Modification of bronchial hyperreactivity after treatment with sodium cromoglycate during pollen season

Repeated bronchial histamine challenges before, during, and after the birch pollen season were performed in 22 allergic patients with bronchial hyperreactivity (BHR) treated for 6 wk with sodium cromoglycate (SCG), 20 mg, four times a day, or placebo in a double-blind, randomized group comparison. Clinical assessments of the asthmatic symptom score and peak expiratory flow revealed less symptoms and less use of bronchodilators in the SCG group. Responsiveness to histamine was significantly increased in the placebo group after 14 days with high pollen counts. After the season there was an immediate return to preseasonal value. There was no change in responsiveness in the SCG group, demonstrating significant protection against pollen-induced increase of BHR. The results support the hypothesis that inhibition of mediator release, which is demonstrated for SCG, leads to a reduction of the nonspecific BHR.     

Dose, plasma concentration, and effect of oral terbutaline in long-term treatment of childhood asthma

Oral terbutaline in gradually increasing doses from 45 to 166 micrograms/kg three times daily was administered to asthmatic school children. There was a linear relationship between dose and steady-state plasma concentration of terbutaline within patients, but the plasma levels varied fourfold between patients taking similar doses. The consumption of beta 2-stimulants in aerosol form decreased, and the symptom score, peak expiratory flow rate, and FEV1 improved during treatment with a roughly linear dose-effect relationship. Significant increases in pulse rate and skeletal muscle tremor were also measurable. There was no clear correlation between plasma levels of terbutaline and reported side effects. Linear regression analysis revealed a statistically significant relationship between bronchodilatation and the same plasma level was considerable. Determination of the plasma terbutaline concentration therefore seems to be of limited value in clinical practice. Instead, the dose should be individualized on the basis of clinical effect and tolerance. Our data indicate that many young asthmatic children will tolerate and sometimes benefit from higher doses than are generally recommended if they are carefully titrated with stepwise increments.     

The effect of troleandomycin on methylprednisolone elimination

Troleandomycin (TAO), a macrolide antibiotic, has an apparent “steroid-sparing” effect when used in the treatment of severe steroid-dependent asthma. This study was designed to investigate the effect of TAO on methylprednisolone elimination. Pharmacokinetic studies were performed before and 1 wk after starting TAO in 10 severe steroid-dependent asthmatics. Baseline total body clearance of methylprednisolone was 406 ± 139 (mean ± SD) ml/min/1.73 m² and decreased significantly (p < 0.001) to 146 ± 57 ml/min/1.73 m² 1 wk after TAO therapy was initiated. Methylprednisolone half-life was 2.46 ± 0.75 hr before TAO and increased significantly (p < 0.001) to 4.63 ± 1.35 hr after 1 wk on TAO therapy. A follow-up evaluation of methylprednisolone pharmacokinetics in three patients after at least 1 mo on TAO therapy demonstrated continuation of the reduced methylprednisolone elimination. TAO inhibition of methylprednisolone clearance may contribute to the beneficial effects observed initially with combined methylprednisolone-troleandomycin therapy in severe steroid-dependent asthma.     

Elevated serum immunoglobulin E in bronchial carcinoma: its relation to the histology and prognosis of the cancer

Total IgE and specific IgE antibodies against six common allergens were measured in the sera of 217 unselected patients with bronchial carcinoma. Their median total IgE level was significantly increased as compared to the median levels found in two control populations consisting of 246 individuals representing the adult general population and 143 patients with benign pulmonary disorders. The frequency of serological atopy, i.e., the presence of specific IgE antibodies, was also significantly increased in the cancer population as compared to the controls. In contrast, the incidence of possible clinical atopy was about five times higher in the general population than in the cancer group. Patients with bronchial carcinoma typed as adenocarcinoma had the best prognosis and also had nonelevated IgE levels in contrast to patients with bronchial carcinoma typed as squamous cell carcinoma, small or large cell carcinoma. The favourable prognosis with nonelevated IgE levels also was demonstrated in patients with squamous cell carcinoma. It is suggested that the elevated IgE levels in bronchial carcinoma reflect impaired cellular immunity.     

Infantile bronchial asthma

There is no evidence that any type of therapy, including hyposensitization therapy, will directly influence prognosis.The long-term prognosis of childhood asthma is less optimistic than previously believed. Approximately 30% of the patients who become symptom-free in adolescence relapse and become symptomatic in early adulthood.⁶² Blair's⁶² recent 20-yr follow-up report on 267 childhood asthmatics revealed that only 50% had become almost or completely symptom-free. Moreover, there is evidence that 60% of those who become symptom-free still demonstrate bronchial hyperreactivity⁶³ and are liable to wheeze again if challenged with an appropriate stimuli. Therefore, the dictum that most children “outgrow” their asthma is incorrect and a more likely explanation is that most childhood asthmatics “outgrow” their pediatricians.     

