The late phase of the immediate wheal and flare skin reaction. Its dependence upon IgE antibodies.

IgE antibodies are usually thought to induce only immediate skin reactions. We have shown that the intradermal injection of a number of different allergens can produce a prolonged inflammatory reaction after the immediate wheal and flare in most sensitive subjects. This late inflammatory response occurs 6-12 h after challenge and is characterized by diffuse edema, erythema, pruritus, and heat. Both immediate and late responses can also be seen after passive sensitization of skin sites in nonatopic subjects. That IgE is involved in inducing the reaction was shown by the abolition of both immediate and late responses by passive transfer tests in the following experiments: (a) heating atopic serum at 56degreesC for 4 h, (b) removing IgE from the atopic serum by a solid phase anti-IgE immunoabsorbent, and (c) competitively inhibiting the binding of IgE antibodies to cells by an IgE myeloma protein. In addition, both responses were induced by affinity chromatography-purified IgE antibody, followed by antigenic challenge. Very similar lesions could also be induced by intradermal injection of Compound 48/80, thus suggesting a central role in the reaction for the mast cell or basophil. Histologically, the late phase is characterized by edema and a mixed cellular infiltration, predominantly lymphocytic but also containing eosinophils, neutrophils and basophils. Direct immunofluorescent staining did not show deposition of immunoglobulins or complement components, except IgM in 2 of 15 and C3 in 1 of 15 patients. This finding indicates that the late phase does not depend on the deposition of immune complexes. The results of the study suggest that IgE-allergen interaction on the surfaces of mast cells or on infiltrating basophils causes both immediate and late cutaneous responses.

Elevated serum levels of the eosinophil granule major basic protein in patients with eosinophilia.

A radioimmunoassay was established for the human eosinophil granule major basic protein (MBP). The mean level of MBP in sera from 105 normal control patients was 454 ng/ml, whereas in a sample of 188 patients with various forms of diseases, including the hypereosinophilic syndrome, levels as high as 14,000 ng/ml were measured. Serum levels of MBP did not correlate with eosinophil counts in normal subjects, but a positive correlation was seen in patients with eosinophilia; the patients with eosinophil counts greater than 350/mm3 generally showed increased levels of MBP. Many patients with skin disease and normal eosinophil counts had elevated levels of serum MBP. Monomer MBP has a molecular weight of 9,300, but in sera of patients with eosinophilia, the MBP activity was of high molecular weight, greater than 50,000. Analyses of serum by Sephadex G-200 and by electrofocusing suggest that MBP is not simply polymerized, but rather is bound to a larger carrier molecule. Monomeric MBP can be isolated from serum by reduction of serum with dithiothreitol, alkylation with iodoacetamide, and acidification to pH 2 followed by fractionation on Sephadex G-50 at pH 2. Under these conditions, up to 80% of the MBP emerges in monomeric form. The results indicate that eosinophil granule proteins circulate in blood covalently bound to serum proteins, and that elevated concentrations of serum MBP are present in some diseases associated with eosinophilia.

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

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

Chronic active liver disease with common variable hypogammaglobulinemia.

Progressive liver injury in chronic active liver disease is usually associated with elevation of serum immunoglobulin levels. However, the role of immunoglobulins in the pathogenesis of this disease is still obscure. We report here the case of a 41-year-old man with hypogammaglobulinemia since at least 1964 in whom chronic active liver disease later developed. From 1954 he had had frequent respiratory tract infections, and these continued, along with diarrhea, despite regular gamma-globulin therapy. Studies in 1969 showed absent serum IgA and IgM and an abnormally low level of IgG. In 1974, liver enzyme abnormalities were recorded and a diagnosis of chronic active liver disease was made. A liver biopsy showed cirrhosis with active hepatitis. Lymphocyte function studies revealed that the T cells suppressed B-cell maturation and production of immunoglobulins. He was treated with azathioprine and prednisone, and this therapy has been associated with a decrease in both the elevation in liver enzymes and the frequency of infections. This case suggests that liver cell injury in chronic active liver disease is independent of the elevation of immunoglobulins and that immunosuppressive therapy may be well tolerated by patients with hypogammaglobulinemia.

Endomyocardiopathy with eosinophilia.

Five patients were seen at the Mayo Clinic over an 8-year period with the following complex of clinical and morphologic features; striking eosinophilia, cardiomyopathy, hepatosplenomegaly, and either a rapidly fatal or a prolonged, debilitating illness. In recent years, controversy has raged over the precise designation of this syndrome, with proposals ranging from eosinophilic leukemia to hypereosinophilic syndromes. To focus on the major target organ of the disease, we have favored the term endomyocardiopathy with eosinophilia. Experience with these five patients showed that (1) eosinophilia can persist for many years before symptoms appear; (2) progressive restrictive cardiac disease was the major cause of death and debility; (3) osmiophilic cytoplasmic inclusions are present in eosinophils of these patients and also in cells from other patients with marked eosinophilia; and (4) echocardiography may prove to be a useful noninvasive tool to diagnose and follow the progress of cardiac involvement. Although none of these patients was thought to have leukemia, intensive therapy with steroids or cytotoxic agents, or both, is considered necessary to control the progression of the disease.

Allergy to stinging and biting insects in Queensland.

