Removal of bronchoalveolar cells augments the late eosinophilic response to segmental allergen challenge.

BACKGROUND: In patients with quiescent asthma, macrophages are the most prevalent cells recovered by bronchoalveolar lavage (BAL). Through activation via their FcepsilonRII receptors or by acting as antigen-presenting cells, macrophages could, in theory, promote the late airway response to allergen. OBJECTIVE: In order to investigate the importance of macrophages and other airway luminal cells in inducing the late airway response, a novel washout experiment was designed. METHODS: Five patients with ragweed-allergic asthma underwent bronchoscopy and segmental bronchial challenge with either normal saline or short ragweed extract in two segments of one lung. In a third segment of the opposite lung, 12 successive BALs (25 mL each) were performed, followed by challenge with an identical dose of short ragweed (washed-challenged segment). After 24 h, all three challenged segments underwent BAL. RESULTS: Initially, in the washed-challenged segment, over 80% (mean 80.4%, range 68-88%) of the recoverable airway dwelling cells were removed. Unexpectedly, 24 h later these same washed-challenged segments contained more eosinophils in the BAL than the challenged segments from the opposite lung (P = 0.033). CONCLUSIONS: Removing the majority of airway luminal cells followed by allergen bronchoprovocation increased the number of eosinophils recovered 24 h after challenge. Our results suggest that in quiescent allergic asthma, the airway luminal cells are protective and attenuate the late eosinophilic response to allergen challenge.

How to manage difficult asthma cases. An action plan for physicians and patients.

Patients with difficult-to-manage asthma represent one of the greatest challenges in primary care practice. Because these patients are at risk for life-threatening attacks, close monitoring is essential to ensure compliance and to control attacks or medication side effects. In this article, Dr Hunt discusses the many aspects of management, including assessment, identification of triggers, treatment planning, and patient and family education. An "action plan" that outlines the management program is described.

Prevalence, pathophysiology, and treatment of patients with asthma and gastroesophageal reflux disease.

About one third of the US adult population experiences symptoms of gastroesophageal reflux on a monthly basis. Asthma is present in about 5% of the same population. This article reviews and summarizes the literature in the following areas: (1) prevalence of gastroesophageal reflux disease (GERD) in asthmatic patients based on clinical symptoms, endoscopic esophagitis, and 24-hour ambulatory esophageal pH recordings; (2) proposed pathophysiologic mechanisms linking the 2 diseases; and (3) medical and surgical treatment trial results of antireflux therapy for asthmatic patients. Asthmatic patients appear to have an increased prevalence of GERD symptoms and 24-hour esophageal acid exposure. The clinical management of these patients remains controversial. Common management approaches to GERD in asthmatic patients include medical therapy with a proton pump inhibitor and/or antireflux surgery, which improve asthma symptoms in many patients but minimally affect pulmonary function.

Latex allergy: a primary care primer.

Latex allergy has become an epidemic among healthcare workers. Other individuals who are frequently exposed to latex gloves or products containing latex have experienced latex hypersensitivity, as well. Identification of patients who have latex allergy is crucial to physicians in order to formulate a management plan. This article includes discussion of the basic background on latex preparation, hypersensitivity, occupational risks, and management of affected patients.

Nebulized lidocaine in the treatment of severe asthma in children: a pilot study.

BACKGROUND: Glucocorticoids have been used to treat asthma since the 1950s; however, their adverse systemic effects have limited their duration of use and dosage. Unfortunately, many patients with severe asthma often require oral glucocorticoids in addition to inhaled glucocorticoids. Alternatives to glucocorticoids have been sought with mixed success. Recently, lidocaine has been added to the list of potent glucocorticoid sparing agents for the treatment of severe asthma. OBJECTIVE: We report the first group of pediatric patients with severe asthma treated with nebulized lidocaine. METHODS: The study was performed in an open manner with 6 severely asthmatic patients followed in the Pediatric Allergy and Immunology Section, Mayo Clinic. The only intervention was the institution of nebulized lidocaine (0.8 mg/kg/dose to 2.5 mg/kg/dose t.i.d to q.i.d). The average daily steroid requirement was followed during the administration of the nebulized lidocaine. RESULTS: During a mean of 11.2 months of therapy (range 7 to 16 months) 5 of the 6 patients completely discontinued their oral glucocorticoids within an average time of 3.4 months (range 1 to 7 months). CONCLUSIONS: After further study, lidocaine may prove to be the first non-toxic, steroid alternative to patients with severe steroid-dependent asthma.

