mimic the morphology of damage to the mucosa of the bronchi in asthma. Concentrations of MBP in the cytotoxic range for the bronchial mucosa in vitro have been measured in sputum of asthmatics (up to 92 micrograms.ml-1) and decline with treatment. Deposits of MBP have been detected by immunofluorescence within ulcerated areas of bronchial mucosa and necrotic portions of the bronchial wall in patients who had died of asthma. Most recently, the eosinophil peroxidase (EPO) and the eosinophil cationic protein (ECP) have also been found to be toxic for the epithelium of the airways in vitro, thus increasing the cytotoxic capability of the eosinophil against the bronchial mucosa in asthma. These latest research data continue to support the "eosinophil hypothesis" in the pathogenesis of this disease. According to this hypothesis, in the formidably complex network of cells and mediators responsible for the bronchial obstruction, the destruction of the mucociliary apparatus and the characteristic hyperresponsiveness of the airways in asthma; the eosinophil is the principal effector cell. In bronchial asthma a T cell modulated eosinophilic bronchitis is the primary abnormality while bronchospasm and hyperreactivity of the airways are secondary phenomena.

Allergic fungal sinusitis secondary to dermatiaceous fungi--Curvularia lunata and Alternaria.

Allergic fungal sinusitis is a newly recognized entity consisting of a pansinusitis with allergic mucinous infiltrates in all involved sinuses. The disease process itself is very different from all other types of rhinosinusitis. Pathophysiologically the disease is a combination of both IgE-mediated and antibody-antigen reactions to the specific fungal antigens. Here we present two cases of allergic fungal sinusitis--one caused by Curvularia lunata species (an ubiquitous soil fungi), another caused by Alternaria. Only one other case of allergic fungal sinusitis caused by curvularia in which extensive immunologic testing was done has appeared in the literature. No reports of alternaria causing allergic fungal sinusitis have appeared in the literature. Diagnostic criteria for allergic fungal sinusitis include radiologic evidence of pansinusitis in an atopic individual; findings at surgery of allergic mucin; positive fungal cultures; and specific immunologic testing, including both humoral and cellular arms of the immune system. Treatment options for allergic fungal sinusitis are discussed and include surgery alone, surgery and steroids, or steroids alone. The role of allergy immunotherapy injections remains to be defined. In general, fungal infections--and especially phaeohyphomycosis--are very rare, but appear to be increasing in frequency, especially in the paranasal sinus region.

Angioedema with acquired deficiency of the C1 inhibitor: a constellation of syndromes.

Patients with angioedema are often referred to an allergist to rule out an allergic cause. In most of these cases, no allergic cause is identified, and the cases are labeled "idiopathic." Occasionally, a deficiency of the inhibitor of the first component of complement (C1INH) is discovered, which may be either hereditary or acquired. In comparison with the hereditary variant, the acquired deficiency of C1INH is extremely rare, approximately 40 cases having been reported to date. Measurement of the C1q subunit is the key to the differential diagnosis between hereditary and acquired deficiencies of C1INH--it is normal in the former and decreased in the latter. The acquired deficiency of C1INH is usually found in association with benign or malignant B-cell lymphoproliferative disorders, and the angioedema responds to therapy with androgens. A subset of six patients with acquired C1INH deficiency has been reported recently; they had anti-C1INH autoantibodies, no evidence of an underlying disease, a benign course, and variable responses to therapy. Two new cases of angioedema in patients with acquired C1INH deficiency are described in this report. One patient had no evidence of an underlying disease 11 years after the onset of angioedema. The other case was associated with a B-cell lymphoproliferative disorder that became evident 9 months after C1INH deficiency was diagnosed, and androgen therapy stopped the attacks of angioedema. In this second case, the functional activity of C1INH mirrored the clinical response to therapy.

Toxicity of eosinophil cationic proteins for guinea pig tracheal epithelium in vitro.

