Non-tuberculous mycobacterial pulmonary infection in the immunocompetent host.

Throughout much of the world, the incidence of non-tuberculous mycobacterial pulmonary infections in immunocompetent hosts is on the rise. These organisms are widespread in the natural environment; the explanation for what appears to be an increased susceptibility among human hosts is uncertain. Among more than 120 known species, the most common pathogenic isolate in the USA is Mycobacterium avium complex. The diagnosis of pulmonary disease caused by M. avium complex requires a compatible history, suggestive radiographic findings (on chest computed tomography) and microbiologic confirmation on culture of respiratory samples (sputum or direct lung sampling). Treatment options have improved with inclusion of macrolide antibiotics in a multi-drug regimen, but failure rates remain high (20-40%) even after a prolonged course of therapy. Newer, less toxic and more effective anti-mycobacterial agents are greatly needed for treatment of this increasingly common respiratory disease.

Late onset asthma: epidemiology, diagnosis and treatment.

Asthma is common among older persons, affecting approximately 4 to 8% of those above the age of 65 years. Despite its prevalence, late onset asthma may be misdiagnosed and inadequately treated, with important negative consequences for the patient's health. The histopathology of late onset disease appears to be similar to that of asthma in general, with persistent airway inflammation a characteristic feature. It is less clear, however, that allergic exposure and sensitisation play the same role in the development of disease in adults as they do in children. Atopy is less common among those with late onset asthma, and the prevalence of elevated immunoglobulin E levels is lower among those aged over 55 years of age than younger patients. Occupational asthma is an aetiological consideration unique to adult onset disease, with important implications for treatment. The differential diagnosis for cough, wheeze, and dyspnoea in the elderly is broad, and includes chronic obstructive bronchitis, bronchiectasis, congestive heart failure, lung cancer with endobronchial lesion and vocal cord dysfunction. Keys to accurate diagnosis include a good history and physical examination, the demonstration of reversible airways obstruction on pulmonary function tests and a favorable response to treatment. Inhaled corticosteroid therapy is recommended for patients with persistent disease, and careful instruction in the use of metered-dose inhalers is particularly important for the elderly.

Medical and ventilatory management of status asthmaticus.

Despite improved understanding of the basic mechanisms underlying asthma, morbidity and mortality remain high, especially in the "inner cities." The treatment of choice in status asthmaticus includes high doses of inhaled beta 2-agonists, systemic corticosteroids, and supplemental oxygen. The roles of theophylline and anticholinergics remain controversial, although in general these agents appear to add little to the bronchodilator effect of inhaled beta-agonists in most patients. Anti-leukotriene medications have not yet been evaluated in acute asthma. Other therapies, such as magnesium sulfate and heliox, have their advocates but are not recommended as part of routine care. If pharmacological therapy does not reverse severe airflow obstruction in the asthmatic attack, mechanical ventilation may be temporarily required. Based on our current understanding of ventilator-induced lung injury, optimal ventilation of asthmatic patients avoids excessive lung inflation by limiting minute ventilation and prolonging expiratory time, despite consequent hypercapnia. Unless respiratory function is extremely unstable, the use of paralytic agents is discouraged because of the increased risk of intensive care myopathy. Patients who have suffered respiratory failure due to asthma are at increased risk for subsequent death due to asthma (14% mortality at 3 years) and should receive very close medical follow-up. In general, severe asthmatic attacks can best be prevented by early intervention in the outpatient setting. In the words of Dr. Thomas Petty, "... the best treatment of status asthmaticus is to treat it three days before it occurs".

Bronchodilator therapy in the management of acute asthma.

Bronchodilator management of acute severe asthma has evolved considerably in recent years. beta-adrenergic agonists have emerged as the single most potent class of bronchodilator available, and the inhalational route of administration has proven to be the most effective and least toxic method of delivery except among apneic or highly uncooperative patients. Other bronchodilators, including aminophylline, inhaled anticholinergics, and intravenous magnesium sulfate, are significantly less potent drugs for reversal of bronchoconstriction. In most patients these agents do not promote significant bronchodilation beyond that achieved with an intensive regimen of inhaled beta agonists; subsets of patients that might benefit from these other agents remain to be identified. Questions remain as to the optimal dose, frequency of administration, and mode of inhalational delivery of the beta agonists in acute asthma. Finally, it is important to remember that bronchodilator therapy constitutes only one component in the treatment of acute severe asthma. Treatment of airway inflammation with systemic corticosteroids is another vital component, as are supplemental oxygen in the hypoxemic patient, close monitoring of lung function, attention to the possibility of hypercapnic respiratory failure, patient education, and a plan of care following emergency department discharge.

