Eugene R. Bleecker

Genetic Susceptibility to Asthma — Bronchial Hyperresponsiveness Coinherited with a Major Gene for Atopy

BACKGROUND Bronchial hyperresponsiveness, a risk factor for asthma, consists of a heightened bronchoconstrictor response to a variety of stimuli. The condition has a heritable component and is closely related to serum IgE levels and airway inflammation. The basis for these relations is unknown, as is the mechanism of genetic susceptibility to bronchial hyperresponsiveness. We attempted to define the interrelation between atopy and bronchial hyperresponsiveness and to investigate the chromosomal location of this component of asthma. METHODS We studied 303 children and grandchildren of 84 probands with asthma selected from a homogeneous population in the Netherlands. Ventilatory function, bronchial responsiveness to histamine, and serum total IgE were measured. The association between the last two variables was evaluated. Using analyses involving pairs of siblings, we tested for linkage between bronchial hyperresponsiveness and genetic markers on chromosome 5q31-q33, previously shown to be linked to a genetic locus regulating serum total IgE levels. RESULTS Serum total IgE levels were strongly correlated (r = 0.65, P < 0.01) in pairs of siblings concordant for bronchial hyperresponsiveness (defined as a > or = 20 percent decrease in the forced expiratory volume in one second produced by histamine [threshold dose, < or = 16 mg per milliliter]), suggesting that these traits are coinherited. However, bronchial hyperresponsiveness was not correlated with serum IgE levels (r = 0.04, P > 0.10). Analyses of pairs of siblings showed linkage of bronchial hyperresponsiveness with several genetic markers on chromosome 5q, including D5S436 (P < 0.001 for a histamine threshold value of < or = 16 mg per milliliter). CONCLUSIONS This study demonstrates that a trait for an elevated level of serum total IgE is coinherited with a trait for bronchial hyperresponsiveness and that a gene governing bronchial hyperresponsiveness is located near a major locus that regulates serum IgE levels on chromosome 5q. These findings are consistent with the existence of one or more genes on chromosome 5q31-q33 causing susceptibility to asthma.

Physiologic manifestations of human anaphylaxis.

In the course of a controlled study to evaluate different forms of immunotherapy for subjects with insect-sting hypersensitivity, we observed 11 subjects who had systemic cutaneous urticarial reactions and 3 subjects who experienced systemic anaphylaxis. With the exception of tachycardia, there were no cardiopulmonary changes in the subjects with urticaria, whereas the major manifestation of anaphylactic shock in the other three subjects was severe hypotension that was probably secondary to peripheral vasodilation. Significant abnormalities in gas exchange developed in two subjects. In one, bronchospasm precipitated a respiratory arrest followed by endotracheal intubation with mechanical ventilation. Although plasma histamine levels were not related to the development of cutaneous reactions, the plasma histamine levels correlated with the severity and duration of the cardiopulmonary changes observed during anaphylactic shock. The two subjects with the most severe shock showed evidence of intravascular coagulation characterized by a diminution of Factor V, Factor VIII, fibrinogen, and high molecular weight kininogen, as well as changes in components of the complement system. Standard therapy with epinephrine and fluids, usually recommended for the treatment of systemic anaphylaxis, did not immediately reverse either the hemodynamic or the respiratory abnormalities in the two subjects with the most severe anaphylactic shock. Hemodynamic recovery was gradual and did not seem directly related to any specific therapeutic intervention.

Flow-volume curves and sleep-disordered breathing: therapeutic implications.

To assess the relationship of abnormal flow-volume curves during awake periods to the clinical severity of sleep-disordered breathing and the need for surgical treatment of obstructive sleep apnoea, flow-volume curves were measured in 72 adults with obstructive apnoea. Patients in whom surgery was recommended for standard clinical indications had significantly lower inspiratory flow rates (p less than 0.01) and a higher incidence of flow-volume curves indicating extrathoracic airway obstruction (p less than 0.01) than did non-surgical patients. These abnormal flow-volume curves correlated with an increased severity of nocturnal oxygen desaturation (p less than 0.01). Furthermore, increases in inspiratory flow rates measured serially in 22 patients were related to improvement in their polysomnography (p less than 0.05), suggesting that alterations of airway function during awake periods correlate with changes in the severity of sleep apnoea.

Learned control of ventricular rate in patients with atrial fibrillation

&NA; Six patients with chronic atrial fibrillation (AF) and rheumatic heart disease on stable digitalis regimens were trained to slow and to speed ventricular rate (VR). Two subjects were more consistent in their ability to slow VR; two subjects were more consistent in their ability to speed VR; and the remaining two subjects were able to slow and to speed VR reliably. All subjects were able to control VR differentially during sequential slowing and speeding phases of experimental training sessions. Analyses of R‐R interval histograms revealed that all subjects significantly changed the statistical frequency distributions of their R‐R intervals. During VR slowing one subject generated a junctional escape rhythm. Another subject produced frequent premature ventricular contractions during speeding of VR under effective B‐adrenergic blockade with propranolol. This control of VR in AF is neurally mediated at the level of the atrioventricular node. Studies with autonomic drugs indicate that this central nervous system control of VR in this arrhythmia usually occurs through activation of efferent cholinergic pathways.