David Sloane, M.D.
Brigham and Women’s Hospital
850 Boylston Street, Suite 540
Chestnut Hill, MA 02467
The following is a list of recent publications for which this Partners Asthma Center physician has been cited as an author in PubMed databases. Study abstracts have been provided for your convenience.
Lee, C. W. and A. L. Sheffer (2003). "Primary acquired cold urticaria." Allergy Asthma Proc 24(1): 9-12.
Primary acquired cold urticaria (ACU) is the most common type of cold urticaria characterized by rapid onset of pruritic hives, swelling, and possible severe systemic reactions including hypotension and shock after cold exposure. Primary ACU is diagnosed by history of such symptoms, a positive immediate cold-contact stimulation test, and negative laboratory evaluation for underlying systemic disorders. Clinicians should be aware that patients with ACU may be susceptible to life-threatening systemic reactions especially during aquatic activities and that proper patient education is extremely important. This article reviews the clinical presentation, pathogenesis, diagnosis, and management of primary ACU.
Castells, M. C., R. F. Horan, et al. (2003). "Exercise-induced Anaphylaxis." Curr Allergy Asthma Rep 3(1): 15-21.
Exercise-induced anaphylaxis has been recognized with increasing frequency since its original description in 1980. Recent studies suggest food-induced reactions may occur frequently in this syndrome, which is a mast cell-dependent phenomenon. In this article, the clinical manifestations of exercise-induced anaphylaxis are reviewed, and food-related factors contributing to the disorder are considered.
Hsieh, F. H. and A. L. Sheffer (2002). "Episodic swelling in a pregnant woman from Bangladesh: evaluation and management of angioedema in pregnancy." Allergy Asthma Proc 23(2): 157-61.
Deficiencies in the C1 inhibitor protein are central to the pathogenesis of acquired and hereditary angioedema syndromes. Here, we present a case of a patient who developed recurrent episodes of angioedema during pregnancy. We discuss the evaluation of patients presenting with angioedema, describe the mechanisms by which deficiencies in C1 inhibitor contribute to the development of angioedema, and focus on the natural history and clinical management of the pregnant patient with angioedema.
Shadick, N. A., M. H. Liang, et al. (1999). "The natural history of exercise-induced anaphylaxis: survey results from a 10-year follow-up study." J Allergy Clin Immunol 104(1): 123-7.
BACKGROUND: Exercise-induced anaphylaxis (EIA) is a unique physical allergy that is triggered by exertion, the clinical spectrum and modifying factors of which have been previously studied. At the time of initial description, it was postulated that other factors contributed to this disorder. OBJECTIVE: We sought to determine the clinical course and potential modifying factors in EIA. METHODS: In 1993, we conducted a cross-sectional analysis of 671 individuals with exercise-associated symptoms for more than a decade using a validated 75-item questionnaire. Subjects met criteria for EIA if they had anaphylactic symptoms, including hypotension or upper airway obstruction, urticaria, or angioedema with physical exertion but without a passive increase in core body temperature. RESULTS: Of 365 (54%) questionnaire respondents, 279 (87%) met criteria for EIA (199 females and 80 males). At the time of study entry, subjects with EIA (mean age, 37.5 years; range, 13 to 77 years) had an average of 10.6 years of symptoms, which were most frequently triggered by aerobic activities such as jogging or brisk walking (78% and 42%, respectively). On average, subjects reported that the frequency of attacks had decreased (47% of subjects) or stabilized (46% of subjects) since onset. One hundred (41%) subjects reported being completely free of attacks in the past year. Subjects reduced their attacks by avoiding exercise during extremely hot or cold weather (44%), avoiding ingestion of certain foods before exercise (37%), and restricting exercise during their allergy season (36%) or humid weather (33%). The most common pharmacologic agents used to manage symptoms were H1 antagonists (56%) and/or epinephrine (31%). However, 28% used no treatment at all. CONCLUSION: EIA is an episodic condition in which the frequency of attacks tends to stabilize or decrease over time. Improvement appears to result from individual modification of exercise and avoidance of known environmental and ingestible precipitants.
DuBuske, L., A. Babahkin, et al. (1999). "Clinical assessment of latex allergy among hospital health care providers." Int Arch Allergy Immunol 118(2-4): 253-4.
Castells, M. C., R. F. Horan, et al. (1999). "Exercise-induced anaphylaxis (EIA)." Clin Rev Allergy Immunol 17(4): 413-24.
EIA is a unique physical allergy with increasing incidence as the exercising population increases. Clinical features are indistinguishable from IgE-mediated anaphylaxis in which the offending allergens are known (food or insect stings). Recognition of the association with exercise is crucial. A wide variety of exercises can induce the symptoms, including brisk walking. Symptoms may not be always reproduced by the same amount and type of exercise in a given patient suggesting that associated factors are also needed. Food is an associated factor recognized with increasing frequency, and in the last 5 yr, wheat has been the most frequently associated. Avoidance of the known associated factors, such as food or nonsteroidals, induces a long-lasting remission of EIA. Treatment does not differ from that of anaphylaxis of any other cause. General recommendations for patients with EIA include avoidance of exercise 4-6 h after eating, avoidance of aspirin and nonsteroidals before exercise, and avoidance of all associated conditions known to trigger attacks in each particular patient. Discontinuation of exercise at the earliest warning symptom is critical.
Partridge, M. R., A. A. Woodcock, et al. (1998). "Chlorofluorocarbon-free inhalers: are we ready for the change?" Eur Respir J 11(5): 1006-8.
Chlorofluorocarbons (CFCs) damage stratospheric ozone permitting enhanced levels of ultraviolet B radiation to reach the Earth's surface. As a result, production of CFCs is now banned under the Montreal Protocol with the exception of their temporary continued use in pressurized metered dose inhalers used to treat those with airway disorders. Replacement propellants have now been identified and shown to be safe and a major exercise is under way to reformulate the commonly used aerosolized medicines with the new propellants. The new products are now undergoing clinical trials and the first reformulated beta-agonist and corticosteroid inhalers have reached the marketplace. The majority of the current products will have been changed over to the new types over the next 3 yrs, and each country will adapt a transition strategy to oversee this process. The politicians, the environmentalists, the pharmaceutical industry and the regulatory authorities have fulfilled their part in this changeover, and respiratory interested health professionals now need to address what this means for them and their patients so that there may be a seamless transition for the millions of people who use inhaled medicines worldwide.