Safety considerations in treating concomitant diseases in patients with asthma.

The treatment for asthma usually involves a combination of drugs used for bronchodilation and to treat underlying airway inflammation. When asthma is severe, the regimen used to treat asthma can become quite complicated, often using as many as 3 or 4 separate pharmacological agents. As patients with asthma get older, their medication regimen can become even more complex with the development of numerous other age-related diseases requiring their own list of medications. Diseases of the joints, diseases of the eye, cardiovascular disease, neurological disease and urological problems represent the most common conditions that patients develop, at times needing medications which might interfere with asthma management. Many of these diseases require the use of nonsteroidal anti-inflammatory agents, well known to provoke wheezing in patients with intrinsic asthma, and diseases of the eye and cardiovascular system frequently require use of beta-blockers which can cause or exacerbate asthma. Managing patients with asthma who have other diseases requires constant supervision of their medication usage and careful and cautious review of the entire list of medications at each presentation.

Lidocaine and its analogues inhibit IL-5-mediated survival and activation of human eosinophils.

Eosinophils and cytokines active on eosinophils, especially IL-5, are believed to be critically involved in chronic allergic diseases. IL-5 activates eosinophils and enhances their survival in vitro by delaying apoptosis. In this study, we found that lidocaine and six analogues blunt responses of eosinophils to IL-5. Lidocaine and its derivatives inhibit IL-5-mediated eosinophil survival in a concentration-dependent manner (IC50 = 110 microM for 30 pg/ml IL-5). At suboptimal lidocaine concentrations, the eosinophil survival response to IL-5 shifts and more IL-5 is required to maintain survival. The inhibitory effect requires at least 24-h exposure of eosinophils to lidocaine, and the protein kinase C activator, PMA, completely reverses the inhibition. A multiparameter flow-cytometric analysis shows that lidocaine hastens the apoptosis of eosinophils normally delayed by IL-5. Lidocaine does not affect IL-5R expression or IL-5-induced protein tyrosine phosphorylation. Lidocaine also inhibits eosinophil survival mediated by IL-3 or granulocyte-macrophage CSF, although less potently than that mediated by IL-5. Furthermore, lidocaine inhibits eosinophil superoxide production stimulated by IL-5, granulocyte-macrophage CSF, or IL-3, but not that stimulated by platelet-activating factor, immobilized IgG, or PMA. Lidocaine and its derivatives show novel immunomodulatory properties and are able to blunt eosinophil responses to cytokines in addition to their local anesthetic or antiarrhythmic properties. Thus, lidocaine and its derivatives may represent a new class of therapeutic agents to treat patients with allergic diseases.

A medical-center-wide, multidisciplinary approach to the problem of natural rubber latex allergy.

Latex is a common cause of occupational allergy in health care workers; latex-sensitized patients are at increased risk of allergic reactions in medical environments. Skin test reagents and latex-specific immunoglobulin E immunoassays were established for diagnosis of latex allergy. Inhibition immunoassays were developed for measuring latex aeroallergens and latex allergens in rubber products. A registry of latex-sensitive employees was established. High-allergen gloves were removed from the medical center inventory; latex aeroallergen levels subsequently declined. Despite an increasing number of gloves used annually, expenditures for gloves in 1994 were lower than in previous years. Latex-sensitive individuals can be identified using skin tests or immunoassays. Latex aeroallergen levels in medical environments can be reduced substantially at lower cost by using powder-free rubber gloves with lower allergen content.

Eosinophil recruitment is associated with IL-5, but not with RANTES, twenty-four hours after allergen challenge.

