Hal B. Richerson

Elevated bronchoalveolar lavage fluid histamine levels in allergic asthmatics are associated with methacholine bronchial hyperresponsiveness.

Using a sensitive single isotope enzymatic assay we measured bronchoalveolar lavage (BAL) fluid histamine in asymptomatic normal (nonallergic), allergic rhinitic, and allergic asthmatic subjects. Normal subjects were found to have little or no detectable amounts of histamine in BAL fluid (11 +/- 11 pg/ml), and few BAL fluid mast cells. In comparison, the allergic rhinitics and allergic asthmatics had much higher amounts of BAL fluid histamine (113 +/- 53 and 188 +/- 42 pg/ml, respectively), and a significantly greater number of BAL fluid mast cells. Furthermore, despite having equivalent baseline pulmonary function values, allergic asthmatics with BAL fluid histamine levels greater than 100 pg/ml required only 7 +/- 2 breath units of methacholine to induce a 20% drop in forced expiratory volume in 1 s (FEV1) (PD20FEV1) while asthmatics with BAL fluid histamine levels less than 100 pg/ml required 49 +/- 19 breath units (P less than 0.05). These data suggest that allergic asthmatics have ongoing lung mast cell degranulation that might contribute to the etiology of airway hyperresponsiveness.

Direct evidence of a role for mast cells in the pathogenesis of antigen-induced bronchoconstriction.

We measured bronchoalveolar lavage (BAL) fluid histamine levels in allergic asthmatics and nonallergic normal subjects after local airway antigen and cold 22 degrees C normal saline challenges. Immediately after instillation of antigen through a bronchoscope wedged into a subsegmental airway, all 17 allergic asthmatics but none of the nine normal subjects had visible airway constriction. The asthmatics had a concomitant mean increase in BAL histamine of 23% (P = 0.005), whereas the normals had no change in BAL histamine. Among the allergic asthmatics, the change in BAL histamine content in response to antigen directly correlated with the control (baseline) BAL histamine content (r = 0.66, P = 0.003). Moreover, asthmatics with large antigen-induced changes in BAL histamine had greater airway methacholine sensitivity than did asthmatics without measurable increases in BAL histamine (8 +/- 2 vs. 41 +/- 31 breath units). Neither asthmatics nor normal subjects had airway constriction or changes in BAL histamine levels in response to nonspecific challenge with cold saline. Our data suggest that when allergic asthmatics are exposed to relevant antigens they have in vivo lung mast cell degranulation which results in airway constriction and contributes to nonspecific airway hyperresponsiveness.

Late asthmatic responses: Inquiry into mechanisms and significance

Summary and ConclusionsLate asthmatic responses are common, simulate a chronic phase of asthma, and are associated with an influx of inflammatory cells. The precise sequence of events leading to late inflammatory responses and increased hyperrespon-siveness of the airways is uncertain, but likely begins with the triggering of mediator release from local (luminal or interstitial) mast cells or, conceivably, alveolar macrophages. Consequent influx and activation of granulocytes, including eosinophils and neutrophils, possibly T lymphocytes, basophils, and platelets, and subsequently later-arriving monocytes and macrophages, may be responsible for a continuing inflammatory reaction, airways hyperrespon-siveness, and continuing active bronchial asthma.Identification of the relative importance of responsible cells and mediators will help clarify pathogenesis of bronchial asthma and should lead to a better understanding and design of therapeutic regimens and preventive measures in the management of this common and important disease.

Nasal airway response to exercise

Abstract Increased nasal airway patency with physical exercise has been a frequent observation of patients with allergic rhinitis. This response has been documented in a patient with allergic rhinitis in whom airway patency was measured by a rhino-manometric technique before and after handball exercise. In an additional six subjects, the phenomenon was further studied using a controlled step exercise. The mechanism of the nasal airway response to exercise was evaluated by autonomic stimulation and blockade. Intravenous infusion of epinephrine and norepinephrine failed to simulate the response to exercise. The exercise response was not significantly blocked by autonomic blockade with intramuscular phentolamine or intravenous guanethidine. Significant blockade occurred with topical phentolamine and especially with stellate ganglion block. These findings indicate that the main mechanism responsible for increased nasal airway patency with exercise is sympathetic nerve discharge. Other possible contributing factors are discussed.