Sheffer, A. L., C. LaForce, et al. (1996). "Fluticasone propionate aerosol: efficacy in patients with mild to moderate asthma. Fluticasone Propionate Asthma Study Group." J Fam Pract 42(4): 369-75.
BACKGROUND: This double-blind, randomized, parallel-group, placebo-controlled study investigated the efficacy and tolerability of fluticasone propionate aerosol (25, 50, or 100 mg bid for 12 weeks) administered as primary maintenance therapy to patients whose mild to moderate asthma was inadequately controlled by as-needed use of an inhaled beta-agonist. RESULTS: At all clinic visits, fluticasone propionate compared with placebo was associated with significant (P<.05) improvement in pulmonary function indexed by forced expiratory volume in 1 second (FEV1) as well as fewer night awakenings and less use of rescue albuterol. Values for patient-measured morning peak expiratory flow rates (PEFR) were significantly (P<.05) higher and the use of rescue albuterol was significantly (P<.05) lower beginning 3 to 5 days after initiation of therapy in the groups treated with fluticasone propionate, compared with the placebo group. Maximal improvement in FEV1 was achieved during the second week of treatment and maintained throughout the course of therapy. Differences among the three fluticasone propionate dosing groups for these efficacy measures were not statistically significant. The incidence of adverse events was similar across groups. CONCLUSIONS: These data indicate that fluticasone propionate aerosol is an effective and well-tolerated treatment for asthma and significantly improves pulmonary function within days of initiation of treatment in patients whose asthma is inadequately controlled with as-needed beta-agonists.
Lanes, S. F., B. M. Birmann, et al. (1996). "Characterisation of asthma management in the Fallon Community Health Plan from 1988 to 1991." Pharmacoeconomics 10(4): 378-85.
In order to characterise asthma management in a managed care setting, we identified 10,301 patients who were diagnosed with asthma between 1 January 1988 and 31 December 1991 at a group model health maintenance organisation in central Massachusetts, US. We obtained for these patients automated utilisation files containing data on medications, hospitalisations, emergency room visits, office visits, and estimated costs of these services. The medication dispensed to the greatest proportion of patients was beta 2 agonists either by inhalation (56%) or orally (21%). Theophylline was dispensed to 23% of the patients. Maintenance therapy was inhaled anti-inflammatory medication was uncommon, as inhaled corticosteroids (17%) and sodium cromoglycate (cromolyn sodium) [8%] were dispensed to fewer patients than other asthma medications. Among patients who had been hospitalised in the previous year, 36% were presently receiving inhaled corticosteroids, and among patients who used at least one beta 2 agonist metered-dose inhaler per month, 49% were presently receiving inhaled corticosteroids. Economic analyses showed that only 8% of the patients had either a hospital admission or an emergency room visit, but hospital costs among these patients accounted for 25% of the total costs of asthma care. In addition, the top 10% most expensive patients accounted for 42% of the total cost of asthma care. We conclude that a substantial proportion of patients at increased risk of a severe attack, by virtue of having a recent hospitalisation, do not receive maintenance anti-inflammatory therapy, and that hospitalisations among a relatively small proportion of asthma patients contribute significantly to the cost of asthma care.
von Vigier, R., A. L. Sheffer, et al. (1995). "[Exercise-induced urticaria and anaphylaxis]." Dtsch Med Wochenschr 120(41): 1381-6.
AIM: The study was designed to characterise more exactly the complex syndrome of exercise-induced urticaria and anaphylaxis in order to obtain guidelines for their management. METHODS: 30 patients (18 women and 12 men with physical exercise-induced urticaria and anaphylaxis were investigated by questionnaire. The following items were of particular interest: age and sex; age at first manifestation; type, duration and intensity of the precipitating activity; type, duration and sequence of symptoms; prophylactic or therapeutic measures as cofactors. RESULTS: Initial symptoms occurred at an average age of 22 (7-50) years. Atopy was present in 70%. Jogging (60%), ball games (40%) and walking (27%) were the most frequent precipitating activities. On each occasion symptoms began a few minutes to hours after the start of the exercise. During a typical episode an average of eight symptoms were observed, most frequently affecting the skin (pruritus, angiooedema, erythema and urticaria), dyspnoea and gastrointestinal manifestations. Syncope occurred in nine patients: before they lost consciousness they noted at least two prodromal symptoms. The most common co-factors were humid-warm weather, severe sweating and eating certain foods shortly before the exercise. Prophylactic measures were quite different between individuals. CONCLUSION: Providing detailed information on how to avoid possible cofactors and manage prodromal symptoms should be at the forefront of looking after such patients, most of whom lead a rather active life.
Sheffer, A. L. (1995). "Management of the adult asthma patient." Allergy Proc 16(1): 1-4.
Lanes, S., B. Birmann, et al. (1995). "The characterization and evaluation of current asthma management." Int Arch Allergy Immunol 107(1-3): 398-9.
Bissler, J. J., M. Cicardi, et al. (1994). "A cluster of mutations within a short triplet repeat in the C1 inhibitor gene." Proc Natl Acad Sci U S A 91(20): 9622-5.
Mutations in the C1 inhibitor gene that result in low functional levels of C1 inhibitor protein cause hereditary angioneurotic edema. This disease is characterized by episodic edema leading to considerable morbidity and death. Among 60 unreported kindred with the disease, four patients were discovered to have mutations clustered within a 12-bp segment of exon 5 from nucleotide 8449 to nucleotide 8460. This short segment of DNA contains three direct repeats of the triplet CAA and is immediately preceded by a similar adenosine-rich sequence (CAAGAACAC). These triplet repeats make this region susceptible to mutation by a slipped mispairing mechanism. There are two other short triplet repeat elements in the coding region for this gene, but they have not become mutated in any kindred examined. This suggests that the apparent enhanced mutation rate in this region of exon 5 may be influenced by DNA structural characteristics.
Sheffer, A. L. (1993). "Allergen-specific immunotherapy: a role for T-cell anergy." Ann Allergy 71(3): 327-9.
