Lymphocytes in multiple sclerosis: correlation with CSF immunoglobulins and cold-reactive lymphocytotoxic antibodies.

Lymphocyte profiles were studied in patients with multiple sclerosis (MS) and normal controls. Apart from cold-reactive lymphocytotoxic antibodies (LCA), which were elevated in MS patients, there was no difference between MS patients and normal controls in terms of lymphocyte subpopulations, serum immunoglobulins, or responses to mitogens. There was no correlation between LCA and any of the immunologic characteristics measured. However, there was a correlation between immunoglobulin-bearing cells in the peripheral blood of MS patients and cerebrospinal fluid (CSF) levels of immunoglobulin and CSF viral antibodies. These results suggest that cold-reactive lymphocytotoxic antibodies do not affect lymphocyte function in patients with MS, that antigens stimulating "local" central nervous system (CNS) antibody production may be located outside the CNS and that locally produced CNS antibody may be made by immunoglobulin-bearing cells that migrate to the CSF from the periphery after exposure to antigen.

Delayed pressure urticaria histologically resembles cutaneous late-phase reactions.

In a recent study, all patients with delayed pressure urticaria (DPU) developed late cutaneous reaction (LCR) after intradermal injection of compound 48/80 and after skin testing with certain food antigens. In the present study, we analyzed the histologic changes in the pressure lesions and compared them with those found in normal skin injected with diluent and in LCR to 48/80. The study included five patients with DPU associated with chronic urticaria (CU) and four patients with CU but without DPU. Six to eight hours after pressure challenge and intradermal skin testing with 48/80 and diluent, skin biopsy specimens were obtained from the pressure lesions, the LCRs, and normal skin (diluent injection). Specimens were assessed by Giemsa staining of 1-micron sections and immunofluorescence of frozen sections. Total cells were counted in each specimen. Interstitial deposits of fibrin were observed by immunofluorescence in LCR and pressure lesions. The total numbers of infiltrating cells in the dermis among LCR sites and pressure lesions were not significantly different, while both LCR sites and pressure lesions contained significantly more infiltrating cells than did normal skin injected with saline diluent. The differential counts in LCR and DPU were mostly mononuclear cells. Infiltrates in the DPU and LCR were mostly perivascular. No histopathologic changes were seen at skin sites challenged with pressure in the control patients with CU without clinical manifestations of DPU. We conclude that lesions seen in DPU are morphologically similar to classic LCR.

Anaphylaxis. A preventable emergency.

Anaphylaxis is a life-threatening reaction that may be caused by a variety of agents. Diagnosis depends on the presence of a constellation of symptoms (eg, laryngeal edema, bronchospasm, hypotension, urticaria). The goal of therapy is maintenance of an effective airway, respiratory function, and circulation. Subcutaneous epinephrine, H1 and H2 antihistamines, and a prolonged period of observation (at least 8 hours) should be used in all patients. After the acute attack has been managed, a thorough investigation of possible causes should be made and the patient referred to a specialist, if indicated. Desensitization therapy, premedication before high-risk exposures, and careful avoidance of known causative agents are effective preventive measures. Direction in self-administration of epinephrine is critical in these patients and may prove lifesaving.

Lymphocytotoxic antibodies in systemic lupus erythematosus and clinically related diseases.

Sera from patients with systemic lupus erythematosus (SLE) and clinically related diseases were examined for cold-reactive lymphocytotoxic antibodies (LCA). The incidence of LCA was significantly increased in SLE (93%), discoid lupus (50%), and "lupus-like" syndromes associated with congenital complement deficiencies (63%) as compared to normal controls (3%) and patients with drug-induced lupus (11%), mixed connective tissue disease (MCTD) (17%), and necrotizing vasculitis (19%). The diagnostic and pathogenetic implications of these differences are discussed.

The effect of H1 and H2 blockade on cutaneous histamine response in man.

Histamine-induced cutaneous wheal responses were measured in 10 healthy subjects. The effect of the potent H1 blocker, hydroxyzine HCl, the H2 blocker, cimetidine, and the two drugs in combination was determined. The H1 blocker alone produced a mean wheal suppression of 75% (p less than 0.001). The H1 plus H2 blocker produced 84% suppression. The augmented suppression of H1 plus H2 blocker vs H1 blocker was statistically significant (p less than 0.02). The H2 blocker alone produced suppression that was not statistically significant. The results provide additional evidence that H2 receptors are present in the human cutaneous microcirculation, and add support to the clinical observation of therapeutic efficacy of H1 plus H2 blockers seen in some patients with chronic urticaria.

Lymphocytotoxic antibodies in family members of patients with multiple sclerosis.