Altered recognition of surface-adsorbed compared to antigen-bound antibodies in the ELISA

We found in preliminary studies using 125I-labelled antibodies that an antibody bound to a solid-phase antigen was recognized more efficiently than an antibody adsorbed directly to the solid phase. The present study was designed therefore to quantitate the differential recognition of an antibody adsorbed directly to the solid phase and an antibody bound to antigen on the solid phase using the amplified enzyme-linked immunosorbent assay (a-ELISA), and to compare results with the amounts of specific antibody determined by quantitative immunoprecipitation. The degree of differential recognition was quantitated for rabbit IgG and SIgA anti-ovalbumin (anti-OA) and anti-fluorescein, and was found to be dependent upon the isotype of the antibody and not its specificity. The ratio describing the differential recognition of SIgA antibodies (1.8) was much less than for IgG antibodies (greater than 30) and remained constant over the titration range analyzed while the ratios obtained for IgG varied substantially (25-60) over the same range. These ratios of differential recognition were used to estimate rabbit IgG antibody levels to OA, bovine serum albumin, ferritin and alpha-lactalbumin. The estimates obtained were consistently much less than total antibody levels measured by quantitative precipitation. The use of glutaraldehyde-aggregated OA in the ELISA, however, increased the amount of IgG anti-OA and SIgA anti-OA capable of recognizing OA adsorbed on plastic from 12 to 50 and from 30 to 80%, respectively.

Generation and partial characterization of eosinophil chemotactic activity and neutrophil chemotactic activity during early and late-phase asthmatic response

Asthma has been recognized to consist of hyperresponsive airways and cellular inflammation. Allergen bronchoprovocation (BPC) may define the early (EAR) and late-phase asthmatic response (LAR). The LAR has now been associated with increased nonspecific airway hyperresponsiveness and cellular inflammation consisting of neutrophils and eosinophils. We used BPC to demonstrate EAR and LAR in 12 subjects with seasonal allergic asthma. One normal subject and one subject with asthma who had been treated with allergy immunotherapy were challenged but did not respond. Plasma was sampled at frequent intervals during these aeroallergen challenges and assayed for eosinophil chemotactic activity (ECA) and neutrophil chemotactic activity (NCA). Of the 12 subjects with asthma who were challenged, nine had dual responses (both EAR and LAR), and three subjects demonstrated only an LAR. Those subjects who had dual airway responses had biphasic rises in both ECA (early = 267 +/- 28%; late = 286 +/- 28%) and NCA (early = 279 +/- 24%; late = 215 +/- 15%) in their plasma, whereas those subjects who demonstrated only an LAR had only a late rise in ECA (218 +/- 61%) and NCA (188 +/- 31%). The two individuals who did not respond to aeroallergen challenge demonstrated no change in their plasma chemotactic activity toward either eosinophils or neutrophils. Those individuals with the most severe LAR (greater than or equal to 1,000 mm2) had combined ECA plus NCA peak values of greater than 500%.(ABSTRACT TRUNCATED AT 250 WORDS)

Cutaneous and nasal allergic responses in ragweed hay fever: Lack of clinical and histopathologic correlations with late phase reactions

The present study was designed to test the hypotheses that late cutaneous and nasal responses to allergen in patients with ragweed hay fever were human correlates of cutaneous basophil hypersensitivity, and that late responses in the nose and skin reflect similar pathogenesis. Forty-seven patients with ragweed hay fever were studied during a ragweed season for peripheral basophilia and clinical patterns reflecting late responses. Provocative nasal challenge, skin testing, and biopsy were carried out subsequently in 21 of the same patients during the winter months. Conclusions were as follows: (1) no histologic features distinguish positive from negative late skin reactions at 24 hr in patients with immediate wheal-and-flare responses; (2) cutaneous basophil hypersensitivity, i.e., tissue basophilia, is not a distinguishing feature of late skin responses in ragweed pollenosis; (3) seasonal peripheral basophilia was not found; (4) late responses in the nose were difficult to document objectively and did not correlate with late skin reactions; and (5) lymphocyte responses to antigen failed to correlate with late responses in either the nose or the skin.

Serious adverse reactions to protamine sulfate: Are alternatives needed?

Protamine sulfate is a strongly cationic polypeptide that is used commonly in clinical medicine. It is administered regularly after cardiac catheterization, cardiothoracic and vascular surgical procedures, and less frequently after dialysis and leukapheresis because of its capacity to reverse the anticoagulant activity of heparin. In addition, because it delays the absorption of insulin, protamine is combined with insulin in protamine zinc insulin and neutral protamine Hagedorn insulin. Recently, there have been reports of adverse reactions to protamine (Table I). Although most of these reactions were relatively mild, three were fatal; one was clearly the result of type I anaphylaxis. Reactions occur predominantly in patients who were previously exposed to protamine through protamine-containing insulins or during heparin neutralization. Almost 50% of these patients were diabetic; most of whom received neutral protamine Hagedorn insulin, thereby enhancing their chance for presensitization. In 1983 we encountered three patients who suffered adverse reactions to protamine sulfate. Two of these patients will be presented here; the third patient, who died of IgE-mediated anaphylaxis, has already been reported and therefore is mentioned only briefly. We shall discuss adverse reactions to protamine sulfate and alternatives to the routine use of this drug.