Several lines of evidence suggest that the chemokine RANTES may play a role in eosinophilia observed during allergic inflammation. To test this hypothesis, six patients with allergic asthma were studied. After performing bronchoalveolar lavage in a lung segment (baseline), segmental bronchoprovocation was performed with saline solution in another segment and with ragweed in a third segment. Bronchoalveolar lavage was performed 24 hours later in the saline-challenged (sham) and ragweed-challenged lung segments. The bronchoalveolar lavage fluids from the baseline, sham, and ragweed segments were analyzed for cell counts and for the levels of IL-5, RANTES, and eosinophil-derived neurotoxin. IL-5 levels were elevated in the ragweed (984 +/- 588 pg/ml) compared with sham segments (2.8 +/- 0.2 pg/ml, p = 0.02). Likewise, RANTES levels were elevated in the ragweed (12.93 +/- 3.4 pg/ml) compared with the sham segments (3.05 +/- 1.19 pg/ml, p = 0.006). The IL-5 levels correlated with both eosinophil numbers (r = 0.90, p < 0.02) and eosinophil-derived neurotoxin levels (r = 0.89, p < 0.02). In contrast, RANTES levels did not correlate with either eosinophil numbers or eosinophil-derived neurotoxin levels. These results indicate that although both IL-5 and RANTES are elevated 24 hours after allergen challenge, only IL-5 correlates with eosinophil recruitment and degranulation.

Cytokine production at the site of disease in chronic eosinophilic pneumonitis.

Chronic eosinophilic pneumonitis (CEP) is characterized by longstanding respiratory symptoms accompanied by a massive pulmonary eosinophil infiltration. We hypothesized that cytokine(s) produced in the disease sites are implicated in the pathophysiology of CEP. We studied peripheral blood and bronchoalveolar lavage fluids (BALF) obtained from two lung segments of a patient with CEP. Seventy times more eosinophils were found in the BALF from an involved lung segment (showing patchy opacification on a chest roentgenogram) than from an uninvolved segment. The eosinophil-active cytokines interleukin-5 (IL-5), IL-6, and IL-10 were strikingly elevated in the BALF from the involved lung segment, whereas no or minimal levels of these cytokines were detectable in the BALF from the uninvolved segment or serum, respectively. Leukocytes in the involved lung segment, but not those in peripheral blood, expressed messenger ribonucleic acid (mRNA) for IL-5, IL-6, and IL-10. In contrast, IL-2, IL-3, IL-4, interferon-gamma (IFN-gamma), granulocyte-macrophage colony-stimulating factor (GM-CSF), and tumor necrosis factor-alpha (TNF-alpha) were not detected in any sample. These findings suggest that increased production of several cytokines, such as IL-5, IL-6, and IL-10, in the involved lung segment, but not in the uninvolved lung segment or peripheral blood, is a critical pathophysiologic feature of CEP.

Effect of nebulized lidocaine on severe glucocorticoid-dependent asthma.

OBJECTIVE: To determine whether nebulized lidocaine is a useful therapy in patients with severe glucocorticoid-dependent asthma. DESIGN: We prospectively conducted an open study of the effects of administration of nebulized lidocaine four times daily in 20 patients with asthma who had side effects of exogenous hypercortisolism. MATERIAL AND METHODS: The 18 women and 2 men, who were 19 to 71 years of age, all had severe asthma that necessitated both topical and systemic administration of glucocorticoids to control symptoms of airflow obstruction. Treatment consisted of nebulized lidocaine, 40 to 160 mg four times daily. Initially, all topical and systemic glucocorticoid regimens were maintained; if peak flow rates remained stable and symptoms of asthma were well controlled, orally administered glucocorticoid regimens were slowly reduced. RESULTS: Thirteen patients were able to discontinue oral use of glucocorticoids entirely, despite prolonged glucocorticoid dependence (mean 6.6 years and median 3 years for the 20 patients); 4 achieved reduction in their daily glucocorticoid requirement while maintaining control of symptoms of asthma (duration of glucocorticoid dependence for responders, mean 6.2 years and median 3.2 years). Three patients had no apparent response, as determined by their continued severe asthma symptoms and inability to reduce oral glucocorticoid requirements. CONCLUSION: These results suggest that nebulized lidocaine is a useful therapy for chronic asthma, allowing reduction or elimination of oral glucocorticoid therapy.

Allergen challenge in asthma: association of eosinophils and lymphocytes with interleukin-5.

