Carlos M. Arroyave

Plasma histamine changes during provoked bronchospasm in asthmatic patients

Seven patients with bronchial asthma underwent bronchial inhalation challenge with aerosolized allergen extracts and methacholine. Simultaneously, venous blood samples were collected and histamine was measured. Each patient was challenged on successive days with an allergen extract to which he had no skin-sensitizing antibody (skin test-negative allergen), followed by methacholine and skin test-positive allergen. Bronchospasm was not induced by inhalation of skin test-negative allergens but was observed in all patients after methacholine and in the majority of patients after skin test-positive allergens. No changes in plasma histamine were detected after challenges with methacholine and skin test-negative allergens. After challenge with skin test-positive allergens, significant rises in plasma histamine were detected in 5 of 7 patients. Plasma histamine was elevated within the first 5 min after inhalation of aerosolized allergen, and elevations persisted as long as 30 min. These studies showing that histamine increases significantly in the plasma during allergen-induced asthma in man suggest that histamine should be considered as at least one of the mediators of bronchospasm in allergic asthma. Bronchospasm induced by the cholinergic drug methacholine, unlike allergen-induced bronchospasm, is not associated with changes in plasma histamine.

The relationship of plasma histamine to the activity of bronchial asthma

Abstract Venous plasma histamine levels were measured in 60 asthmatic subjects in order to investigate the role of histamine in naturally occurring asthmatic episodes. The patients were divided into 3 groups of 20 according to the degree of disease activity. Group A consisted of asthmatic patients with severe exacerbations. Flow/volume curves demonstrated a forced expiratory volume in 1 sec to forced vital capacity ratio (FEV1FVC) of less than 55% and a maximum expiratory flow at 50% of FVC (MEF 50 ) of less than 1.0 L/sec. Asthmatics in group B were in partial remission. The patients in this group had FEV1FVC ratios between 55% and 75% and MEF 50 values between 1.0 and 4.0 L/sec. The remaining asthmatic patients (group C) were in complete remission. They were asymptomatic and had normal physical examinations and flow/volume curves. Venous plasma histamine levels were also measured in 50 normal control subjects (group D). Every asthmatic subject in group A had plasma histamine above 1.25 ng/ml (mean, 1.9 ng/ml ± 0.5). Only 3 asthmatic patients in group B and 3 in group C had venous plasma histamine levels greater than 1 ng/ml. None of the normal subjects in group D had plasma histamine above 1 ng/ml. These data show a relationship between spontaneously occurring asthmatic attacks and elevated plasma histamine and support previous studies suggesting that histamine may play a role in the mediation of bronchial asthma.

Hypocomplementemia in Chronic Idiopathic Urticaria

A discrete evoking factor or presumed pathophysiologic mechanism is not recognized in the majority of patients with chronic urticaria or angioedema. Two cases are reported in which chronic urticaria was the main manifestation of an immune cutaneous vasculitis associated with hypocomplementemia attributable to classic and alternative mechanisms of complement activation. Among 72 consecutive patients evaluated for chronic urticaria, 10 additional patients with idiopathic urticaria were found to have hypocomplementemia. Of these, two had evidence of classic and alternative mechanisms of complement activation, five had evidence of only classic pathway activation, and three evidence of predominately or exclusively alternative pathway activation. Circulating immune complexes were found in the majority of patients with classic pathway activation. Hypocomplementemia may provide clues to pathophysiologic mechanisms operative in some patients with chronic urticaria.

Radiographic contrast media infusions. Measurement of histamine, complement, and fibrin split products and correlation with clinical parameters.

