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and blood gases) ; in addition, the changes in ventilation-perfusion relationships were measured by the nitrogen washout technique. Comparing subjects having a decrease in Pa02 after bronchodilator to those who did not, the following data were obtained. There were no differences in FVC and FEV I ,D, Pa02, Aa P02 breathing air or in venous admixture. By nitrogen washout, the volume, ventilation and ventilation-perfusion ratio of the slow space were greater in those subjects whose Pa02 fell with bronchodilator. The perfusion of the slow space increased in these

subjects. The mechanism of bronchodilator-induced fall in Pa02 can be explained by the relationship of vascular resistance to lung inflation ; lung units with the greatest degree of hyperinflation have the highest vascular resistance and the lowest perfusion. Under the impact of bronchodilator, these units will have an increase in perfusion as hyperinflation decreases. Therefore, those subjects with larger slow spaces will have a greater tendency to increase perfusion of this poorly ventilated compartment as hyperinflation is decreased and a fall in Pa02 ensues.

Studies on Responses to Adrenocorticosteroid Therapy in Bronchial Asthma Howard ] . Schwartz, M.D. o

I t has been noted that asthmatics vary in their

clinical responsiveness to adrenocorticosteroid therapy. A small group of patients seems to be relatively steroid resistant, in that unusually large doses must be used in conjunction with standard antiasthma drugs to maintain them symptomfree. Walsh and Crant! found in 65 chronic asthmatics that an average daily dose of 10 mg prednisone was effective ; in our experience the "resistant" patient requires upwards of 15-20 mg prednisone per day, and then is often bordering on the symptomatic state. We began studies on these clinical findings several years ago,2 and have made the following observations. The eosinopenic response to a single intravenous injection of 40 mg of cortisol was studied in both unselected asthmatics, and asthmatics exhibiting clinical resistance to cortisol's antiasthma effect. No other distinctive clinical feature was noted. Highly significant differences in the eosinopenic responses were observed. The responsive group had changes in the total circulating eosinophil count of -35 percent, -77 percent, and -73 percent at two, four, and six hours after injection, while the changes in the resistant group were -10 percent, - 36 per, cent, and + 4 percent. In an effort to understand these findings, cortisol turnover studies were carried out in four patients from each group using a tracer dose of tritium labeled cortisol. Cortisol half-life determinations were done; the responsive group showed a mean T 1/2 of 128 minutes; the resistant group showed a T oAssistant Professor of Medicine, Case Western Reserve University School of Medicine ; Associate Physician, University Hospitals of Cleveland.

1/2 of 86 minutes. Urinary steroid excretion was comparable in both groups. While these significant differences in plasma cortisol turnover rates are not yet fully explained, it is clear that the decreased biologic potency of hydrocortisone is associated with, but not directly explainable by, its rapid clearance from plasma. Similar findings have been reported in a study from Australia. 3 We have been able to use these findings in the treatment of severe acute bronchial asthma requiring hospitalization. Here we find that the presence of tissue and blood eosinophilia is useful both in diagnosis of asthma ( as opposed to infectious bronchitis, emphysema, etc) and in determining its proper treatment. We find that a therapeutic response of asthma to steroid therapy usually occurs within 24 to 48 hours, while significant eosinopenia occurs within the first four hours. One of the parameters we use in following the course of hospitalized asthmatics are changes in the peripheral total eosinophil count. If profound eosinopenia (60-70 percent fall) does not occur within six to eight hours of starting steroid therapy, we feel it likely that the steroid dose is too low, and that relative steroid resistance may exist. Thus, monitoring total eosinophil counts affords us the opportunity to make early adjustments in steroid dosages, so that more prompt and satisfactory therapy of severe asthma can be accomplished. REFERENCES

1 Walsh SD, Grant IWB: Corticosteroids in treatment of chronic asthma. Brit Med J 1:796, 1966 2 Schwartz HJ, Lowell FR, Melby JC : Steroid resistance in

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metabolism in patients with chronic asthma. Aust Ann 16:297. 1967

bronchial astluna. Ann Int 69 :493 , 1968 3 Dwyer J. Lazarus L, Rickie JB : A study of cortisol

Discussion Dr. Macklem: Are the mast cells innervated? Are

there any data on that? Dr. Gold: I am not aware of any data directly pertaining to your question. I think that one of the very interesting problems that has to be considered is the anatomic relationship between the receptor site on the smooth muscle, the depot of the pharmacologic mediator, the site of the antigen-antibody reaction and the afferent nerve endings. I am not aware of any data on this subject. We do know there are certain experimental situations that suggest these anatomic relationships are of critical importance. For example, we have observed marked inhib ition of bronchoconstriction by aerosols of bronchodilators at much lower doses than required by intravenous routes, suggesting that there may be a problem with distances involved . It is something we are very interested in. The other point about the Orange-Austin data is that not only do they block mediator release by atropine, but they facilitate mediator release by acetylcholine or mecholyl which ties in very nicely with our work. These are the first data I know of that tie together the cell physiology with the autonomic nervous system. Dr. Simonsson: Is it possible that you first get the contraction of smooth muscles and that by the contraction you induce changes in the afferent nerve endings going through the vagal path? I think Whitcomb and Sellig have shown that if you relax muscles and if you are given histamine and you measure activity in vagal nerves, you find you get less if you have the smooth muscle relaxed. That is one way the remaining constriction may be local and the rest reflex. Dr. Gold: I don't mean to imply by our data that we know how the vagally-mediated reflexes are turned on. It is conceivable that there is direct stimulation of the nerve endings by the antigenantibody reaction per se that does not involve mast cells or pharmacologic mediators. On the other hand, it is possible that the reaction requires release of mediator and that the histamine or other mediators stimulate the nerve endings. Finally, it may be a secondary reflex, as you suggest, in which mediator release causes some smooth muscle contraction which becomes amplified by stimulation of irritant receptors and induction of vagally-mediated reflex. The work by Whitcomb and Sellig does suggest that the reflex in their system may be secondary,