Bronchiectasis. A late feature of severe rheumatoid arthritis.

Bronchiectasis as a feature of rheumatoid arthritis is considered rare and, in most series, has preceded rheumatoid arthritis. We identified 23 patients with rheumatoid arthritis and bronchiectasis at the Brigham and Women's Hospital followed between 1984 and 1991, 18 of whom had arthritis preceding lung disease. The 18 patients with rheumatoid arthritis and subsequent bronchiectasis had a mean age of 63.8 years. Fourteen were women and 4 were men, with a mean arthritis duration of 24.7 years before bronchiectasis developed. Most patients had seropositive and nodular disease. All but 1 had advanced radiographic changes of rheumatoid arthritis, and many had received joint replacement surgery. In addition to standard treatment regimens, 17 patients had received corticosteroids. Productive cough, hemoptysis, and dyspnea were the most common respiratory symptoms and were present for an average of 4.3 years prior to bronchiectasis diagnosis. The most common radiographic abnormalities were bibasilar diffusely increased interstitial markings and focal infiltrates, although nodules, bullae, cysts, and air-fluid levels were found. Common pulmonary-function abnormalities were obstructive and/or restrictive abnormalities. Three patients died of complications relating to bronchiectasis. Five patients with rheumatoid arthritis had antecedent bronchiectasis. Compared with patients with rheumatoid arthritis and subsequent bronchiectasis, those with antecedent lung disease had milder arthritis (stage I or II radiographic changes, p < 0.001), a lower frequency of rheumatoid nodules (p < 0.05) and a lower comorbidity score (5.8 versus 9.4, p < 0.01). They also had received fewer disease-modifying agents for the treatment of their rheumatoid arthritis. Bronchiectasis can be a feature of rheumatoid arthritis and is often found in patients with severe, long-standing nodular disease. Recurrent pulmonary infections and respiratory failure occur and may be fatal.

Recovery of leukotriene E4 from the urine of patients with airway obstruction.

The urinary excretion of leukotriene E4 (LTE4) was measured in subjects presenting for emergency treatment of airway obstruction. A total of 72 subjects presenting with airway obstruction performed peak flow determinations before and after three treatments with nebulized albuterol given at 20-min intervals. Of these subjects, 22 more than doubled their peak flow rates, while 19 failed to increase their peak flow rates more than 25% during the treatment period. These groups were designated "responders" and "nonresponders," respectively. Urinary LTE4 excretion was determined in 16 of the 22 responders and 12 of the 19 nonresponders as well as 13 normal subjects by precolumn extraction, analytic reversed-phase high-performance liquid chromatography, and enzyme immunoassay. In the normal subjects the urinary LTE4 excretion was significantly (p less than 0.0001) less than the urinary LTE4 measured in the responder subjects, but not less than the urinary LTE4 excretion in the nonresponder group (p = 0.071). The enhanced recovery of LTE4 from the urine of subjects with acutely reversible airway narrowing is consistent with a bronchoconstrictor role for the cysteinyl leukotrienes in spontaneous acute asthma.

In vivo bronchodilator activity of nifedipine in the guinea pig.

We administered histamine subcutaneously to anesthetized guinea pigs to induce prolonged bronchoconstriction and then tested the effect of intravenously administered nifedipine on pulmonary resistance (RL) and dynamic compliance (Cdyn). One mg of subcutaneously administered histamine caused RL to increase by an average of more than 250% and Cdyn to fall on average to 26% of baseline; mean RL remained more than twice baseline, and mean Cdyn remained less than half baseline for 80 min. Intravenously administered nifedipine 3 micrograms/kg and ethanol (diluent) administered 25 min after histamine had no effect on RL but caused a slightly greater fall in Cdyn than in the control animals treated with histamine alone. Nifedipine 30 micrograms/kg, however, exhibited significant bronchodilator activity: 35 min after nifedipine 30 micrograms/kg, RL decreased on average to 41 +/- 17% above baseline (p less than 0.02), and Cdyn increased to 49 +/- 5% below baseline (p less than 0.0001). By comparison, isoproterenol (0.3 to 3.0 micrograms/kg) caused bronchodilation of more rapid onset (within 1 min) and shorter duration of action (approximately 10 min). Thus, we were able to demonstrate bronchodilator activity of nifedipine in vivo, as had been predicted by in vitro studies of guinea pig and human tracheal strips. These results would appear to justify continued exploration of the potential role for calcium channel blockers in the treatment of obstructive lung disease.