Intravenous isoproterenol: Rationale for bronchial asthma

Intravenous isoproterenol was infused into 7 adult asthmatic patients with refractory bronchial obstruction. Over a dose range of 0.0375 to 0.225 μg per kilogram per minute, maximal bronchodilator effect (or reversal of effect) occurred within 2 to 5 minutes of starting (or stopping) the infusion. Obstruction to airflow improved with each increment of dose. Average heart rate reached a maximum at 0.075 μg per kilogram per minute. Over the lower dose range alveolar to arterial oxygen gradients widened and heart rate increased; over the higher dose range, as heart rate plateaued, bronchodilator effect continued and oxygen gradient narrowed. When combined with adequate oxygenation and continual monitoring of cardiac rhythm and blood pressure, intravenous isoproterenol appears safe for asthmatic patients. Major advantages are (1) administration of bronchodilator to airways not reached by inhalation, (2) prompt onset and offset of effects, and (3) reversal of undesirable side effects. The use of intravenous isoproterenol may obviate the need for intubation and ventilatory assist.     

Fatal myocardial toxicity during continuous infusion intravenous isoproterenol therapy of asthma

We recently utilized continuous infusion intravenous isoproterenol in the treatment of respiratory failure in an 18-yr-old steroid-dependent asthmatic female. Aminophylline, hydrocortisone, aerosolized isoetharine, and oxygen were also administrered. The patient responded to this therapy, with PaCO2 falling from 70 torr to 33 torr in 18 hr. The maximum isoproterenol dosage administered was 0.32 microgram/kg/min. Thirty-six hours following the institution of therapy, while the isoproterenol was being tapered, the patient experienced an increase in respiratory distress followed by cardiac arrest. Postmortem examination revealed multiple small areas of myocardial necrosis. These findings, unusual in asthma, probably were related to the effects of isoproterenol or the combination of isoproterenol and aminophylline on the stressed myocardium. The vulnerability of the hypoxic myocardium to the effects of isoproterenol suggests that careful cardiac monitoring is essential in the management of patients receiving this medication for treatment of respiratory failure secondary to severe asthma.     

Nightly asthma caused by allergens in silk-filled bed quilts: clinical and immunologic studies

Bed quilts filled with silk waste were found to cause nightly attacks of asthma. The first symptoms appeared on an average after 7 mo of exposure at a mean patient age of 30 yr. About 50% of the patients could be classified as atopic. Extract of the filling material revealed positive scratch and RAST tests in most patients. The bed quilts were advertised as being filled with pure wild silk (from silk moths of the genus Antheraea feeding on oak leaves), but it was found that in most cases the filling also included waste of cultivated silk (Bombyx mori). The origin of the allergen was sought. Since textile products of silk are considered to be practically nonallergenic, some type of contaminant appeared the most likely candidate. No allergen was found in cocoons, chrysalis (pupa), or moths of Antheraea. However, some cocoons of Bombyx mori, usually in small amounts, and excretions of the silkworm did contain allergen. High concentrations of allergen were found in an extract of living insects of the genus Anthrenus that was present in one batch of Bombyx mori cocoons. Thus, the silk waste appeared to be contaminated with material from the silkworms and also with infesting insects, which together create a very potent allergen repertoire that after a short incubation time, in a considerable frequency, elicits a rise in asthmatic symptoms and high serum IgE antibody levels.     

IgE synthesis in man. II. Comparison of tetanus and diphtheria IgE antibody in allergic and nonallergic children.