To test whether eosinophil recruitment after pulmonary allergen challenge is associated with interleukin (IL)-5 in patients with asthma, we performed segmental bronchoprovocation (SBP) with saline, and with low and high dosages of ragweed extract in six patients with allergic asthma. Bronchoalveolar lavage (BAL) of the challenged segments was performed 5 min after challenge (immediate BAL fluid) and repeated 24 h later (late BAL fluid). Allergen challenge resulted in recruitment of eosinophils, and increased levels of eosinophil-active cytokines. A bioassay showed the predominant eosinophil-active cytokine in the late BAL fluids to be IL-5. Analysis of the late BAL fluids revealed that IL-5 levels correlated with the numbers of eosinophils and lymphocytes. This study provides evidence that IL-5 is a critical cytokine associated with eosinophil and lymphocyte recruitment into the airways of patients with asthma following exposure to allergen.

An epidemic of occupational allergy to latex involving health care workers.

IgE-mediated sensitivity to natural rubber latex is being recognized more frequently among health care workers. Between January 1990 and June 1993, we evaluated 342 consecutive Mayo Medical Center employees who reported symptoms suggestive of latex allergy. All were interviewed and underwent puncture skin testing with extracts of rubber gloves. In some cases, latex-specific IgE antibodies were measured by immunoassay. One hundred four of the 342 employees evaluated (30%) were latex-allergic. Risk factors for sensitization included frequent use of disposable gloves, presence of prior atopic disease, and prior or current hand dermatitis. The peak onset of symptoms occurred in late 1989 and early 1990 and did not correlate with a peak in glove usage at our medical center, which continued to rise. Most sensitized employees (78%) reported contact urticaria from rubber gloves, and over two thirds also experienced allergic rhinitis, conjunctivitis, or asthma when working in areas where large numbers of gloves were being used. Sixteen episodes of rubber-induced anaphylaxis were documented in 12 employees; six episodes occurred after latex skin testing and were easily reversed with appropriate therapy. Our findings substantiate a local epidemic of latex allergy among medical center employees. Epidemiologic studies are needed to assess the effects of various interventions to reduce occupational exposure to latex allergens. Although prick skin testing with concentrated latex glove extracts presents some risk of systemic reaction, pending availability of commercial diagnostic extracts, such testing is generally safe when performed by skilled laboratory personnel. Skin testing is warranted to investigate health care workers suspected of being latex-sensitive.

Anaphylaxis induced by the carboxymethylcellulose component of injectable triamcinolone acetonide suspension (Kenalog).

BACKGROUND: Allergic reactions to various corticosteroids are rare but have been reported previously. OBJECTIVE: We wished to determine the etiology of an anaphylactic reaction in a patient who had received intracutaneous Kenalog (triamcinolone acetonide). METHODS: Skin testing and serologic testing for allergen-specific IgE antibodies was performed for triamcinolone acetonide, its individual components, and three other corticosteroid preparations in both the patient and six other nonallergic persons. RESULTS: The patient had positive skin tests to only the carboxymethylcellulose component of triamcinolone acetonide. He had negative skin test reactions to three other steroid preparations which did not contain carboxymethylcellulose. Specific IgE antibodies to carboxymethylcellulose were also elevated by immunoassay and immunoblotting. Control patients had negative skin tests to triamcinolone acetonide, its components, and three other corticosteroid preparations, and their sera lacked significant specific IgE antibodies to these materials. CONCLUSIONS: Our results indicate that the triamcinolone acetonide component responsible for the patient's reaction was the suspending agent carboxymethylcellulose. We urge physicians to consider component testing when patients experience allergic-type reactions to drugs.

Quantification of occupational latex aeroallergens in a medical center.

To determine the quantity, variability, and mean aerodynamic diameter of latex aeroallergens in a large medical center, we collected air samples from work sites by using area and personal breathing zone air samplers, and we measured latex allergens by an inhibition assay with IgE antibodies from latex-sensitive individuals. Latex aeroallergen concentrations in 11 areas where powdered latex gloves were frequently used ranged from 13 to 208 ng/m3, and in areas where powdered latex gloves were never or seldom used, concentrations ranged from 0.3 to 1.8 ng/m3. Installation and use of a laminar flow glove changing station in one work area did not reduce latex aeroallergen levels. Large quantities of allergen were recovered from used laboratory coats and anesthesia scrub suits and from laboratory surfaces. Latex allergen concentrations in personal breathing zone samplers worn by health care workers in areas where powdered gloves were frequently used ranged from 8 to 974 ng/m3. Exposure likely occurs when gloves are changed and as a result of resuspension from reservoirs of powder in the room and clothing. Latex allergens were found in all particle sizes but were predominant in particles greater than 7 microns in mass median aerodynamic diameter. Results of electrophoretic immunoblotting showed that the aeroallergens are primarily the higher molecular mass components of the latex glove proteins. Measures to control exposure can be monitored by both area and personal air sampling with this immunochemical approach. Use of gloves with low allergen content or powder-free gloves appears to be more effective than use of a laminar flow glove changing station in reducing aeroallergen levels.