Orally administered nifedipine in chronic stable asthma. Comparison with an orally administered sympathomimetic.

Calcium channel blockers have been shown to attenuate bronchoconstriction when given prior to bronchoprovocation challenge testing. However, they have not been found to induce bronchodilation when administered to asthmatic subjects with normal baseline lung function. In vitro data, on the other hand, suggest that preconstricted tracheal strips can be made to relax by the addition of calcium channel blockers. Therefore, we compared the effects of orally administered nifedipine (20 mg), albuterol (4 mg), and placebo on airway function in 10 asthmatic subjects with chronic stable asthma and baseline bronchoconstriction in a double-blinded, randomized, cross-over trial. Nifedipine caused a significant increase in FEV1 (0.21 +/- 0.08 SEM L) at 40 min after administration of the drug. The mean of the change in FEV1 throughout the 2-h observation period after nifedipine (0.19 +/- 0.08 L) was significant when compared with baseline (p less than 0.05) and placebo control values (p less than 0.005) but tended to be less than the bronchodilation observed after albuterol. Only 3 subjects had an increase in FEV1 greater than 10% of their baseline value after nifedipine compared with 7 subjects after albuterol and 2 subjects after placebo. These results are at least consistent with the hypothesis of a direct action of calcium channel blockers on bronchial smooth muscle and indicate that orally administered nifedipine has a weak bronchodilating effect in subjects with chronic stable asthma who have abnormal lung function.

Treatment of acute asthma. Is combination therapy with sympathomimetics and methylxanthines indicated?

The role of bronchodilator regimens combining a sympathomimetic and a methylxanthine in the treatment of acute exacerbations of asthma remains controversial. This report describes the outcome of 157 emergency room visits for asthma in which patients were randomly assigned to single-drug therapy with intravenous aminophylline, subcutaneous epinephrine, or inhaled isoproterenol or to one of three regimens combining a sympathomimetic and a methylxanthine. The increase in one-second forced expiratory volume after one hour of treatment with the two-drug combinations (0.79 +/- 0.07 liter) was significantly greater than for epinephrine alone (0.57 +/- 0.08 liter; p less than 0.05) but did not differ significantly from that occurring with therapy with isoproterenol alone (0.72 +/- 0.09 liter; p = NS). This disparity reflects the greater bronchodilation effected by isoproterenol as a single agent than by epinephrine, in the dosing schedules and routes of administration chosen. Among patients presenting with severe airflow obstruction (one-second forced expiratory volume 35 percent or less of normal), the bronchodilator response to isoproterenol alone was 0.88 +/- 0.14 liter versus 0.51 +/- 0.11 for epinephrine alone (p less than 0.05). It is concluded that the observed benefit derived from use of combination therapy depends on the dosage and potency of the particular sympathomimetic to which a methylxanthine is added, and on the severity of the airflow obstruction at presentation.

Pharmacokinetics and clinical response to single- and multiple-dose sustained-release theophylline compounds in perennial bronchial asthma.

Nine adult subjects with perennial bronchial asthma participated in a single-blind, cross-over, placebo-controlled study to evaluate and compare the effectiveness of a 24-hour sustained-release theophylline formulation, Uniphyl, with that of a twice-daily compound, Theo-Dur. The subjects took each drug for two weeks and monitored peak expiratory flow and recorded their symptoms in a diary three times daily. At the end of each experimental period, they were hospitalized for 24 hours for determination of the pharmacokinetics of the compound they were taking and the relationship between fluctuations in theophylline blood levels and changes in pulmonary mechanics. Both drugs were highly effective, and no significant differences between formulations were found in any aspects of the study. The results demonstrate that a single daily dose of Uniphyl is an efficacious form of therapy for controlling perennial asthma in adults.

Breathing pattern affects airway wall temperature during cold air hyperpnea in humans.

We studied the influence of flow rate on respiratory heat exchange in 9 healthy adult subjects using a new noninvasive technique, the single-breath temperature washout (SBTW) curve. The SBTW curve is a plot of exhaled gas temperature versus exhaled volume during a standard exhalation and consists of an initial rise (within the first 200 ml) to a plateau temperature that persists through the remainder of exhalation. We found that exhaled gas temperatures within the initial expirate were colder at every airway locus than corresponding intra-airway gas temperatures at end-inspiration, suggesting that heat exchange occurs between lumenal gas and the relatively cooler airway walls during exhalation. The SBTW plateau temperatures were: (1) lower after preconditioning the airways with rapid (80 L/min) isocapnic hyperpnea of frigid air than after less rapid (40 L/min) cold-air hyperpnea or after quiet breathing; (2) lower when, after identical airway preconditioning regimens, the SBTW exhalation was performed with a slower (0.5 versus 2.5 L/s) expiratory flow; and (3) lower when SBTW curves were obtained after airway preconditioning using respiratory patterns with larger inspiration-expiration duration (I:E) ratios (5:1 versus 1:5) at fixed minute ventilation and respiratory rate. Our results indicate that the global respiratory gas-wall heat transfer coefficient increases with velocity to the 0.9 power, a finding similar to that in previous studies of turbulent flow in rigid pipes.