We tested the effects of four eosinophil granule cationic proteins: major basic protein (MBP), eosinophil cationic protein (ECP), eosinophil peroxidase (EPO), and eosinophil-derived neurotoxin (EDN), on guinea pig tracheal epithelium in vitro. Examination by inverted microscopy revealed that MBP, both the form stabilized by alkylation of sulfhydryl groups as well as the native form of the molecule, ECP, EPO by itself, as well as EPO + H2O2 + halide, but not EDN, cause dose-related damage to the tracheal epithelium. The lowest concentrations of MBP and ECP causing damage were 10 and 100 micrograms/ml, respectively. In contrast, EDN, although biochemically similar to ECP, did not damage the tracheal epithelium in concentrations of up to 200 micrograms/ml. MBP caused exfoliation, as well as bleb formation and ciliostasis. EPO in the presence of the H2O2-producing enzyme glucose oxidase (GO), Cl-, 0.11 M, and iodide caused ciliostasis, bleb formation, and exfoliation of epithelial cells at concentrations as low as 1 U/ml (3.9 micrograms/ml). EPO + GO in the presence of Cl-, 0.11 M, alone or with Cl- and l-, 10(-4) M, or Cl- and Br-, 5 x 10(-5) M, were all toxic to epithelium. Surprisingly, EPO by itself caused partial ciliostasis, bleb formation, and exfoliation of epithelial cells in a dose-related manner at concentrations as low as 10 to 30 U/ml (39 to 121 micrograms/ml). These results confirm prior observations showing the toxicity of MBP to tracheal epithelium and indicate that ECP and EPO alone, as well as EPO + GO + halide, cause damage. Thus, several eosinophil granule proteins are able to damage respiratory epithelium.

The eosinophilic leukocyte and the pathology of fatal bronchial asthma: evidence for pathologic heterogeneity.

Classically, bronchial asthma is associated with peripheral blood eosinophilia and striking eosinophilia of bronchial tissues and sputum. Evidence exists that eosinophil degranulation commonly occurs during bronchial asthma and eosinophil granule proteins are discharged onto damaged bronchial epithelium. Analyses of 10 patients with fatal asthma showed striking eosinophil participation in eight, whereas two patients showed marked epithelial desquamation in the virtual absence of eosinophils. These results point to the possibility that a pathologic heterogeneity exists in fatal bronchial asthma, with most, but not all, patients showing evidence of eosinophil participation.

Exercise-induced "asthma" as a presentation of bronchial carcinoid.

Exercise-induced wheezing developed in a previously healthy 14-year-old boy. Chest radiographs revealed hyperlucency of the left lung. Bronchial tomography and bronchoscopy revealed a mass in the left mainstem bronchus, identified as a carcinoid tumor after surgical excision. The patient is now asymptomatic. Exercise-induced wheezing as the sole manifestation of this tumor has not been previously reported.

The eosinophil and the pathophysiology of asthma.

Eosinophilia of lung and blood associated with injury to the mucociliary escalator and excessive shedding of bronchial epithelium are hallmarks of both allergic and nonallergic asthma. In vitro, the eosinophil granule major basic protein (MBP) is toxic to helminths and to mammalian cells, including human respiratory epithelium. The MBP-mediated damage to the respiratory epithelium consists of desquamation and frank destruction of ciliated cells. Increased sputum MBP concentration is a good marker for asthma, and patients treated for acute asthma have high levels of MBP in their sputa, which decrease after treatment. Peak sputum MBP levels approximate concentrations toxic to respiratory epithelium in vitro. In the lungs of patients who had died of asthma, MBP has been localized outside of the eosinophil in association with damage to the epithelium. Overall, these and other findings suggest the hypothesis that the eosinophil mediates damage to the respiratory epithelium and is the prime effector cell in the pathophysiology of asthma.

Eosinophilic panniculitis: a clinicopathologic study.