T cells induce both a specific and nonspecific effect during an allergic immune response. Antigen receptors on T cells recognize peptide fragments of foreign proteins associated with products of the major histocompatibility complex expressed on the membranes of antigen-presenting cells. The recognition event triggers T-cell activation, secretion of lymphokines, and the isotypic switch from IgG to IgE synthesis, which is mediated by IL-4. This cascade results in sensitization of the mast cell, elaboration of various mediators, and local tissue inflammation. The interaction of the antigen-presenting cell and T cell holds implications for therapeutic modulation of the allergic response by the antigen. Animal studies have demonstrated that peptides containing T-cell epitopes can be used to control the immune response. Peptides delivered with adjuvants cause stimulation, whereas peptides delivered without adjuvants result in specific T-cell anergy or tolerance. Soluble peptide can be used to induce tolerance to the peptide and to protein molecules containing that peptide. The administration of peptides containing T-cell epitopes to allergic individuals may thereby represent an important component of the next generation of allergen-specific immunotherapy.
Sheffer, A. L. and V. S. Taggart (1993). "The National Asthma Education Program. Expert panel report guidelines for the diagnosis and management of asthma. National Heart, Lung, and Blood Institute." Med Care 31(3 Suppl): MS20-8.
The significant worldwide increase in asthma-related severity and mortality has evoked increasing concern from the medical community. To enhance early recognition and appropriate therapeutic intervention of asthma, the National Heart, Lung, and Blood Institute's National Asthma Education Program convened an expert panel to develop guidelines for the diagnosis and treatment of asthma. The guidelines discussed in this article emphasize that airway inflammation is a central characteristic of asthma. Appropriate therapy must include four components: the use of objective measures of lung function to assess the severity of asthma and to monitor the course of therapy, comprehensive pharmacologic therapy that includes medications to reverse and prevent the underlying airway inflammation and to relieve the bronchoconstriction, environmental control measures to avoid or control factors that precipitate asthma exacerbations, and patient education to foster a partnership among the patient, the patient's family, and the clinician.
Horan, R. F., L. C. Schneider, et al. (1992). "Allergic skin disorders and mastocytosis." Jama 268(20): 2858-68.
Horan, R. F., A. L. Sheffer, et al. (1992). "Physical allergies." Med Sci Sports Exerc 24(8): 845-8.
Allergic responses that occur as a result of exposure to physical stimuli are discussed. Most of these conditions are mediated by vasoactive substances, resulting in urticaria and/or angioedema. Susceptible individuals who engage in athletic activities may place themselves at particular risk for these problems. The physical allergies include cholinergic urticaria, exercise-induced anaphylaxis, cold urticaria, dermatographism, solar urticaria, and aquagenic urticaria. Management of these conditions includes patient education, selective avoidance, antihistamines, and, in some cases, induction of tolerance.
Briner, W. W., Jr. and A. L. Sheffer (1992). "Exercise-induced anaphylaxis." Med Sci Sports Exerc 24(8): 849-50.
Exercise-induced anaphylaxis (EIA) is a unique form of physical allergy that has been recognized with increasing frequency in recent years. The hallmarks of this syndrome are generalized pruritus with a flushing sensation, a feeling of warmth, and the development of urticaria in association with vigorous physical exertion. These symptoms tend to occur variably with exercise, but not with passive warming. Most patients report typical giant urticarial eruptions. Skin mast cells degranulate, and serum histamine increases during symptomatic attacks. Treatment is often problematic, but cessation of exercise with onset of symptoms and self-administration of epinephrine are recommended.
Sheffer, A. L. (1991). "The National Asthma Education Program attacks asthma." J Allergy Clin Immunol 87(2): 468-9.
Sheffer, A. L. and L. L. Samuels (1990). "Cetirizine: antiallergic therapy beyond traditional H1 antihistamines." J Allergy Clin Immunol 86(6 Pt 2): 1040-6.
For three decades, traditional H1 antihistamines have been used in the treatment of allergic diseases. They are effective in reducing histamine-related symptoms, but the use of such agents has been limited by sedation and anticholinergic side effects. These adverse effects are fewer with the recently introduced H1 antihistamines. One of these, cetirizine, a human metabolite of hydroxyzine, is characterized by its high selectivity for the H1 receptor site and its reliable and consistent inhibition of histamine-induced allergic reactions. It also blocks eosinophil infiltration to the site of allergen-induced cutaneous reactions. Cetirizine has proved effective in the treatment of seasonal and perennial allergic rhinitis and urticaria. It is excreted primarily by renal mechanisms. It is well tolerated by elderly patients. Cetirizine has a low rate of penetration of the blood-brain barrier, and it has minimal central nervous system impairment. Furthermore, it can be given once a day. Cetirizine's low incidence of sedation and anticholinergic side effects contribute to its high profile of safety. In this article the characteristics, pharmacology, pharmacokinetics, and mode of action of cetirizine are reviewed.
Owen, W. F., Jr., J. Petersen, et al. (1990). "Hypodense eosinophils and interleukin 5 activity in the blood of patients with the eosinophilia-myalgia syndrome." Proc Natl Acad Sci U S A 87(21): 8647-51.
The recent recognition of the eosinophilia-myalgia syndrome (EMS) associated with the ingestion of L-tryptophan prompted an analysis of the peripheral blood eosinophil phenotypes and of the serum eosinophil hematopoietins in this disorder. Five patients with an illness characterized by the abrupt onset of aching skeletal muscles, edema, thickening and induration of the skin, and marked blood eosinophilia associated with L-tryptophan ingestion provided eosinophils, serum, or both, for evaluation. Gradient sedimentation density analysis of the peripheral blood eosinophils from four of these patients revealed that 43 +/- 13% (mean +/- SEM) of the cells had converted to the abnormal (hypodense) sedimenting phenotype. When normodense eosinophils from the reference donors were cultured for 3 days in medium supplemented with increasing concentrations of serum from the patients with EMS, their viability increased in a dose-dependent manner to 45%, which was significantly augmented over the effect of normal serum. This eosinophil viability-sustaining activity was inhibited by 76 +/- 7% (mean +/- SEM; n = 3) by the addition of anti-interleukin 5 (IL-5) but not by neutralizing antibodies monospecific for either granulocyte/macrophage colony-stimulating factor (GM-CSF) or IL-3. IL-5, an eosinophilopoietic factor, converts normodense peripheral blood eosinophils in vitro to a hypodense sedimenting form with extended viability and augmented biologic responses to activating stimuli. Thus, the presence of IL-5 in the sera of patients with EMS may contribute to the development and maintenance of the eosinophilia and may regulate the conversion of the peripheral blood eosinophils to the hypodense phenotype with augmented pathobiologic potential.