Differential inhibition of bronchoconstriction by the calcium channel blockers, verapamil and nifedipine.

Recent studies have demonstrated that the calcium channel blocking agents can inhibit experimentally induced bronchoconstriction in asthmatics, but their protective action has been variable. To clarify the influence of stimulus intensity and choice of calcium blocker on these reported differences in outcome, we performed noncumulative thermal stimulus-response curves using isocapnic hyperventilation of cold air in 8 asthmatics. Subjects received pretreatment with orally administered nifedipine (20 mg), intravenously administered verapamil (10 mg bolus followed by a continuous infusion), or appropriate placebos in a randomized, double-blind fashion. Verapamil afforded no consistent protection against the thermal challenges, whereas nifedipine significantly blunted the bronchoconstrictor response to stimuli of low (p less than 0.02) and middle (p less than 0.03) intensity. At the highest thermal burden, the effect of nifedipine was inconsistent and not significantly different from that of placebo. These results indicate that the protection from bronchoconstriction afforded by the calcium channel blockers depends on the choice of agent and the intensity of the bronchoconstricting stimulus, and they raise the possibility that the contribution of transmembrane calcium ion influx to the pathogenesis of bronchoconstriction may vary according to stimulus intensity.

Clinical aspects of mucus and mucous plugging in asthma.

Abnormalities in the production and transport of airway secretions play an important role in the pathophysiology of asthma, especially during acute exacerbations of the disease. The synthesis of mucus becomes disordered, and other constituents of airway contents, including eosinophils and shed bronchial epithelial cells, contribute to the abnormal sputum that is produced. Altered viscoelastic properties of asthmatic mucus lead to impaired mucus transport rates. In addition, ciliary function may be directly inhibited by factors within the secretions. The consequence of these derangements is often widespread plugging of small bronchi and bronchioles. Occasionally, segmental or subsegmental atelectasis develops, but in most series radiographically visible atelectasis is uncommon. A rare complication is mucoid impaction of the bronchi, in which a central masslike opacity on chest radiograph is the manifestation of a large mucous plug in a major bronchus. A hypersensitivity reaction to fungi has been implicated in the formation of at least some mucoid impactions. A variety of pharmacological and other methods have been used in attempts to modify abnormal airway secretions and to promote their clearance, but none is of proven benefit. The development of effective therapies will probably require a better understanding of the regulation of normal mucociliary transport and of the disturbances that occur in asthma.

Calcium-channel blockers in prophylaxis and treatment of asthma.

Calcium-channel blocking drugs do not induce bronchoconstriction in susceptible persons with cardiac disease and concomitant hyperreactive airways (such as asthma or chronic bronchitis). The ways in which calcium blockers might in fact play a beneficial role in preventing bronchoconstriction or inducing bronchodilation in asthma are explored. Nifedipine and verapamil have been shown to inhibit the bronchoconstriction provoked by exercise, histamine, methacholine and antigen. The potential mechanisms by which this protective effect is mediated--whether by direct action on tracheobronchial smooth muscle, inhibition of release of mediators from activated mast cells or both--are examined by reviewing in vitro studies of both cell systems. Calcium blockers also exhibit some bronchodilating activity in vitro. Early clinical trials of these drugs in ambulatory asthmatic patients have shown little, if any, therapeutic benefit, but results must be considered preliminary in view of the nature of the short-term, small-scale trials performed to date. Regardless of their therapeutic potential in obstructive lung diseases, the calcium-channel blockers offer a powerful probe into the role of calcium in the physiologic make-up of airways and, in particular, the pathophysiologic features of airway hyperreactivity.

Role of calcium in airway smooth muscle contraction and mast cell secretion.

