Similarities and Differences in Bacterial and Nonbacterial Allergy

There is much confusion connected with the subject of allergy which can be clarified only by accurate observation and frank discussion.

Wherever we find nonbacterial allergic phenomena producing disease, we are to assume that the reaction is the answer of the tissues to an insult produced by some substance which, having entered the tissues through some abnormal route, and having escaped the body’s normal action by which it is prepared for assimilation, finds itself a foreign substance, in intimate connection with the body cells and disturbing their physicochemical properties. That the occurrence of this reaction in some individuals and not in others may depend upon a particular property of the tissues, a certain physicochemical background, seems more than a possibility.

Wherever we find allergic phenomena in the course of bacterial disease, we must assume that the reaction is due to some substance or substances produced during the growth of the causative microorganisms or derived from their destroyed bodies, which has come in intimate contact with the patient’s cells after they have been acted upon and sensitized by a previous identical infection. The result of this contact is an inflammatory response.

While allergy is a phenomenon connected with many diseases, such as tuberculosis, streptococcal infection, undulant fever, and typhoid, it is probably best known in tuberculosis, the phenomena connected with it having been observed and described by Koch in 1891,¹ but not named until after the studies of von Pirquet² in 1907, which resulted in discovering the allergic phenomena in the skin of those who were infected by the tubercle bacillus.

Tubercle bacilli, on entering the body for the first time, irritate the local cells which answer the insult by the formation of tubercle, which is an attempt on the part of the body to localize them. This is a nonspecific and largely a noninflammatory defensive effort. It has recently been shown that the protein fraction of the bacillus has no part in the stimulation of epithelioid cells and tubercle formation, but that this belongs to the lipoid fraction of the bacillus (Auclair and Paris,³ Sabin^4,5 and Anderson^6,7). So far as we know there is no similar epithelioid cell defense against nonbacterial allergens. Both bacterial and nonbacterial protein, however, as well as certain other allergens, cause a hypersensitivity of the body cells, which causes them to react allergically whenever they come again in contact with the same substances. Before allergic phenomena can stand on a secure scientific footing, and before the clinical allergic problems can be satisfactorily explained, it will be necessary to understand in what manner this cellular allergic response of the body to these two classes of substances corresponds and in what way it differs; and the reason for this similarity and difference.

There is some doubt as to the specific nature of nonbacterial allergy and as to its being more than an accidental part of the disease. We find patients sensitized to so many substances at times that it seems far more rational to assume that we are dealing with an underlying cellular state on the part of the individual which permits of an unnatural entrance of allergens, in general, into the body, and which requires an unnatural reaction to them when they have once entered, rather than with a condition which is brought about by a definite substance. Yet when an individual is found to be sensitized to several substances, more than one reagin can be demonstrated in the blood (Coca⁸). In bacterial allergy, on the other hand, the reaction does not occur simply because of the fact that bacteria find themselves in the tissues, but because the body cells have been sensitized by the action of certain substances produced and released during the growth and destruction of microorganisms responsible for a previous identical infection.

 

Relation of Allergy to Immunity

That allergy, as we describe it, takes part in the specific defense of the organism against a variety of substances, both bacterial and nonbacterial, is definite; but just what this part is, is the question. In tuberculosis, after the body cells have once been sensitized by previous infection with tubercle bacilli, allergy of varying degree, from a slight hyperemia to a severe exudation, even to necrosis of tissue, may be met whenever reinoculations of bacilli or bacillary protein take place; the degree of allergy depending on the dosage and virulence of the bacilli and the reacting capacity of the host (Krause,^9,10 and Pottenger^11,12,13). Such allergy is a specifically acquired reaction and is usually considered as a part of the host’s protective mechanism. The relationship as usually accepted has recently been questioned by Rich.¹⁴ It seems definite that allergy is not coextensive with immunity, and if we may use the experience gained by the study of nonbacterial allergy and also ideas suggested in our studies of the phenomena as met in bacterial disease, we might be justified in assuming that it is a protective mechanism which is rendered unnecessary when immunity has been attained; for, if the host were in a state of absolute immunity, it is probable that he would also be in a state of desensitization.

Allergy, then, should be looked upon as an increased alertness of the cells toward bacilli and bacillary protein developed as a part of specific resistance but only necessary until such a time as immunity can be established. When immunity has been established, however, the host no longer finds it necessary to react violently with inflammation when bacilli attempt an implantation, for the tissues are uncongenial to bacillary habitation the same as we find them after infections which produce, as a rule, only one disease episode in man, such as measles, whooping cough, and smallpox. Individuals who have been rendered immune to the microorganisms which produce these diseases by one infection are often exposed to them again during life, but disease rarely appears a second time.