Cold-reactive lymphocytotoxic antibodies were found in sera from 14 of 21 (67%) patients with multiple sclerosis. A significantly (p less than 0.01) greater frequency of these antibodies was also demonstrated in patients' household members (12 of 18 [67%]) compared to siblings living elsewhere (3 of 14 [21%]) or normal controls (1 of 13 [8%]). No difference in antibody frequency was found between consanguineous and non-consanguineous family members. These findings suggest that the increase frequency of lymphocytotoxic antibodies in these multiple-sclerosis patients and their family members is an indicator of the presence of a transmissible agent, probably a virus, in many patients with multiple sclerosis.

A comparison of the actions of H1 and H2 antihistamines on histamine-induced bronchoconstriction and cutaneous wheal response in asthmatic patients.

The effect of an H1 antihistamine, an H2 antihistamine, and the combination of the two drugs on both histamine-induced bronchoconstriction and dermal whealing was examined in five patients with mild asthma. Chlorpheniramine 8 mg, cimetidine 300 mg, the combination of both, and placebo were administered orally to each patient for a single dose and for seven consecutive doses given every 6 hr after a double-blind, randomized protocol. The airway response to inhaled histamine and the wheal size induced by the intradermal injection of histamine were determined in every patient 2 hr after the final drug dose. The results indicate that a single dose of chlorpheniramine produces a significant increase in the threshold of histamine-induced bronchoconstriction as measured by the provocative histamine dose producing 20% decrease in 1-sec forced expiratory volume (PD20-FEV1), and this effect was significantly enhanced after seven doses. Cimetidine caused a significant decrease in the threshold of histamine-induced bronchoconstriction, but this was not augmented by seven doses. Only chlorpheniramine, when given for seven doses, improved the baseline FEV1 and forced expiratory flow during middle half of forced vital capacity (FEF25%-75%). Chlorpheniramine in both single and multiple doses and the combination of chlorpheniramine and cimetidine given for seven doses produced a significant inhibition of histamine-induced dermal wheals, whereas cimetidine alone had no effect. These results confirm our previous observation that both H1 and H2 receptors are present in the airways of asthmatic patients and that they mediate opposite effects. We also demonstrated a cumulative effect with the repeated administration of chlorpheniramine but not with cimetidine. Finally, the results suggest that the role of H1 and H2 receptors differs in the bronchi from that seen in the dermal vessels of asthmatic patients and are in contrast to those of normals. The H2 receptor effect on histamine-induced skin wheals appears deficient, further supporting earlier suggestions of the presence of an H2 receptor defect in asthmatic patients.

Exercise-induced anaphylactic reaction to shellfish.

The syndrome of immediate type I food hypersensitivity, mediated by tissue-bound IgE antibody and mast cell histamine release, is well recorded in the medical literature. This case study represents a previously undescribed late food hypersensitivity, induced only by strenuous exercise. Identification of this new syndrome illustrates classical epidemiologic analysis, improves medical advice for the allergic and athletically inclined, and raises new questions in the areas of allergy and immunology.

A controlled trial of therapy in chronic urticaria.

Nineteen patients with chronic idiopathic urticaria (duration 2 to 192 mo) referred to our clinic as therapeutic failures were treated sequentially with five regimens. These were administered orally in a double-blind random sequence and included hydroxyzine pamoate (25 mg q.i.d.) plus one of the following: (1) placebo, (2) terbutaline (2.5 mg q.i.d.), (3) cyproheptadine (4 mg q.i.d.), (4) chlorpheniramine (4 mig q.i.d.), (5) cimetidine (300 mg q.i.d.). Therapeutic response was assessed by patient's subjective choice, symptom diary scores, and suppression of wheal response to intradermal injections of histamine and compound 48/80. At least 35% improvement was noted in all patients with an average optimal response of 70%. The hydroxyzine-cimetidine combination was favored by 11 of 19 (58%) patients, in addition to producing the lowest symptom scores and the greatest histamine-48/80 wheal suppression. These results support the efficacy of combination H1 and H2 antihistamines in the management of some patients with difficult chronic urticaria.

Steroid-resistant chronic urticaria associated with anti-thyroid microsomal antibodies in a nine-year-old boy.

The case of a 9-year-old boy with severe chronic urticaria of 6 months' duration is described. The urticaria was associated with intractable bronchospasm and abdominal cramping and was unresponsive to antihistamines and high doses of corticosteroids. Even though the child was euthyroid, he was treated with thyroid hormone after the presence of anti-thyroid microsomal antibodies was documented. Within 1 month the patient demonstrated full remission. He remained free of symptoms for 9 months after discontinuation of treatment. After a relapse he again responded to thyroid hormone therapy. Children with chronic, intractable urticaria and documented evidence of anti-thyroid microsomal antibodies may benefit from treatment with thyroid hormone.