Over an eight and a half year period 742 patients were assessed for allergy to stinging and biting insects in Queensland; 452 (61%) had allergic reactions to honey bees, 244 (33%) to wasps, 30 (4%) to various ants, 11 (1.5%) to march flies (Tabanus sp.) and five to tick infestation. One hundred and fifty one patients (20%) presented with large local swelling only (RXN1), 98 (13%) with urticaria and/or facial angioedema distant from the sting site (RXN2) and 492 (66%) with subjective or objective evidence of dyspnoea or hypotension (RXN3). Allergy testing was performed with honey bee and wasp venoms by skin testing or by Radioallergosorbent testing. Fifty nine patients (30%) with RXN3 responses to wasps failed to react to either test, while this applied to only 19 (6%) of the patients with RXN3 responses to bee stings. Thus, a large number of wasp-allergic patients with RXN3 responses could not be offered immunotherapy. A similar problem exists in the lack of availability of specific reagents for anti- and tick-induced dyspnoea or hypotension. A whole-body insect extract of march fly, however, appears useful.

Hypersensitivity pneumonitis induced by Penicillium species.

An entomologist developed an illness with typical features of hypersensitivity pneumonitis. On-site investigations indicated that on the days of his attacks he was exposed to dust laden with several species of mold, especially Penicillium spp., as well as to mists generated by reservoir-type humidifiers. Serologic tests to more than 40 antigens prepared from organisms and sources known to cause hypersensitivity pneumonitis showed strong reactions to Penicillium and to antigens prepared from the scum of a large industrial humidifier and from his laboratory humidifier. PFTs revealed a significant reduction in DLCO, Following a 4-mo period without laboratory exposure, he experienced no further episodes, a return to his previous exercise tolerance, and a normal DLCO, BP studies with extracts of Penicillium casei and humidifier water from his laboratory (H1) resulted in objective evidence, both clinically and by hematologic and pulmonary function testing, of hypersensitivity to Penicillium spp. and possibly also to the H1 preparation.

Correlation between regional enterocolitis and cutaneous polyarteritis nodosa. Two case reports and review of the literature.

Dermatological manifestations of chronic infammatory bowel disease are numerous. We report herein 2 cases that demonstrated the uncommon association of cutaneous polyarteritis nodosa with regional enterocolitis. The clinical and histopathological features of this skin disease are important. Particular emphasis is placed on its relative benignity, in contrast to the serious prognosis associated with systemic polyarteritis nodosa.

Late cutaneous reactions due to IgE antibodies.

IgE antibodies can produce a late inflammatory response 6--12 h after allergen challenge which is characterized by diffuse edema, erythema, pruritus, tenderness and heat. That IgE is involved in inducing the late reaction was shown by the abolition of both immediate and late responses by passive transfer tests: (1) by heating atopic serum at 56 degrees C for 4 h; (2) by removing IgE from the atopic serum by a solid phase anti-IgE immunoabsorbent, and (3) by competitively inhibiting the binding of IgE antibodies to cells by an IgE myeloma protein. Also, both responses were induced by affinity chromatography-purified IgE antibody followed by antigenic challenge. Very similar lesions could be induced by intradermal injection of Compound 48/80. The late phase is characterized by edema and a mixed cellular infiltration, predominantly lymphocytic but also containing eosinophils, neutrophils and basophils. Direct immunofluorescent staining did not show deposition of immunoglobulins or complement components, except IgM in two of 15 and C3 in one of 15 patients, respectively.

Penicillin allergy: clinical experience with a battery of skin-test reagents.

From 1971 through August 1978, 778 patients underwent penicillin skin testing. Each patient gave a history of previous penicillin allergy. The skin-test reagents consisted of (1) fresh solutions of commercially prepared penicillin G (PEN G), ampicillin (AMP), and methicillin (METH); (2) polylysine conjugates of the major antigenic determinants of each of the three drugs: and (3) alkaline hydrolysates of each drug. A total of 108 (14%) patients showed positive reactions to one or more of the reagents. Certain patients showed reactivity to many reagents, whereas others reacted selectively to only one or two reagents. Addition of reagents of AMP and METH resulted in a greater number of positive reactors than when reagents of PEN G alone were used. Of the group whose skin tests were negative, 290 (43%) were later treated with penicillin, twelve of these (4.1%) had allergic reactions. Eight of the group of whose skin tests were positive were subsequently treated, and four of these (50%) had allergic reactions again. A group 151 patients whose skin tests were negative and 27 patients whose skin tests were positive were treated with a cephalosporin. Only two patients had allergic reactions to the drug: both had had negative skin tests to penicillin. We conclude that the risk of subsequent allergic reactivity to penicillin is much lower if the skin tests are negative than if positive, that testing with semisynthetic penicillins increases the number of skin-test reactors, and that the incidence of allergic reactions is low in patients treated with cephalosporin.

The therapeutic response of urticarial vasculitis to indomethacin.

Ten patients with urticarial vasculitis, characterized clinically by persistent painful urticarial lesions, angioedema, recurrent arthralgia, abdominal pain, and low-grade fever, were selected for study. All patients had histologic evidence of leukocytoclastic vasculitis in the urticarial lesions. Results of direct immunofluorescence microscopy of urticarial lesions were positive in all nine of the patients tested. Treatment with indomethacin in dosages from 25 mg three times daily to 50 mg four times daily resulted in complete clearing of all disease manifestations in six of ten patients within 17 days and partial improvement in three. In eight of the ten patients, disease activity recurred within 48 hours after discontinuation of the use of indomethacin. Gastrointestinal irritation was the only side effect noted. Indomethacin is proposed as an effective mode of therapy in a disorder unresponsive to treatment with conventional medications for urticaria, including high-dose corticosteroids.