Respiratory pathophysiologic responses: Comparisons of specific and nonspecific bronchoprovocation in subjects with asthma, rhinitis, and healthy subjects☆

BACKGROUND We studied subjects with atopic asthma, atopic rhinitis, and nonatopic healthy subjects to evaluate responsiveness to bronchoprovocation with both methacholine and allergen. METHODS Subjects with a demonstrable FEV1 PD20 to methacholine or allergen (responders) were further analyzed for putative sensitivity (PD20 FEV1) and reactivity (dose-response slopes) to determine whether any characteristics could distinguish individuals with asthma from other responders. Subjects were recruited without sex restrictions and were between the ages of 18 and 45 years old. They were nonsmokers, had no other medical problems, and were free of upper respiratory infection for at least 6 weeks before challenge. All had a history taken, physical examination, limited laboratory screening, chest radiography, pulmonary function testing, and intradermal skin testing before admission to the study. RESULTS Although the groups were significantly different in both sensitivity and reactivity to methacholine, responses to allergen bronchoprovocation were sufficiently similar between responders with asthma and those with rhinitis to prevent separation on the basis of either sensitivity or reactivity. The fall in FEV1 at the nadir of the late response, which was greater in the asthma group, was significantly correlated with sensitivity and reactivity of the immediate response to allergen but not to methacholine. Regression analysis demonstrated a stronger association between allergen and methacholine responsiveness in subjects with rhinitis than in subjects with asthma. CONCLUSION We concluded that (1) nonspecific bronchial hyperresponsiveness fails to explain why patients with allergic asthma have clinical asthma as a result of allergen exposure and patients with allergic rhinitis do not; (2) hyperresponsiveness to allergen does not simply reflect quantitative or qualitative airway nonspecific hyperresponsiveness; and (3) clinical asthma may involve mechanisms difficult to elucidate by laboratory bronchoprovocation techniques.Abstract Background: We studied subjects with atopic asthma, atopic rhinitis, and nonatopic healthy subjects to evaluate responsiveness to bronchoprovocation with both methacholine and allergen. Methods: Subjects with a demonstrable FEV 1 PD 20 to methacholine or allergen (responders) were further analyzed for putative sensitivity (PD 20 FEV 1 ) and reactivity (dose-response slopes) to determine whether any characteristics could distinguish individuals with asthma from other responders. Subjects were recruited without sex restrictions and were between the ages of 18 and 45 years old. They were nonsmokers, had no other medical problems, and were free of upper respiratory infection for at least 6 weeks before challenge. All had a history taken, physical examination, limited laboratory screening, chest radiography, pulmonary function testing, and intradermal skin testing before admission to the study. Results: Although the groups were significantly different in both sensitivity and reactivity to methacholine, responses to allergen bronchoprovocation were sufficiently similar between responders with asthma and those with rhinitis to prevent separation on the basis of either sensitivity or reactivity. The fall in FEV 1 at the nadir of the late response, which was greater in the asthma group, was significantly correlated with sensitivity and reactivity of the immediate response to allergen but not to methacholine. Regression analysis demonstrated a stronger association between allergen and methacholine responsiveness in subjects with rhinitis than in subjects with asthma. Conclusion: We concluded that (1) nonspecific bronchial hyperresponsiveness fails to explain why patients with allergic asthma have clinical asthma as a result of allergen exposure and patients with allergic rhinitis do not; (2) hyperresponsiveness to allergen does not simply reflect quantitative or qualitative airway nonspecific hyperresponsiveness; and (3) clinical asthma may involve mechanisms difficult to elucidate by laboratory bronchoprovocation techniques.

Clinical evaluation of intranasal topical flunisolide therapy in allergic rhinitis

A double-blind, vehicle control, parallel clinical trial evaluated the effectiveness and safety of the local application of flunisolide, a potent new topical steroid, in the treatment of ragweed hay fever. Fifty patients with well-defined, poorly controlled ragweed allergy were studied during the 1974 ragweed season. Analysis of the data showed that the active drug group had a significant decrease in individual symptoms of sneezing, nasal stuffiness, and nasal secretions, compared with the placebo group. Antihistamine usage was statistically decreased in the active drug over placebo group. There was no evidence of adrenal suppression. This study indicates that intranasal administration of flunisolide in adult patients is both efficacious and safe in the treatment of seasonal allergic rhinitis.