Mirowski, G., K. F. Austen, et al. (1990). "Characterization of cellular dermal infiltrates in human cutaneous mastocytosis." Lab Invest 63(1): 52-62.
Biopsies of lesional and nonlesional skin from 14 patients with localized cutaneous or associated systemic mastocytosis were examined by ultrastructural and immunohistochemical techniques. Mast cells within lesions of the dermis were highly variable between patients with regard to cell number and extent of degranulation, although lesional sites consistently contained more mast cells than did nonlesional sites. Two mast cell patterns were identified based upon granule morphology. In biopsies from 8 patients, the majority of granules contained electron-dense amorphous zones; crystalline lattices; and indistinct, incomplete solid scrolls forming parallel lamellae. In biopsies from 6 patients, in addition to these granules, there were also granules composed of electron-dense amorphous zones, reticulated matrices, and/or distinct scrolls with lucent cores interrupted by dense spheres. The granule morphology for the first group (N = 8) was identical with that seen in the preponderant type of skin mast cell of 6 normal control subjects, whereas the granule morphology of the second group (N = 6) displayed an abnormal ultrastructural phenotype for skin that included granule types normally found not only in skin but also in intestinal lamina propria and lung. For individual patients, the patterns of granule ultrastructure were consistent between clinically nonlesional and lesional skin. A minority of cells in both patient groups appeared primitive ultrastructurally, exhibiting rudimentary, Golgi-associated progranules; monocyte-like morphologic characteristics; and mitotic activity. Moreover, when mast cells in lesional skin were screened for a limited panel of surface antigens, they displayed common patterns of reactivity (M718+, HLA-DR/DQ+, CD4+), and in a selected case, immunoelectron microscopy confirmed the presence of these antigens on mast cell plasma membranes. Dermal mast cells from normal donors (N = 6) lack these epitopes. These observations suggest that infiltrates in cutaneous mastocytosis may exhibit phenotypic characteristics not only of cutaneous mast cells, but in some patients also of mucosal mast cells. In either circumstance, the mast cells may display antigenic determinants common to monocyte/macrophages. Concordance of granule phenotype between lesional and clinically uninvolved skin of individual patients furthers the notion that even localized mastocytosis reflects covertly defective systemic mast cell homeostasis.
Horan, R. F., A. L. Sheffer, et al. (1990). "Cromolyn sodium in the management of systemic mastocytosis." J Allergy Clin Immunol 85(5): 852-5.
A multicenter, double-blind, placebo-controlled trial of the efficacy of oral cromolyn sodium (200 mg orally four times per day) was conducted in 11 patients with systemic mastocytosis who had been maintained with the drug on an individualized compassionate-need basis. Efficacy was measured by physician assessment of overall disease severity based on history and physical examination at specified intervals and by the average daily patient symptom diary scores for each of three mastocytosis-related symptoms that had previously appeared to be alleviated by the use of this drug. Efficacy variables were compared for a 4-week baseline period, during which patients received open-labeled cromolyn sodium, and at 4-week intervals during a 16-week period of random assignment to cromolyn sodium or placebo. Overall disease severity and symptoms recorded in patient diaries were graded on a scale of 0 (absent) to 5 (incapacitating). The average physician assessment of disease severity and symptom scores of the patients in the placebo-treated group increased significantly during the randomization phase relative to patients in the cromolyn sodium-treated group, reflecting an exacerbation of symptoms with drug withdrawal (p less than 0.05 and less than 0.028, respectively). When the symptom scores were analyzed separately for gastrointestinal manifestations of disease (diarrhea, abdominal pain, nausea, and vomiting), cromolyn sodium treatment was significantly beneficial relative to placebo (p less than 0.02), whereas the benefit for nongastrointestinal manifestations did not reach statistical significance.
Wade, J. P., M. H. Liang, et al. (1989). "Exercise-induced anaphylaxis: epidemiologic observations." Prog Clin Biol Res 297: 175-82.
Sheffer, A. L. and R. F. Horan (1989). "Current concepts of urticaria and angioedema." Allergy Proc 10(3): 237-41.
An operational classification based on immunoreactants provides insight to possible pathogenetic mechanisms participating in the genesis of urticaria and angioedema. Such an approach addresses the causes of urticaria and angioedema. Therapy can then be developed depending on the established mechanism-etiology. Unfortunately, in less than a third of the instances can a distinct etiology be established, but symptomatic therapy provides relief in a significant portion of such afflicted individuals.
Sheffer, A. L. (1989). "President's address. Allergy: at the academic/clinical interface." J Allergy Clin Immunol 83(1): 1-4.
Owen, W. F., M. E. Rothenberg, et al. (1989). "Interleukin 5 and phenotypically altered eosinophils in the blood of patients with the idiopathic hypereosinophilic syndrome." J Exp Med 170(1): 343-8.
We report that the hypodense eosinophil population in three patients with corticosteroid-unresponsive IHES was uniquely long lived ex vivo in the absence of exogenous cytokines. Serum or plasma from these patients conferred prolonged viability ex vivo to normodense eosinophils from reference donors and converted them to a functionally activated hypodense phenotype. In that antibody against IL-5 neutralized this activity in IHES serum, excessive quantities of this cytokine may account for the characteristic eosinophilia and long-lived, functionally augmented eosinophil phenotype in this disorder.
Cloud, M. L., G. C. Enas, et al. (1989). "A specific LTD4/LTE4-receptor antagonist improves pulmonary function in patients with mild, chronic asthma." Am Rev Respir Dis 140(5): 1336-9.
LY171883 is a new selective LTD4/LTE4-receptor antagonist. To evaluate the efficacy of LY171883, we studied 138 nonsmoking asthmatic patients, 18 to 65 yr old, in a double-blind, randomized block-design study. All patients were required to demonstrate a greater than or equal to 15% increase in FEV1 after inhaled bronchodilator use and were then randomly assigned to either LY171883 (600 mg) or placebo twice daily for 6 weeks. Assessment of efficacy was measured by inhaled metaproterenol use (mg/wk), symptoms, twice-daily peak expiratory flow, and weekly FEV1 measurements. LY171883-treated patients had improved FEV1 values upon completion of the treatment period compared with placebo recipients (p = 0.003). Metaproterenol use decreased in both groups, but treatment differences, though not statistically significant, favored LY171883 (p = 0.089). Of patients who used at least 23 mg/wk of metaproterenol (36 inhalations) at initiation of the study, those who received LY171883 used significantly less metaproterenol than those who received placebo (p = 0.007). LY171883 was well tolerated and reduced the need for a bronchodilator drug while improving pulmonary function. Results of this study support the hypothesis that leukotrienes LTD4 and/or LTE4 may be important in the pathogenesis of asthma in humans.