Evaluation of skin test response using two techniques of measurement.

This study shows that lodoxamide ethyl has no significant effect on 48/80 or histamine skin tests using a double-blind protocol in 10 normal subjects. Direct measurement of area by planimetry is also demonstrated to be less variable than diameters in quantitating skin test results.

Resolution of chronic urticaria in patients with thyroid autoimmunity.

BACKGROUND: Autoimmune disease has been implicated as a cause of chronic urticaria, and anti-thyroid antibodies have been found in patients with chronic urticaria. Because some patients with chronic urticaria and autoimmune hypothyroidism have had clinical resolution with thyroid hormone replacement, we investigated the effect of thyroid hormone in euthyroid patients with chronic urticaria and thyroid autoimmunity. METHODS: Ten euthyroid patients with refractory hives were treated with thyroxine. Seven patients had elevated anti-thyroid antibodies at baseline. Thyroid function and anti-microsomal and anti-thyroglobulin antibody levels were monitored during treatment. If a clinical response was achieved, thyroxine was discontinued and restarted if symptoms recurred. RESULTS: Seven patients with elevated anti-thyroid antibodies reported resolution of symptoms within 4 weeks. Three patients without elevated anti-thyroid antibodies did not respond. Five patients had a recurrence of symptoms after treatment was stopped, which resolved after treatment was restarted. Thyroid-stimulating hormone levels decreased in all patients with a clinical response. No correlation between clinical resolution and anti-thyroid antibody levels was seen. CONCLUSION: Thyroid autoimmunity in euthyroid patients may be associated with chronic urticaria, and treatment with thyroid suppression can result in clinical remission.

Delayed pressure urticaria.

Delayed pressure urticaria (DPU) is a poorly understood syndrome. We describe 17 patients with DPU. Chronic urticaria was present in 94%. All had negative challenges for immediate demographism and cold urticaria. DPU was induced with a pressure challenge on the shoulder of 15 pounds for 15 min. Average onset of pressure lesions after challenge was 6.5. Lesions were painful, not pruritic, peaked at 9 hr, and disappeared by 24 to 48 hr. Fever, chills, and/or arthralgias occurred in 78%. Positive laboratory abnormalities included leukocytosis in 20% and elevated erythrocyte sedimentation rate in 37.5%. Skin biopsies of lesions showed perivascular round cell infiltrates and negative immunofluorescence. Urticaria responded to antihistamines, but not aspirin, in 100% of patients, while pressure lesions improved with nonsteroidal anti-inflammatory drugs (NSAID), but not antihistamines, in 80% of patients. Both urticaria and DPU were controlled with prednisone, which was necessary in 87.5% of patients. A severe nonremitting course was noted in 7%, 40% had a moderate remitting course requiring intermittent prednisone, and 53% had a mild remitting disease requiring no medication or antihistamines and/or NSAID only. We conclude that DPU is more common than previously appreciated and likely involves mediators other than histamine, possibly the prostaglandin system.

Intravenous iron dextran in clinical medicine.

Four hundred seventy-one adult patients and ten adult prisoner volunteers received 2,099 intravenous (IV) injections of iron dextran (Imferon), usually 250 to 500 mg at less than 100 mg/min. Intravenous iron supplies enough iron to permit RBC formation greater than 50 mL/day and repletion of tissue iron. Tissue iron did not always supply iron at an optimal rate. Hemoglobin production was higher after IV than oral or intramuscular iron if the hemoglobin level was less than 9 g/dL. Three life-threatening immediate anaphylactoid and eight severe delayed reactions were observed. There were no deaths. Delayed reactions were more frequent in women and collagen-vascular diseases and less frequent in pregnancy. Because anaphylactoid reactions are serious and unpredictable, IV iron dextran should be used only when iron deficiency anemia cannot be treated adequately with oral iron.

Lymphocytotoxic antibodies and intermediate immune complexes in hypergammaglobulinemic purpura of Waldenström.

Immune complexes, lymphopenia, and lymphocytotoxic antibodies were detected in two patients with hypergammaglobulinemic purpura of Waldenström. These abnormalities were further characterized in one patient. Ultracentrifugation analysis of this patient's serum showed an intermediate peak likely representing medium sized immune complexes. Circulating IgG-containing immune complexes (2-ME resistant Clq binding material) and IgM rheumatoid factor (2-ME sensitive) were also detected. A sequential study of cold reactive IgM lymphocytotoxic antibodies revealed a significant inverse correlation between antibody levels and peripheral lymphocyte counts. The possible implications of these findings in the pathogenesis of hypergammaglobulinemic purpura are discussed.