Abstract To further an understanding of the effects of radiographic contrast media (RCM) infusions, 43 patients underwent clinical evaluation, including allergy history and skin testing, at least 48 hr before receiving a bolus of Renografin-60 (meglumine diatrizoate [52] and sodium diatrizoate [8]) for intravenous pyelography. Venous plasma samples were obtained serially before and at 2, 4, 10, 30, and 60 min after the infusion. Each sample was assayed for histamine by isotopic enzyme assay, for complement by total hemolytic activity, and for fibrin split products by radioimmunoassay. Immediate generalized reactions occurred in 6 of the patients. Each of the 43 patients had a change in at least 1 of the mediators measured. Plasma histamine rose in 40% of the patients (mean, 3.1 ± 1.62 ng/ml). Plasma complement hemolytic activity decreased in 63% (mean, 29 ± 19%). Fibrin split products were detected in 41%. In comparing the 6 patients who experienced reactions to the 37 who did not, there were no statistically significant differences in rise in plasma histamine, decrease in complement activity, presence of fibrin split products, personal history of allergy, prior exposure or reaction to RCM, skin tests to RCM, and histamine or saline. Although histamine levels, complement activity, and fibrin split products changed in a substantial number of patients undergoing RCM infusions, these changes did not correlate with immediate generalized reactions or with the previously described clinical parameters. It is probable that other modulating factors play significant roles in determining whether or not a reaction occurs.

Oral aspirin challenges in asthmatic patients: a study of plasma histamine

Under carefully controlled conditions, seven aspirin‐intolerant asthmatic patients were challenged with oral aspirin and experienced respiratory tract reactions with a decline in forced expiratory volume in 1 sec (FEV1), ranging from 26 to 64%. Venous blood samples, which were collected during the challenges, showed a rise in plasma histamine in all seven patients. The increase in plasma histamine occurred at the onset of their respiratory reactions and those patients with the most severe asthmatic responses were found to have the highest and most prolonged levels of plasma histamine. The same aspirin‐intolerant asthmatic patients were able to ingest Maalox® or sodium salicylate without untoward effects, decline in FEV1 values or changes in plasma histamine levels. Ten non‐asthmatic individuals and eight out of ten asthmatic control patients were able to ingest aspirin without any reactions or changes in their plasma histamine levels. However, two asthmatic control individuals, with severe asthma requiring treatment with moderate dosages of corticosteroids, were found to have elevated pre‐challenge plasma histamine levels which increased during their ASA challenges despite the absence of respiratory reactions or changes in FEV1 values. It is possible that these two individuals were unsuspected aspirin‐intolerant asthmatics. These studies demonstrate that asthmatic reactions to acetylsalicylates are associated with release of histamine into plasma in the subgroup of asthmatic patients with the aspirin‐intolerance syndrome. Such a finding suggests that histamine may be one of the mediators of bronchospasm in aspirin‐induced asthma.

Skin histamine in chronic urticaria

Abstract To further study the role of histamine in the pathogenesis of chronic urticaria, the concentration of histamine in tissue extracts from skin biopsy samples and in plasma from patients with chronic urticaria was measured by a sensitive radioenzymatic assay. Tissue histamine levels from urticarial lesions and uninvolved skin were compared with extracts of biopsy samples taken from normal controls. The average tissue histamine content in 15 biopsy samples from the chronic urticaria patients was significantly higher than in those of 15 normal controls. Forty percent of the patients had levels 2 SD greater than the mean of the control group. Elevated histamine levels were also found in biopsy samples of uninvolved skin from some urticaria patients. Circulating histamine levels from chronic urticaria patients were rarely elevated and did not correlate with skin concentration. No correlation was noted between tissue histamine concentration and estimated mast cell concentration on Giemsa-stained sections of five biopsy samples. These results indicate that tissue histamine levels are increased in some patients with chronic urticaria. This suggests that local histamine elevations may be important in the pathogenesis of many patients with this disease. In addition, increased tissue histamine in these patients is not reflected by elevated circulating levels.