Sheffer, A. L. (1988). "Exercise-induced anaphylaxis." N Engl Reg Allergy Proc 9(3): 215-7.
Anaphylaxis, the most emergent manifestation of allergy, is best described by its clinical pathologic alterations. Sites of involvement include skin (urticaria), upper respiratory tract (laryngeal edema), lower respiratory tract (bronchospasm), and the cardiovascular system (severe hypotension). Ultrastructural analysis of skin biopsies obtained from individuals experiencing exercise-induced anaphylaxis prior to and immediately after exercise revealed changes indistinguishable from those observed following immunologic challenge of pulmonary mast cells. These alterations included enlargement of the mast cell granules, solubilization (discharge) of mast cell granule contents, merger of the granule membranes with adjacent granule membranes, as well as the mast cell membrane. The successful reversal of anaphylaxis requires the prompt recognition of symptoms and early institution of therapy for anaphylaxis. Patients suffering from exercise-induced anaphylaxis should avoid any foods, drinks, or pharmaceutical agents, particularly acetyl salicylic acid for four and preferably six hours prior to exercise.
Sheffer, A. L. (1988). "Anaphylaxis." J Allergy Clin Immunol 81(5 Pt 2): 1048-50.
Anaphylaxis, the most emergent manifestation of allergy, is best described by its clinicopathologic alterations. Sites of involvement include skin (urticaria), upper respiratory tract (laryngeal edema), lower respiratory tract (bronchospasm), and the cardiovascular system (severe hypotension). Ultrastructural analysis of skin biopsy specimens obtained from individuals experiencing exercise-induced anaphylaxis before and immediately after exercise revealed changes indistinguishable from those observed after immunologic challenge of pulmonary mast cells, and included enlargement of the mast cell granules, solubilization (discharge) of mast cell granule contents, and merger of the granule membranes with adjacent granule membranes and the mast cell membranes. Successful reversal of anaphylaxis requires prompt recognition of symptoms and early institution of therapy. Patients prone to exercise-induced anaphylaxis should avoid any foods, drinks, or pharmaceutical agents, particularly acetylsalicylic acid, for 4, and preferably 6, hours before exercise.
Sheffer, A. L., P. L. Lieberman, et al. (1988). "Measurement of circulating IgG and IgE food-immune complexes." J Allergy Clin Immunol 81(4): 758-60.
Sheffer, A. L., D. T. Fearon, et al. (1987). "Hereditary angioedema: a decade of management with stanozolol." J Allergy Clin Immunol 80(6): 855-60.
Thirty-seven patients with hereditary angioedema, who, without therapy, had attacks of cutaneous angioedema, gastrointestinal colic, and/or upper respiratory symptoms at a frequency and severity sufficient to prompt treatment with an attenuated androgen, have been evaluated for the incidence of side effects and biochemical toxicity during various schedules leading to the minimal effective dose. Stanozolol was administered in a 2 mg daily dose, initially, and after the symptoms and signs were adequately controlled for 2 months at this dose or at 1 mg per day, the drug was administered every other day at 4 mg. Patients who responded adequately to this schedule were administered 2 or 1 mg every other day, and then the interval between doses was gradually increased to 1 week, after which the agent was stopped. Eighteen patients experienced adverse reactions to stanozolol while the minimal effective dose was attained. In each instance the side effect subsided with a reduction in dosage. The most common adverse reactions were biochemical evidence of hepatic dysfunction and, to a lesser extent, hirsutism and menstrual irregularities. Although 21 of 27 patients in an initial study of the minimal effective dose were maintained with daily therapy in 1980, by 1986 this group and 10 additional patients were distributed so that three patients were receiving daily maintenance, 18 were receiving alternate-day maintenance, and 16 patients were receiving no maintenance therapy [corrected]. Thus, stanozolol appears to be a safe and effective agent for management of hereditary angioedema when patients are continually monitored to define the minimal effective dose or the feasibility of stopping the drug.
Sheffer, A. L. (1987). "Exercise-induced anaphylaxis." Acta Paediatr Jpn 29(5): 692-4.
Owen, W. F., Jr., R. J. Soberman, et al. (1987). "Synthesis and release of leukotriene C4 by human eosinophils." J Immunol 138(2): 532-8.
When human peripheral blood eosinophils isolated to 92.5% +/- 6.9 purity were stimulated with either the calcium ionophore A23187 or N-formyl-L-methionyl-L-leucyl-L-phenylalanine (FMLP), immunoreactive leukotriene C4 (LTC4) was initially localized intracellularly and was subsequently released to the external medium in kinetically distinguishable steps. Eosinophils were stimulated with 2.5 microM A23187 in the presence of 20 mM L-serine, a hypochlorous acid scavenger that prevents the oxidative metabolism of sulfidopeptide leukotrienes. Total production of immunoreactive LTC4, the sum of intra- and extracellular LTC4, was complete within 5 to 10 min. At 5, 10, and 30 min, 65.9% +/- 15.2, 42.3% +/- 24.3, and 5.5% +/- 3.9, respectively, of the total amount of LTC4 measured remained intracellular as detected after the media and cells were separated and the latter was extracted with methanol. The time course for the intracellular synthesis and extracellular release of immunoreactive LTC4 from eosinophils pretreated with 5 micrograms/ml cytochalasin B and stimulated with 0.5 microM FMLP was like that obtained with ionophore, although the total LTC4 production was only approximately 10%. The identity of the intracellular LTC4 was confirmed by elution with reverse-phase high pressure liquid chromatography followed by scanning UV spectroscopy, radioimmunoassay, and bioassay. Eosinophils that were stimulated with A23187 in the absence of L-serine metabolized newly synthesized LTC4 to 6-trans-LTB4 diastereoisomers and subclass-specific diastereoisomeric sulfoxides that were identified only in the extracellular medium. Thus the response of purified eosinophils to two different stimuli demonstrates a transient intracellular accumulation of biologically active LTC4, the distinct extracellular release, and the apparent limitation of oxidative metabolism to the extracellular location.