Study of 18 patients with biopsy diagnoses of eosinophilic panniculitis revealed diverse patterns of systemic disease, including Wells' syndrome, vasculitis, atopy, and erythema nodosum as well as localized panniculitis. Significant associated diseases included psychiatric illness, 6 (drug dependency, 4); atopy, 5 (asthma, 3); malignancies, 5; immune complex vasculitis, 4; thyroid disease, 2; Wells' eosinophilic cellulitis, 2; glomerulonephritis and sarcoidosis, 1 each. The skin lesions varied from urticarial papules and plaques to purpura, pustules, and ulcerative lesions but always included a nodular subcutaneous component, frequently as a presenting complaint. Eosinophilic panniculitis is a non-specific finding that can signify localized disease, such as an insect bite or injection lipophagic granuloma in a drug-dependent patient, or systemic lymphoma or immune reactive disease. Eosinophilic panniculitis in erythema nodosum is perhaps its most confusing presentation.

Bronchial challenge with formaldehyde gas: lack of bronchoconstriction in 13 patients suspected of having formaldehyde-induced asthma.

We studied 13 selected patients with symptoms suggestive of asthma who suspected exposure to formaldehyde as a cause. These patients had a history of exposure to formaldehyde gas which either coincided with the onset of or aggravated their symptoms of asthma. The levels of exposure at their homes or at work ranged from 0.1 to 1.2 parts per million (ppm) of formaldehyde gas. The patients were tested with bronchial challenges of 0.1-, 1-, and 3-ppm concentrations of formaldehyde gas and randomly interspersed room-air placebos. The formaldehyde gas or placebo was delivered via a Dynacalibrator . The period of exposure to formaldehyde gas or placebo with each challenge was 20 minutes. Pulmonary function was measured before and for 24 hours after each bronchial challenge. No patient had a significantly greater decrease in the forced expiratory volume in 1 second after exposure to formaldehyde than after exposure to air. In no case were we able to substantiate that exposure to formaldehyde gas (3 ppm or less) was indeed causing or aggravating the asthmatic symptoms.

[Radioimmunologic assay of the major basic protein of eosinophilic granules in sputum. A diagnostic contribution in asthma]. / Dosage radioimmunologique de la protéine majeure basique du granule éosinophile dans l'expectoration. Un appoint diagnostique dans l'asthme.

The concentration of major basic protein (MBP) of the eosinophilic granules in bronchial expectoration (Sputum) were measured by radioimmunoassay in 204 subjects suffering from various illnesses of both the respiratory tract and other systems. 31 of these subjects were later revealed to have asthma and all had very high sputum MBP levels. The MBP level was much greater in asthmatics than any other respiratory or non-respiratory ailment and in a statistically significant fashion (p less than 0.001). 25 other subjects who were in hospital for exacerbations of asthma were subsequently tested; their MBP concentrations were higher still. During the course of their hospital stay the sputum MBP levels fell significantly following treatment with steroids and broncho-dilators. The measurement of the MBP level would seem useful in those situations where the diagnosis of asthma is not evident from the history and may help in predicting the effectiveness of steroid treatment.

Elevated levels of the eosinophil granule major basic protein in the sputum of patients with bronchial asthma.

The eosinophil granule major basic protein (MBP) is toxic to parasites and mammalian cells. Because eosinophilia is characteristic of asthma, we tested the effect of MBP on bronchi and assayed sputa for this protein. We found that MBP damaged bronchial epithelium in vitro and produced changes that mimicked those in asthma. Radioimmunoassay of sputa from 100 consecutive patients with respiratory diseases revealed MBP levels above 0.1 mug/ml in 13 patients, and 11 of these had asthma. In 15 patient hospitalized for asthma, MBP levels of sputum were markedly elevated. Treatment with bronchodilators and glucocorticoids caused an increase peak expiratory flow rate, a reduction in blood eosinophils, and a decrease in the serum and sputum levels of MBP. The results indicate that eosinophil granule constituents are released into the bronchi in asthma and that measurement of sputum MBP may be useful in identifying asthma. The possibility that the eosinophil damages bronchial epithelium in asthma is discussed.