Chlorofluorocarbon-free inhalers: are we ready for the change?

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.

A cluster of mutations within a short triplet repeat in the C1 inhibitor gene.

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.

Characterization of cellular dermal infiltrates in human cutaneous mastocytosis.

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.

Cromolyn sodium in the management of systemic mastocytosis.

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.

Exercise-induced anaphylaxis.

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.

Anaphylaxis.

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.

Morphologically distinctive forms of cutaneous mast cell degranulation induced by cold and mechanical stimuli: an ultrastructural study.

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.

Synthesis and release of leukotriene C4 by human eosinophils.

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.

Acquired deficiency of the inhibitor of the first component of complement: report of five additional cases with commentary on the syndrome.

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.

Exercise-induced anaphylaxis: a serious form of physical allergy associated with mast cell degranulation.

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.

Management of adverse drug reactions.

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.

Clinical and biochemical effects of stanozolol therapy for hereditary angioedema.

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.

Diagnosis of sarcoidosis by lip biopsy of minor salivary glands.

In two patients with bilateral parotid gland swelling of unknown etiology the diagnosis of sarcoidosis was established by lip biopsy of the minor salivary glands. This simple, innocuous biopsy procedure may prove useful in tissue documentation of sarcoidosis.