Specific IgE and IgG antibodies were quantitated in 91 allergic and 80 nonallergic age- and sex-matched children between 4 and 17 yr of age. Statistically significant increased antidiphtheria and antitetanus IgE antibodies (p < 0.01) measured by the radioallergosorbent test (RAST) were noted in allergic compared with nonallergic subjects. Of the allergic children with total serum IgE >500 U/ml, 19 of 52 (37%) and 25 of 52 (48%) had elevations (>2 SD above nonallergic control mean) of serum antitetanus or antidiphtheria IgE antibody, respectively, whereas only 2 of 35 allergic children with serum IgE <500 U/ml had elevation (>2 SD) of these antibodies. Antitetanus and antidiphtheria IgG antibodies were measured by passive sheep red blood cell (SRBC) hemagglutination. Geometric mean antitetanus IgG antibodies were higher in allergic (4.9 AU/ml) as compared to nonallergic (1.7 AU/ml) children (p < 0.001). Geometric mean antidiphtheria IgG antibodies were higher (0.31 AU/ml) in nonallergic and lower in allergic (0.10 AU/ml) subjects (p < 0.01). These data suggest that allergic individuals with markedly elevated total serum IgE have unique antibody responses following routine immunization with tetanus-diphtheria (Td) toxoids and tetanus-pertussis-diphtheria (DPT) which are manifest by enhanced specific IgE synthesis.     

Reagin synthesis in inbred rats: II. Genetic control of reaginic antibody synthesis

Specific reaginic (IgE) and hemagglutinating (IgG) antibodies were quantified after immunization with ovalbumin aluminum hydroxide gel in BN and ACI inbred rats, as well as their F₁, F₁ X BN backcross, F₂, and F₃ progeny. The dissimilarity of these immune responses indicated that reaginic (IgE) antibody synthesis was influenced by polygenic factors, but not sex, and was controlled by loci different from that governing hemagglutinating (IgG) antibody synthesis. In addition, tissue typing of the BN, ACI, F₁, and F₃ hybrids suggested that reaginic antibody synthesis was not linked to the major rat histocompatibility locus.     

The quantification of neutrophil orientation and migration under agarose — a new method for detecting directed and random movements

Polymorphonuclear (PMN) granulocyte migration under agarose has been examined quantitatively with regard to measurement of the distance to the leading front cells, the location of maximal cell density and the limits for 50% of the migrating cells, and assessment of the degree of orientation of migrating neutrophils after fixation and staining. It was found that two cytotaxins, bacterial factors from E. coli (BF) and serum, both elicited directed and stimulated migration during the first hour of incubation. Thereafter, a continuous decrease of cell orientation and the distance to the boundary of the cell front occured, with some differences between the cytotaxins. Leukocytes were also incubated with vinblastine and cytochalasin B, serving as models for selective impairment of migration coordination and locomotive ability. With vinblastine, the foremost PMNs did not migrate as far as untreated cells, but treatment did not influence the distance migrated by most of the cells although the PMNs moved in an disoriented manner. Cytochalasin B impaired forward movement of the cells while orientation was well preserved. It is suggested that the agarose assay inexpensively and easily assesses whether chemotaxis or chemokinesis is occuring. Estimation of the degree of orientation of migrating neutrophils was a particularly valuable variable not previously used for this purpose. Two unrelated cytotaxins elicited chemotactic followed by chemokinetic migration, emphasizing that both types of movement may occur in a time-associated manner during incubation.     

Late allergic bronchial reactions and the effect of allergen provocation on the complement system

Forty-nine bronchial provocations were performed with different allergens in allergic asthmatic patients. Immediate bronchial reactions occurred in 33 instances, and late reactions occurred in nine instances. The material was divided into three groups according to patients with no reactions, patients with early reactions alone, and patients with late reactions. Titers of whole complement and factors C2 and C3 were determined hemolytically, and the serum protein contents of factors C3, C4, and C1q were measured immunochemically. Decreases in complement and complement components were observed on a number of occasions after bronchial challenge. When the groups were compared with respect to mean change in complement titers, the three groups were indistinguishable. No change was noted in the ratio between the complement contents in venous and arterial blood as a result of provocation, nor did the specific hemolytic activity of factor C3 change. No C3 split products could be traced. It is likely that there will be a higher proportion of patients with C2 consumption among those with late bronchial reactions. No special feature could be assigned to these individuals, however. It is concluded that no major complement activation is regularly found in allergic asthmatic patients as a result of exposure to allergens. However, groups of patients in whom such activation takes place might exist.     

The effect of inhaled nifedipine on bronchial reactivity to histamine in man

We have administered nifedipine by aerosol to six patients with mild asthma to determine whether local administration of a potent calcium channel blocker has any effect on resting airway tone or histamine reactivity. Subjects had their responsiveness to histamine measured and then received either nifedipine, 10 mg in 40% ethanol, or diluent alone in a randomized, double-blind fashion. Specific airway conductance, blood pressure, and heart rate did not change after either inhalation. Histamine reactivity was significantly reduced after the nifedipine aerosol, the geometric mean provocative concentration causing a 35% fall in specific airway conductance, rising from 5.0 to 10.9 mg/ml of histamine (p less than 0.05). In individuals this protective effect was variable but overall was no greater than that observed after sublingual nifedipine. Plasma nifedipine concentrations were measured in two subjects after administration of the aerosol and confirmed that inhaled nifedipine is absorbed across the bronchial mucosa.     