Late cutaneous reactions in patients with delayed pressure urticaria.

Late cutaneous reactions ( LCRs ) have been described in patients after allergen skin testing, skin testing with heterologous anti-human IgE, autologous skin-blister fluid, and, variably, after 48/80 injection. We report our results of skin testing patients with delayed pressure urticaria ( DPU ), chronic urticaria, and normal volunteers with histamine and 48/80. All patients with DPU had LCRs after 48/80. No patients in either of the other groups developed LCRs . This may be a clue to pathogenic mechanisms involved in DPU .

The hypocomplementemic urticarial-vasculitis syndrome: therapeutic response to hydroxychloroquine.

We report a patient with hypocomplementemic urticarial-vasculitis syndrome. This case illustrates the continuum between urticaria and purpura characteristic of hypocomplementemic urticarial-vasculitis syndrome. Clq precipitin was demonstrated in the patient's serum and in the diethylaminoethylcellulose-ion exchange fraction containing only IgG. A skin biopsy specimen of urticarial and purpuric lesions demonstrated leukocytoclastic vasculitis and granular deposition of C3 and Clq in the basement membrane with IgA, IgM, C3, and Clq in postcapillary venules. Serial total hemolytic complement activity and Clq determinations were performed, and the response to several treatment regimens is presented. Symptomatic and serologic improvement was observed only with hydroxychloroquine.

The effects of H1 and H2 antihistamines on histamine inhalation challenges in asthmatic patients.

This study was designed to examine the effect of an H1 antihistamine, chlorpheniramine, an H2 antihistamine, cimetidine, and the combination of chlorpheniramine and cimetidine on histamine-induced bronchoconstriction in a double-blind, randomized protocol on 11 patients with asthma. Each patient underwent a histamine inhalation challenge on 5 separate days. After a control day, histamine inhalation challenges were performed 2 h after the administration of a single oral dose of 8 mg of chlorpheniramine, 300 mg of cimetidine, the combination of chlorpheniramine and cimetidine, or placebo. Baseline pulmonary function measurements were not significantly altered by the 4 treatments. Body plethysmography data and measurements from the forced vital capacity maneuver were obtained before and after the histamine inhalation challenges. The provocation dose of histamine that produced a 20% decrease in forced expiratory volume in one second, a 35% decrease in mean forced expiratory flow during the middle half of the forced vital capacity, and a 50% decrease in specific airway conductance was significantly increased after administration of chlorpheniramine (p less than 0.002) and decreased after administration of cimetidine (p less than 0.02), where as no significant effect was noted after the combination of chlorpheniramine and cimetidine. The results suggest the presence of both H1 and H2 receptors in the airways of asthmatic patients.

Immune complex vasculitis as a cause of ascites and pleural effusions in systemic lupus erythematosus.

A patient is described with systemic lupus erythematosus and large painless ascites and pleural effusions. Pleural and peritoneal fluid complement levels were depressed, and DNA binding was elevated in the presence of normal serum values. Immunoglobulin and complement deposits were demonstrated in vessels of the pleura, peritoneum, and skin, along with histologic evidence of vasculitis. The relation of the ascites and pleural effusions to the presence of widespread vasculitis and local immune complex formation is discussed. These complications responded poorly to corticosteroid therapy but slowly resolved following the addition of an immunosuppressive agent.

Evaluation of a patient with both aquagenic and cholinergic urticaria.

An 11-yr-old girl presented with a history of urticaria induced by warm or cool showers, exercise, and emotional stimuli. During evaluation she repeatedly developed generalized punctate urticaria, pruritus, palpitations, and headaches after warm baths or exercise, and she had a positive methacholine skin test. She developed similar lesions and pruritus after local application of sterile water, tap water, ethanol, normal saline, or 3% saline. The diagnosis of combined aquagenic and cholinergic urticaria was made and presented a unique opportunity to study and compare mediator release and clinical symptoms in both conditions. The patient was submerged in bath water at either 37 degree or 41 degree C to induce either aquagenic or cholinergic urticaria, respectively. Histamine was released into the systemic circulation in both conditions in a similar time course; however, systemic symptoms occurred only after the 41 degree C bath. After failure to induce tolerance to the 41 degree C bath water, hydroxyzine therapy was instituted. One week later she was rechallenged; few symptoms appeared, and a rise in serum histamine was not detected as had been shown in previous challenges. The data suggest that in our patient, hydroxyzine may have contributed to the inhibition of both histamine release and the appearance of symptoms during hot bath challenging.