Severe asthma complicated by bilateral diaphragmatic paralysis attributed to Parsonage-Turner syndrome.

Progressive dyspnea that developed in a 52-year-old woman with a lifelong history of asthma did not respond to high-dose orally administered glucocorticoids. Initially, a diagnosis of allergic bronchopulmonary aspergillosis or hypersensitivity pneumonia was suggested as the cause of the worsening dyspnea. Pulmonary function tests demonstrated severe airway obstruction; substantial improvement was noted after bronchodilator therapy. Maximal inspiratory pressure was decreased, and the diffusing capacity of the lungs was abnormal. Computed tomography of the chest showed no parenchymal or mediastinal abnormalities. During a sniff test, fluoroscopy of her diaphragm disclosed paradoxical motion of both hemidiaphragms during inspiration, consistent with bilateral hemidiaphragmatic paralysis. Parsonage-Turner syndrome was diagnosed. The dose of glucocorticoids was tapered. Follow-up of the patient by telephone contact in March 1994 (9 months after her initial examination at our clinic) revealed that the dyspnea was still severe.

Endotoxin contamination causes neutrophilia following pulmonary allergen challenge.

Segmental bronchoprovocation (SBP) with allergen was used in an attempt to study eosinophils recruited to the airway 24 h after challenge. Unexpectedly, in the first four patients, neutrophils (rather than eosinophils) were recruited in the bronchoalveolar lavage (BAL) fluids, and we hypothesized that the allergen extracts were contaminated with endotoxin. The extracts used for challenge in the first four patients tested positive for bacterial endotoxin in a limulus amebocyte lysate assay. Rechallenge of one patient from the first group with a comparable dose of an endotoxin-free extract and SBP with endotoxin-free extract in five additional patients resulted in preferential recruitment of eosinophils rather than neutrophils. The number of neutrophils recovered from the challenged segments in the patients challenged with endotoxin-free extract was significantly less than that observed in the first four patients. Taken together, these observations suggest that neutrophil recruitment in the 24-h BAL fluids from the first four patients was probably due to endotoxin contamination of the allergen extract. We caution investigators that endotoxin contamination of allergen extract may alter the cellular inflammation during the late airway response following allergen challenge.

Extractable latex allergens and proteins in disposable medical gloves and other rubber products.

BACKGROUND: IgE-mediated sensitization to rubber proteins is being reported with increasing frequency in health care workers. To explore the relative importance of various sources of allergen exposure, we measured the total rubber allergen and protein levels in extracts of disposable rubber gloves and compared the allergen levels with those in extracts of other medical and consumer rubber products. METHODS: Rubber allergens were measured by inhibition immunoassay with a rubber glove extract as the solid-phase allergen and pooled plasma from five rubber-sensitized health care workers as the IgE antibody source. Proteins were measured by Ninhydrin assay. RESULTS: Among 71 lots of gloves tested, the extractable allergen and protein levels were significantly correlated and were appreciably higher in powdered gloves than in powder-free gloves. Allergen levels varied 3000-fold among gloves from different manufacturers and were higher in examination gloves than in surgical or chemotherapy gloves. Measurable allergen was found in 11 of 24 lots of "hypoallergenic" gloves tested. Allergen levels in toy balloons were comparable to those in powdered gloves; much lower allergen levels were measured in condoms and anesthesia rebreathing bags. CONCLUSIONS: The allergen content of disposable rubber gloves varies widely and is higher in powdered gloves than in powder-free gloves and higher in examination gloves than in surgical gloves. Hypoallergenic gloves may contain substantial amounts of IgE-binding proteins. Gloves and toy balloons appear to be more important sources of rubber allergens than the other rubber products tested.