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but they have a very complicated preparation which involves not only bronchoconstriction but systemic anaphylaxis with both hypoxemia and hypotension (both of which can stimulate vagallymediated reflex bronchoconstriction ). Dr . Ellis: Dr. Schwartz, were these patients on any other drugs , such as barbiturates or diphenylhydantoin (Dilantin) ? Dr. Schwartz: These patients were virtually all on theophylline-ephedrine-phenobarbital (Tedral) . If it is true that phenobarbital in the Tedral accounted for the diHerence in steroid metabolism, one might properly expect that this would appear in virtually all asthmatics, but we found very sharp breaks regardless of the fact that they were all on Tedral. Secondly, other workers reported findings that urinary excretion of steroids was greater in patients who had phenobarbital along with the steroids. We did not find a difference between the groups in urinary steroid excretion . So, while it still remains a possibility that the phenobarbital can influence steroid metabolism in asthmatics, I don't think that it explains the diHerences we observed because I would have expected the differences to be obscured by the fact that everybody was on Tedral. Dr. Ellis: Dr. Schwartz, was this a transient phenomenon? Did you restudy any of the patients? Dr . Schwartz: This was a phenomenon that was. present for several years. Subsequently, Dr . Lowell looked at some of the patients again and found that some of them had "lost their resistance," at least in terms of the eosinopenia, and again no good .explanation can be offered. Dr. Pepys: I would like to make two comments. Firstly, cyclic GMP is guanosine monophosphate. It is interesting that if one goes back into the literature to 1944, there were reports from the London Hospital by Barakan, Gulland and Parsons that the injection of guanosine nucleotide into mice stimulated an eosinophilia and adenine nucleotide stimulated a neutrophilia. My other comment deals with the last paper on cortisone in asthma. I think that it is very exciting, but to look at these asthmatics as if they are one body of asthmatics is not entirely the whole story. We have been challenging patients by inhalation for a very long time and we get two types of asthmatic reactions. The first is an immediate reaction which is short lived, is clearly IgE mediated and associated with eosinophil cells and is not at all inhibited by corticosteroid drugs . This raises

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the problem of what it is that is being modified when we give our patients steroids. In addition to this immediate reaction, we get a later one, coming on after several hours and which we believe to be immune complex mediated-a type III sort of reaction . This reaction is very well inhibited by corticosteroids and I have a strong feeling that when our patients are benefited by corticosteroids, what we are in fact modifying is this immune complex reaction. Now, if this is so, why are they no longer reacting in an immediate sense? This is a problem which we now come to appreciate and face. Such findings make it necessary to reassess our views on the immunologic mechanisms underlying asthma. Dr. Farr: I think we certainly have to incorporate the heterogeneity among asthmatics into our way of thinking and use the term reversible obstructive airway disease, and to try to put an etiologic diagnosis on it-reagin mediated, looked for, not found or found-or type III disease, looked for, found or not found-that infection is playing an important role, frequent or infrequent. I would really like to make this pitch. We are doing this on our charts now and it is very comfortable. People picking up the charts can tell what we are thinking; we may be wrong, but they can at least tell what we are thinking. Dr. Schwartz: I certainly have no particular quarrel with the comments. I would just like to re-emphasize that when we looked at the patients, both groups contained what we would have referred to as intrinsic asthmatics, as well as extrinsic asth-

matics. The role of infection, cigarette smoking and so on seemed by our analysis to be prevalent in both groups to a similar degree. The groups were not separable by clinical criteria. In other words, we did not challenge them by aerosol, did not study them with regard to an early and late pulmonary response, which I suppose would have been the final way to settle this question. Dr. Nadel : Concerning the autonomic regulation, if we leave the alpha adrenergic system out, we know that the vagus nerves innervate the lungs ; when we stimulate the vagus nerves we get contraction of the muscle. If we then stimulate the sympathetic nerves to the airways, we can partially inhibit that contraction. So, we have a potent cholinergic system contracting the muscle and a sympathetic system that inhibits contraction. When the nerves are intact some tone normally exists in the airways. Now under that circumstance, if you give atropine, the airways will dilate. However, since these airways now have little or no tone, one would expect no further effect when the sympathetic nerves are stimulated. If propranolol is administered when the system has a great deal of cholinergic tone, any sympathetic dilator tone that is present will be abolished and further bronchoconstriction will occur. The studies of propranolol suggest that beta blockade unmasks cholinergic activity (bronchospasm) that can be abolished by cholinergic blockade (atropine). Alpha adrenergic receptors need not be implicated to explain the findings I

SESSION III: EPIDEMIOLOGY AND ADVERSE AIRWAY RESPONSES

New Orleans E·pidemic Asthma: Semiquantitative Aerometric Sampling, Epidemiologic and Immunologic Studies" John Salvaggio, M.D., Takeshi Kawai, M.D . and John Seabury, M.D.

periodic outbreaks of reversible obstructive pulmonary disease have been noted in the city of New Orleans for years, but a plethora of studies have incriminated no point source industrial pollutant. The episodes are primarily nocturnal and ·From Louisiana State University Medical Center, New Orleans .

often involve more than 100 "asthma" admissions to the Charity Hospital emergency room in a single 24hour period. We demonstrated that atopic individuals with broad patterns of type 1 skin reactivity to a battery of common inhalant allergens were involved in "epidemics." Individuals involved in epidemics did not differ quantitatively from nonin-

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