Plasma complement changes during bronchospasm provoked in asthmatic patients

Two different groups of asthmatic patients were studied. The first group of seven reagin‐mediated asthmatic patients underwent bronchial inhalation challenges with skin test positive antigen (STPA), skin test negative antigen (STNA) and methacholine. Three patients undergoing inhalation challenge with STPA showed a drop in plasma complement. In this group the drop in plasma complement was found only when the patient was challenged with STPA but not with STNA or methacholine. The second group consisted of seventeen patients, seven of whom were intolerant of aspirin (ASA) and ten asthmatic patients who experienced no untoward effects to ASA. The second group of seventeen patients was challenged with oral ASA. Venous blood samples collected during the challenges, showed a decrease in plasma complement in five patients intolerant to ASA. The ASA intolerant asthmatic patients were challenged also with either Maalox® or sodium salicylate. Only patients who ingested sodium salicylate showed a decrease in plasma complement. Activation of the alternative pathway was demonstrated in some patients. These studies demonstrated that complement activation occurred during STPA or aspirin challenges in asthmatic individuals. The role of the complement system is not clear, but it may participate in some of the pathogenetic mechanisms regulating bronchospasm through the mediations of its split products.

Detection of complement activation by counterimmunoelectrophoresis (CIE).

Counterimmunoelectrophoresis (CIE) was used as a method of detecting activation of the third component of the complement system (C3). Highly purified C3, normal human serum (NHS), EDTA-treated plasma and serum activated with aggregated human immunoglobulin (agg-IgG) or inulin were used as sources of C3 and/or C3 split products. Activation of the alternative pathway of complement was assayed in the presence of EGTA (10 mM) and MgCl2 (0.3 mM), conditions which block activation of the classical pathway. When purified native C3, fresh NHS and fresh EDTA-plasma were tested in CIE against either antisera to whole C3 or to C3 split products, only one precipitin line was found, which was identified as native C3. However, when serum activated with agg-IgG or inulin were tested against the same reagents, two precipitin lines were seen. The first, with more cathodal mobility was identical to that of native C3. The second line had a more anodal mobility, was distinctly separated from the first and contained C3c and C3d as shown immunochemically with specific antisera. Native C3 and split products of C3 were identified by this CIE method in patients showing evidence of activated complement by having subnormal total complement (CH50) levels. When C3 split products were identified, the C3c-C3d precipitin line could always be distinguished from native C3 by its different electrophoretic mobility, even when C3 concentrations in serum varied from 0.25 mg/ml to 1.5 mg/ml. The sensitivity of CIE was compared to that of CH50 by asssaying at different time intervals after agg-IgG was added to fresh NHS. C3c-C3d split products were detected by CIE before any fall in CH50 and at all times when a significant decrease in CH50 was present. This study shows that the CIE technique is a highly sensitive, specific and rapid method for detecting activation of the complement system via classical or alternative pathways in human disease.

The Complement System of the Newborn Infant

Whole complement activity (CH50), and levels of some components of the classical (C1q, C4, C3) and alternative (factor B and properdin) pathways were determined in 55 non-infected and 11 infected newborn infants. Normal newborn infants were lower than adults in all complement measurements; preterm infants being significantly lower than term infants. Complement was not effected by intrauterine growth retardation. Absence of C3 split products indicated that the deficiencies were developmental and not due to activation of the complement system. Complement levels were lower in infected infants and this was due to activation of the complement system as C3 split products were present in 54%. Because of the high incidence of split products in infected infants, incorporating a test to determine their presence may be of benefit in the diagnosis of the presence of infection in newborn infants.

Plasma complement and histamine changes in atopic dermatitis

Fifteen patients with atopic dermatitis were investigated to evaluate the total of complement and histamine. In five patients total serum complement haemolytic activity (CH50) was significantly decreased as was the haemolytic activity of complement components C2 (C2H50) and C3 (C3H50) By counter immunoelectrophoresis split products of C3 were detected. There was no evidence for alternative pathway activation or the presence of an activator of the alternative pathway. In three patients plasma histamine concetrations were elevated. The intensity of the complement and histamine changes observed seemed to be correlated to the severity of the disease.