Murphy, G. F., K. F. Austen, et al. (1987). "Morphologically distinctive forms of cutaneous mast cell degranulation induced by cold and mechanical stimuli: an ultrastructural study." J Allergy Clin Immunol 80(4): 603-11.
To determine whether morphological differences in the response of cutaneous mast cells characterize clinically distinct forms of urticaria, we used ultrastructural techniques to examine skin biopsy specimens from three patients with cold-induced urticaria and four patients with dermographism. Biopsy specimens were obtained before application of the stimulus and at the time of lesion formation. Patients with cold-induced urticaria exhibited morphological alterations only after stimulus application consisting of enlargement and uniform disorganization of some, but not all, granules, fusion of the membranes of adjacent granules, fusion of granule membranes with mast cell membranes, and discharge of electron-lucent and disorganized granule contents into the extracellular space. Mast cells from patients with immediate as well as delayed dermographism exhibited alterations before and after stimulus application consisting of enlargement of most granules, nonuniform (zonal) disorganization or solubilization of granule contents, fusion of granule membranes with mast cell membranes, and extracellular discharge of granule contents. Small cytoplasmic vesicles containing disorganized granular material were associated with the degranulation process. Endothelial cells lining nearby postcapillary venules exhibited prominent perinuclear condensation of contractile microfilaments during degranulation in both groups. Both before and after application of the stimulus, the walls of the superficial dermal vessels of the patients with dermographism were thinner and contained less extracellular matrix material than vessel walls of the patients with cold-induced urticaria. The morphologically distinctive types of mast cell degranulation that characterize these two clinically separable urticarial disorders may indicate different pathogenic mechanisms of lesion formation.
Tinkelman, D. G., B. A. Moss, et al. (1985). "A multicenter trial of the prophylactic effect of ketotifen, theophylline, and placebo in atopic asthma." J Allergy Clin Immunol 76(3): 487-97.
Three hundred seventy-four patients with asthma were entered into a year-long, double-blind, double-placebo controlled study comparing the prophylactic effect of ketotifen (229 patients), theophylline (73 patients), and placebo (72 patients). The ketotifen group was larger to allow the accumulation of additional long-term safety data. The primary measure of therapeutic effect was a decrease in concomitant medication without a significant increase in symptomatology or a decrement in pulmonary functions. A patient daily diary was used to document symptoms (cough, shortness of breath, and wheeze) and concomitant medications taken during the 2-week baseline and the subsequent 12 monthly periods. After 2 months of study-drug therapy, the ketotifen patients had a greater decrease in both concomitant medication and symptomatology than either of the other groups. This delay in the onset of therapeutic activity has been observed in other studies and is characteristic of this compound. The principal side effect observed with ketotifen is initial sedation, which was found to be self-limiting and of little concern to the patient after the first month.
Sheffer, A. L., K. F. Austen, et al. (1985). "Acquired deficiency of the inhibitor of the first component of complement: report of five additional cases with commentary on the syndrome." J Allergy Clin Immunol 75(6): 640-6.
The association of late onset recurrent angioedema with a deficiency of the inhibitor of the first component of complement (C1INH) and of the binding subunit of the first component, Clq, defines the syndrome of acquired C1INH deficiency. The description of five new cases, along with the original two and the 18 others in the literature, brings the total reported cases to 25 and highlights the associated B cell abnormalities that are present in 23 and are of a malignant nature in 19 cases. In three of the five newly reported cases, the occurrence of angioedema, which prompted recognition of the acquired deficiency of C1INH, C1q, and C4, preceded the delineation of the underlying B cell malignancy by 2 to 3 yr despite efforts to recognize neoplastic disease in two of these patients throughout the interval. Because the acquired C1INH deficiency reflects increased catabolism rather than impaired biosynthesis, only high-dose attenuated androgens elicit a measurable increment in serum C1INH. The occurrence of the syndrome with multiple myeloma is noted for the first time.
Sheffer, A. L., A. K. Tong, et al. (1985). "Exercise-induced anaphylaxis: a serious form of physical allergy associated with mast cell degranulation." J Allergy Clin Immunol 75(4): 479-84.
Exercise-induced anaphylaxis (EIA) is a unique and an increasingly recognized syndrome consisting of premonitory symptoms and signs of generalized body warmth, pruritus, and erythema, which progresses on continued exertion to confluent urticaria, laryngeal edema with stridor or hoarseness, and gastrointestinal colic and frequently culminates in vascular collapse. Previous studies of five individuals with this condition have demonstrated significant elevations of serum histamine concurrent with the early clinical manifestations after experimental exercise. To assess relevant morphologic alterations in the skin of these patients, cutaneous mast cells were examined by light and transmission electron microscopy before and during the initial erythema elicited by exertion. The marked alterations observed in mast cells immediately after exercise consisted of (1) loss of electron density and internal substructure of granules, (2) fusion of granule membranes with those of adjacent granules and with mast cell membranes creating conduits to the extracellular space, and (3) an apparent decrease in the number of intact granules per cell. Biopsy specimens obtained before exercise from patients with EIA and from two normal individuals who served as control subjects were identical, and the control subjects had normal mast cell morphology after exercise. Serum histamine levels were significantly elevated in patients with EIA after exercise at the time of biopsy, whereas control subjects had normal levels. These observations provide evidence that EIA is a distinct form of physical allergy associated with mast cell degranulation similar in morphology to that of human pulmonary mast cell IgE-Fc-dependent activation secretion. Characterization of this disorder is important because its prevalence may be underestimated, and its clinical consequences, which may include some morbidity, are not fully known.
Sheffer, A. L. (1985). "Anaphylaxis." J Allergy Clin Immunol 75(2): 227-33.
Sheffer, A. L. (1984). "Unraveling the mystery of idiopathic anaphylaxis." N Engl J Med 311(19): 1248-9.
Sheffer, A. L. and D. S. Pennoyer (1984). "Management of adverse drug reactions." J Allergy Clin Immunol 74(4 Pt 2): 580-8.