The principal pathological features of asthma, including tracheobronchial smooth muscle contraction and mast cell mediator synthesis and release, are calcium-dependent processes. Calcium plays an integral role in transmitting signals at the cell surface to the enzymatic machinery of the cell interior; its role as the agent for "excitation-contraction coupling" of airway smooth muscle and for "stimulus-secretion coupling" of mast cells is reviewed. A rise in intracellular calcium ion concentration triggers cellular activation. In smooth muscle, calcium bound to calmodulin stimulates the myosin light chain kinase which is important in the regulation of actin-myosin interaction. In mast cells, calcium may bind to calmodulin or to a calmodulinlike regulatory protein, and it also stimulates enzymes important in the synthesis of newly generated mediators including prostaglandins and leukotrienes. The regulatory role of cyclic AMP in both cell systems is discussed, especially as it pertains to calcium metabolism. By interfering with transmembrane calcium fluxes, the calcium channel blocking drugs have the potential for significantly modifying bronchoconstriction and airway inflammation in asthma and related bronchospastic disorders. Some of the in vitro studies of calcium channel blockers in these two cell systems are reviewed. Finally a speculation about the role of abnormal sensitivity to calcium in airway smooth muscle as a potential cause of airway hyperreactivity is entertained.

Effect of outpatient treatment of asthma with beta agonists on the response to sympathomimetics in an emergency room.

It has been suggested that tolerance to the bronchodilating effects of sympathomimetics may develop in asthmatic patients after long-term use of these agents. In an emergency room setting, the effects of inhaled and injected sympathomimetic therapy in 58 patients who had pretreated themselves with beta agonists were compared with the results observed in 38 patients who had not used such drugs. The two groups had similar degrees of obstruction on presentation and were also well-matched with respect to the clinical features of their illness. Both populations showed equal responses to treatment; no significant differences were found in either the amount of bronchodilation or the incidence of adverse effects in those who had or had not taken sympathomimetics as outpatients. These findings indicate that drug resistance does not account for outpatient treatment failures with sympathomimetics and that beta agonists can be usefully employed in the treatment of acute asthma, irrespective of a patient's medication history.

Maximal shortening of inspiratory muscles: effect of training.

Normal subjects can increase their vital capacity by appropriate training. We tested whether that change can be achieved by greater maximal shortening of the inspiratory muscles without concomitant increases in peak static inspiratory pressures. Sixteen healthy volunteers participated in the study: eight were randomly assigned to make 20 inhalations to total lung capacity, held for 10 s with the glottis open, each day for 6 wk; the remainder served as nontraining controls. Before and after the 6-wk study period, we made multiple determinations of lung volumes and of curves relating lung volume to maximal static inspiratory (and expiratory) pressure. Control subjects had no significant changes from base line in any variable. In the training group, the mean vital capacity increased 200 +/- 74 ml (P less than 0.05) or 3.9 +/- 1.3% (P less than 0.02), without a significant change in residual volume. After training, the mean maximal inspiratory pressure at the airway opening (PI) at a lung volume equal to the base-line total lung capacity was 27 +/- 8 cmH2O in this group (vs. zero before training; P less than 0.02). Values of PI in the mid-vital capacity range did not change. We conclude that in response to appropriate training stimuli inspiratory muscles can contract to shorter minimal lengths, a capacity potentially important in progressive pulmonary hyperinflation.

Glucocorticoids in acute asthma. A critical controlled trial.

In order to determine objectively the efficacy of corticosteroids in relieving severe acute episodes of asthma, we administered infusions of hydrocortisone or placebo in a random, double-blind manner to 20 asthmatic subjects after they had been documented to be refractory to eight hours of conventional therapy. Eleven subjects received hydrocortisone (2 mg/kg bolus, then 0.5 mg/kg per hour for 24 hours) and nine received saline. All were given identical bronchodilator treatment during the study period, and all had multiple aspects of lung function serially recorded along with plasma cortisol levels. Although subjects in both groups had severe obstruction of similar magnitude at the beginning of treatment (one-second forced expiratory volume [FEV1] in placebo-treated group = 32 +/- 3 [SEM] percent of predicted, and 25 +/- 3 percent of predicted in steroid-treated group, p = NS), at the end of 24 hours, the subjects given corticosteroids had significantly greater resolution of airway obstruction (FEV1 in steroid-treated group increased 118 +/- 25 percent from control value, versus 35 +/- 22 percent with placebo). In five of nine subjects treated with placebo, pulmonary mechanics either were unchanged or deteriorated during the period of observation. There was no effect of the glucocorticoids on arterial blood gases, and no significant correlation could be found between plasma cortisol levels and the improvement in pulmonary mechanics and clinical status. These results provide objective documentation of the time course over which administration of parenteral corticosteroids speeds the recovery of asthmatic patients who are unresponsive to standard therapy.