The effect of ranitidine, alone and in combination with clemastine, on allergen-induced cutaneous wheal-and-flare reactions in human skin

The effect of intradermal ranitidine (administered alone and in combination with clemastine) on allergen-mediated wheal-and-flare reactions has been evaluated in a double-blind study on 10 healthy atopic volunteers. Ranitidine alone, administered in doses over a 10(4)-fold concentration range, had no effect on the size either of allergen-induced wheal or flare reactions. Clemastine alone evoked a dose-related inhibition of both wheal and flare. Compared to the inhibition achieved by clemastine alone, the combination of ranitidine with clemastine produced a small but significant increase in inhibition of allergen-induced flare at ranitidine concentrations of 10(-5) mol/L (p less than 0.001) and 10(-6) mol/L (p less than 0.01), and of allergen-induced wheal at ranitidine concentration 10(-5) mol/L (p less than 0.01). Our results provide further evidence for the presence of cutaneous histamine H2 receptors and their participation in the formation of allergen-mediated skin reactions but indicate that the contribution of cutaneous histamine H2-receptor stimulation to the production of immediate wheal-and-flare reactions evoked by allergen is only modest.     

Chromosome and DNA cytometric study of a papillary carcinoma of the bladder with a high stemline and numerous double minutes

A papillary cancer of the bladder [WHO grade 3] was studied with chromosome and DNA analysis. A high frequency of mitoses was noted, and analysis of 151 metaphases revealed a dominating stemline in the pentaploid region. More than 95% of the cells contained double minutes (dm). Flow cytometry showed the dominant stemline to be in the hexaploid region, that is, about 20% above the numerical chromosome value. This difference is generally obtained when these two methods are compared and is not influenced by the presence of dm. Both methods have been complementary in the evaluation of this tumor.     

Study on cockroach antigen as a probable causative agent in bronchial asthma

Bronchial provocative test (BPT) with cockroach (CR) antigen was performed in 22 asthmatic subjects. Sixteen had positive reaction (CR-positive) and 6 had negative reaction (CR-negative) to CR antigen by skin test. Immediate bronchoconstrictive response was noted following the antigen inhalation in 14 of 16 CR-positive asthmatics, while none of 6 CR-negative asthmatics showed bronchospasm. Late asthmatic responses also were noted in 13 of 16 CR-positive asthmatic individuals following BPT with CR antigen. The dual asthmatic reactions in CR-positive individuals were mostly inhibited by the prior administration of cromolyn sodium. Three-fold increases in peripheral eosinophil counts were noted 24 hr following BPT with CR antigen. Results indicate that CR-induced asthmatic responses are allergen-specific and CR plays a causative role in allergic asthma in the population studied.     

Hypersensitivity to pancreatic extracts in parents of patients with cystic fibrosis.

Because immediate hypersensitivity reactions can occur in individuals exposed to powdered pancreatic extracts, 36 patients with cystic fibrosis and 51 patents of such patients wwer studied for evidence of sensitization. Sensitivity to the extracts as evidence by history and skin testing was infrequent in the children with cystic fibrosis. However, skin testing for immediate hypersensitivity with either crude pancreatic extracts or inactivated trypsin correlated well in their patents with a history of clinical symptoms. IgE mediation of these reactions in sensitized individuals was demonstrated by antigen-induced histamine release from leukocytes, passive transfer studies, and immediate response to inhalation challenge.     

Synthesis of IgE by the human conceptus

The capability of the human conceptus in synthesizing IgE was investigated in this study. Embryonic and fetal tissues obtained from spontaneously or therapeutically aborted conceptuses were cultured in the presence of ¹⁴C-labeled amino acids, and the culture fluids were then analyzed by radioimmunoelectrophoresis for the presence of radioactive IgE and IgG. Synthesis of IgE was noted as early as 11 weeks in fetal lung and liver, and by 21 weeks in fetal spleen. Interestingly, synthesis of IgG was also found as early as 11 weeks of gestation. The data indicate: (1) that the conceptus has the potential, in terms of IgE synthesis, for developing reaginmediated sensitivity in utero; and (2) that each of the immunoglobulin classes of man may be synthesized by separate lymphoid cell lines rather than from a single cell line that develops immunoglobulin synthesis sequentially.