Successful management of adverse drug reactions requires early identification and prompt treatment of anaphylaxis, whether due to immunoglobulin (Ig) E- or non-IgE-mediated mechanisms of mast cell mediator release. Acute therapy is directed toward enhancement of oxygenation and maintenance of normotension. Requisite measures include the use of epinephrine, oxygen, and adequate fluid replacement; in some instances, vasopressors or corticosteroid drug therapy may be warranted. Emergency measures may be needed to maintain the airway. Although the offending drug is usually discontinued, a necessary drug for which there is no satisfactory alternative occasionally may be continued without danger of further anaphylaxis as long as therapy is not interrupted. Other nonemergent adverse drug reactions requiring an early decision include accelerated urticarial and late maculopapular eruptions, in both of which the patient may tolerate a necessary drug with schedule manipulation. Differentiation of an adverse drug reaction from problems unrelated to the drug is essential so that needed medication is not inappropriately discontinued. Good management also requires anticipation of adverse reactions whenever a therapeutic program is instituted. Familiarity with the drug groups most commonly responsible for immunologic reactions is helpful, as is knowledge of satisfactory alternatives for these drugs in the presence of known hypersensitivity. An adverse reaction can often be minimized through use of established protocols for premedication. Desensitization, when essential, may be achieved for most drugs with graduated dosage schedules and maintained through continued administration of the drug. Identification to avoid inadvertent exposure to agents that have caused immunologic reactions in the past is essential.
Sheffer, A. L. and K. F. Austen (1984). "Exercise-induced anaphylaxis." J Allergy Clin Immunol 73(5 Pt 2): 699-703.
Exercise-related anaphylaxis is a novel form of physical allergy that is being recognized with increasing frequency in a society with a growing commitment to health through planned exercise. The clinical manifestations progress from pruritus, erythema, and urticaria to some combination of cutaneous angioedema, gastrointestinal and laryngeal symptoms and signs of angioedema, and vascular collapse. The finding of an elevated serum histamine level during experimentally-induced attenuated attacks indicates mast cell participation, as in a physical allergy, and the signs and symptoms are characteristic of a classic anaphylactic reaction to a foreign substance in an allergic human.
Sheffer, A. L., N. A. Soter, et al. (1983). "Exercise-induced anaphylaxis: a distinct form of physical allergy." J Allergy Clin Immunol 71(3): 311-6.
Seven individuals with exercise-induced anaphylaxis under natural circumstances, characterized by the appearance of pruritic cutaneous erythema and urticaria and associated vascular collapse and/or upper respiratory tract symptoms and signs of angioedema, were subjected to a controlled period of exercise in a laboratory. Experimental challenge consisted of running in an occlusive suit on a treadmill of moving grade with maintenance or acceleration of speed for 5 to 17 min. Cutaneous pruritus and erythema without urticaria developed in four of the subjects and progressed to angioedema in two of them; the other three subjects were unaffected. Repeat challenge of three of the abnormal responders elicited a clinical response similar to that of the previous exercise challenge. In those subjects with a clinical response to exercise challenge, mean change from baseline levels of histamine to peak levels was 7.0 +/- 3.0 ng/ml (mean +/- SEM), whereas in the group without clinical symptoms the mean change from baseline was an increase of 0.6 +/- 1.6 ng/ml (mean +/- SEM). The abnormal elevations in serum histamine during the seven exercise-induced symptomatic episodes returned to normal in about 20 min while clinical signs were also subsiding. There were no changes in pulmonary function. Exercise-induced anaphylaxis is clinically separable from cholinergic urticaria and represents a distinct form of physical allergy.
Sheffer, A. L., N. A. Soter, et al. (1983). "Exercise-induced anaphylaxis: a distinct form of physical allergy." Monogr Allergy 18: 138.
Sheffer, A. L., D. T. Fearon, et al. (1981). "Clinical and biochemical effects of stanozolol therapy for hereditary angioedema." J Allergy Clin Immunol 68(3): 181-7.
Stanozolol, an inexpensive anabolic steroid with a 30:1 anabolic:androgenic ratio, was administered to 12 male and 15 female patients with biochemically proven hereditary angioedema over a 2-yr period to obtain a systematic assessment of the relationship between drug dosage and clinical response, incidence of side effects, and amelioration of complement abnormalities. All 27 patients attained the minimal effective dose, ranging from 0.5 to 2 mg daily, which controlled the frequency and intensity of symptoms with minimal side effects. At daily maintenance doses of 2, 1, and 0.5 mg the frequencies of attacks per weeks of therapy were 1/14.6, 1/7.2, and 1/8.2 wk, respectively. Side effects with maintenance therapy included menstrual abnormalities and virilization in four females and elevation of serum creatinine phosphokinase (CPK) in five males. In six patients on maintenance doses of stanozolol, serum levels of testosterone, free thyroxin (T4), and thyroxin binding globulin (TBG) (four males), and of estradiol, progesterone, T4, and TBG (two females) were normal. Slightly low serum levels of progesterone and TBG were found in two females who had normal menstrual cycles. Statistically significant elevations above pretherapy levels of serum inhibitor to the activated first component of complement function and C4 protein and function occurred when patients were on maintenance therapy, but these measurements remained below the lower limit of normal range. Higher doses of stanozolol (4 mg/day), which caused greater immunochemical responses, were unnecessary for control of clinical disease and were unjustified for chronic therapy because of more frequent side effects.
Schwartz, H. J., R. F. Lockey, et al. (1981). "A multicenter study on skin-test reactivity of human volunteers to venom as compared with whole body Hymenoptera antigens." J Allergy Clin Immunol 67(1): 81-5.
Twenty-four control and 104 stinging insect-allergic patients were tested in this multicenter study, which compared the utility of individual venom and whole body extract (WBE) preparations for diagnosis. This study indicates that venom skin testing is more specific and more reliable than is testing with WBE. There was a high rate of WBE skin-test reactivity among controls. False-positive skin testing with venom was not a problem at concentrations of 1 microgram/ml or less. Only one mild and easily treated adverse reaction occurred in this study.
Sheffer, A. L. and K. F. Austen (1980). "Exercise-induced anaphylaxis." J Allergy Clin Immunol 66(2): 106-11.
Sixteen patients were seen because of possibly life-threatening exercise-associated symptoms similar to anaphylactic reactions. Asthma attacks, cholinergic urticaria and angioedema, and cardiac arrythmias are recognized as exertion-related phenomena in predisposed patients but are distinct from the syndrome described here. A syndrome characterized by the exertion-related onset of cutaneous pruritus and warmth, the development of generalized urticaria, and the appearance of such additional manifestations as collapse in 12 patients, gastrointestinal tract symptoms in five patients, and upper respiratory distress in 10 patients has been designated exercise-induced anaphylaxis, because of the striking similarity of this symptom complex to the anaphylactic syndrome elicited by ingestion or injection of a foreign antigenic substance. There is a family history of atopic desease for 11 patients and cold urticaria for two others and a personal history of atopy in six. The size of the wheals, the failure to develop an attack with a warm bath or shower or a fever, and the prominence of syncope rule against the diagnosis of conventional cholinergic urticaria. There is no history or evidence of an encounter with an environmental source of antigen during the exercise period.
Rocklin, R. E., A. L. Sheffer, et al. (1980). "Generation of antigen-specific suppressor cells during allergy desensitization." N Engl J Med 302(22): 1213-9.
We used a suppressor-cell assay to study a possible mechanism of allergy desensitization. Before specific immunotherapy, blood mononuclear cells from 20 patients with ragweed hayfever failed to exhibit suppressor activity in vitro after stimulation by ragweed antigen E. However, when the 10 patients with allergic rhinitis had been desensitized by injections of ragweed extract, their mononuclear cells specifically suppressed a ragweed proliferative response six and 12 months after desensitization was begun (31 per cent and 48 per cent suppression, respectively). Suppressor mononuclear cells were not detected in 10 control subjects of in 10 patients with ragweed hayfever who were not desensitized. When mononuclear cells taken from treated patients were passed over columns containing insolubilized histamine, antigen-specific suppressor cells that could be activated by ragweed antigen were depleted. These results indicate that antigen-specific suppressor cells, probably bearing histamine receptors, are generated during desensitization to allergy and may be partly responsible for the efficacy of this therapy.
Hendrix, S. G., R. Patterson, et al. (1980). "A multi-institutional trial of polymerized whole ragweed for immunotherapy of ragweed allergy." J Allergy Clin Immunol 66(6): 486-94.
Sheffer, A. L., D. T. Fearon, et al. (1979). "Clinical and biochemical effects of impeded androgen (oxymetholone) therapy of hereditary angioedema." J Allergy Clin Immunol 64(4): 275-80.
Daily therapy and alternate-day therapy with the attenuated androgen oxymetholone were compared in patients with hereditary angioedema (HAE). Fifteen of 16 patients who experienced at least monthly attacks of HAE without treatment were asymptomatic on administration of 5 mg oxymetholene daily. When 13 of the patients who had been maintained asymptomatically on 5 mg oxymetholone daily were advanced to a treatment schedule of 5 mg every other day, seven attacks occurred during a cummulative 50 mo of therapy. The adverse effects that occurred with daily oxymetholone therapy largely subsided when the patients received alternate-day therapy, while a significant mean rise in C4 protein and function occurred only on daily therapy. Statistically significant mean increases in serum levels of C1INH occurred with daily therapy and were maintained with alternate-day therapy. Clinical benefit can be obtained with a treatment program that does not produce a statistically significant rise in C4 protein or function and does not raise C1INH to the lower limit of normal. The finding that alternate-day therapy diminished the side effects of the drug while affording a substantial reduction in the incidence and severity of attacks indicates the feasibility of this therapeutic approach.
Sheffer, A. L., D. T. Fearon, et al. (1977). "Tranexamic acid: preoperative prophylactic therapy for patients with hereditary angioneurotic edema." J Allergy Clin Immunol 60(1): 38-40.
Sheffer, A. L., D. T. Fearon, et al. (1977). "Methyltestosterone therapy in hereditary angioedema." Ann Intern Med 86(3): 306-8.
In a double-blind study of four patients with hereditary angioedema, the efficacy of methyltestosterone (taken daily in 10-mg linguet form) in preventing attacks was shown. There were 19 episodes during 11.8 months of placebo administration, compared with only four attacks during the 46 months of cumulative methyltestosterone treatment (P less than 0.001). The mean serum C4 protein level was twice as high in all patients when they were taking the drug (176 +/- 36 mug/ml) as compared with the placebo (84 +/- 21 mug/ml), and rose to normal range in three of four patients.
Tannenbaum, H., R. E. Rocklin, et al. (1976). "Immune function in sarcoidosis. Studies on delayed hypersensitivity, B and T lymphocytes, serum immunoglobulins and serum complement components." Clin Exp Immunol 26(3): 511-9.
An assessment of immune function was performed in twenty-four patients with recently diagnosed active sarcoidosis. Four patients manifested skin anergy to four antigens. All subjects except one were capable of generating a positive skin response to a croton oil patch test. The incorporation of [3H]thymidine by lymphocytes in vitro in response to the nonspecific mitogens--phytohaemagglutinin, pokeweed mitogen and Con A did not differ between anergic and non-anergic thymidine incorporation in vitro when stimulated by the specific antigens, streptokinase/streptodornase or Candida albicans. Lymphocytes obtained from nine of eleven patients having positive delayed hypersensitivity skin reactions demonstrated MIF production in vitro upon specific antigen challenge. Quantities of circulating B and T lymphocytes did not differ between anergic and absolute numbers of circulating B and T lymphocytes, as well as hypercomplementaemia and hypergammaglobulinaemia when compared to the control group.
Sheffer, A. L., R. E. Rocklin, et al. (1975). "Immunologic components of hypersensitivity reactions to cromolyn sodium." N Engl J Med 293(24): 1220-4.
Manifestations of cellular and humoral hypersensitivity to cromolyn sodium were sought in six asthmatic patients suspected of having acute (three cases) or subacute (three cases) adverse reactions to cromolyn inhalation. Lymphocytes from all patients produced migration inhibition factor (MIF), and those from four patients incorporated increased amounts of 3H-thymidine in response to cromolyn in vitro. Lymphocytes from four of nine cromolyn-tolerant asthmatics demonstrated increased 3H-thymidine incorporation but none showed MIF production, whereas lymphocytes from normal subjects failed to react to cromolyn in either assay. Two of three patients with subacute reactions had increased serum binding of 3H-cromoglycate which was attributable to the IgG fraction. Thus although patients tolerating cromolyn therapy may demonstrate lymphocyte transformation in vitro, only those with clinically apparent adverse reactions produce lymphocyte MIF or possess serum-binding activity for the drug.