A condition of absolute resistance to reinfection with tubercle bacilli is never supposed to be attained in man; yet we do have instances reported in which patients who have recovered from tuberculosis, later failed to show skin reactions to cutaneous and intracutaneous tests of tuberculin. Krause reports such a case which he kept under observation for several years. I have seen patients who failed to react to the usual test dose of tuberculin years after treatment, although they had previously harbored lesions of sufficient magnitude to cause clinical symptoms. Whether they would have reacted to still larger doses had they been given, of course, was not proved. Certain clinicians have insisted that the way to use tuberculin to the best advantage of the patient is to use very large doses, and repeat and increase them until they no longer cause reactions on the part of the patient. Rich¹⁴ believes the desensitizing effect of tuberculin by which the patient becomes better able to withstand his own tuberculoprotein is an important factor in tuberculin therapy.

The idea of there being a difference between allergy and immunity is in line with the clinical observation that, as tuberculosis advances and becomes chronic, the degree of allergic inflammatory reaction seems to grow less severe, not only relatively, but, actually, in proportion to the size of the reinoculations of bacillary protein which take place. We cannot, by any process of reasoning, assume that the numbers of bacilli or the amount of tuberculoprotein gaining access to new tissues and the blood stream are less in these far advanced lesions, where very extensive areas of disease are present, than in the limited ones of the early periods of the disease. On the contrary, it is reasonable to assume that the quantities are multiplied many fold. Therefore, we must assume as an alternative that the cells are less sensitive and that consequently they fail to show a degree of allergic inflammatory response corresponding to that which characterized their earlier contact with bacillary protein. Desensitization of the body cells to tuberculoprotein thus becomes an important part of specific defense and a necessary accompaniment of advancing disease.¹⁵

Again, the probable truth of the assumption of a relatively greater hypersensitivity of cells in early tuberculosis than in late tuberculosis is shown in the difference between early and late cavity formation. Cavity often forms promptly when relatively large numbers of bacilli and relatively large amounts of bacillary protein are present in the tissues during the early days of clinical tuberculosis; but later, when with what seem, so far as we are able to judge, to be equal reinoculations, are met by even a reduced exudative inflammatory response, and not by a destructive caseating process. To account for this we must assume either that equally large reinoculations do not occur, which, on the face of it, is untenable, or that the host’s reaction toward them has diminished or changed; for, after an early cavity has formed, patients may go through months of active tuberculosis with the disease steadily advancing, and yet escape further tissue destruction of a magnitude such as is represented by the first cavity.

Evidence that immunity may be established without cell sensitization and allergic reaction is furnished by the experimental work of Swift¹⁶ in nonhemolytic streptococci; and by that of Mackenzie,^17,18 on pneumococci. Swift found that by intravenous injection he was able to create a high degree of resistance without producing skin sensitiveness, while in the intracutaneously and subcutaneously injected animals, skin sensitiveness accompanied the increased resistance.

In tuberculosis it seems perfectly reasonable to assume that while cell sensitization and the allergic reaction are necessary for defending the patient against the spread of bacilli during certain phases of the disease, immunity is a further accomplishment and probably such a state of the body cells that protection against the specific microorganism no longer requires such explosive reactions as those represented by the acute inflammatory phenomena of active allergy.

The desensitization which is practiced in the treatment of so-called allergic diseases has for its purpose the changing of the state of the cells so that they are no longer sensitive to the causative substance, or changing the condition of the patient so he will no longer need to combat these substances by sensitized cells and the consequent allergic phenomena. Desensitization to the reinoculations of tuberculoprotein, which occur so frequently during an extending tuberculous process, is doubtless a similar accomplishment. Its artificial production has long been recognized by clinicians as being one of the principal aims of the therapeutic use of tuberculin.

 

Bacteria and Nonbacterial Substances which Produce Allergy Gain Access to Tissues in Different Manner

There is a difference in the manner in which bacteria and nonbacterial substances gain access to the tissues.

There is a hereditary element back of so-called allergic disease (Pottenger¹⁹ and Hurst²⁰). Patients who suffer from asthma, hay fever, and urticaria give a history of the same condition being present in forebears in about 50 per cent of instances and the same is transmitted to future generations, as shown by the history analysis by Spain and Cooke²¹ and by Ratner and Gruehl.²² They seem to inherit a tissue which is more permeable than normal. Constitutionalists speak of them as belonging to the exudative and arthritic diatheses and as possessing cells which on account of their permeability allow the passage of foreign protein with greater facility than those whose cells are less permeable (Bauer²³ and Pende²⁴). This is supposed to be at least one factor which is responsible for certain persons becoming asthmatic or suffering from hay fever, urticaria, or other forms of allergic reaction, while others do not. The cells of susceptible persons fail to interpose an effective barrier against such substances as pollens, foods, and animal substances. Entering the body through abnormal routes, they are attacked by the body forces in an abnormal way, and in their destruction a mechanism is set up which is applicable to future reaction against the same or similar substances; so that on reentry these substances are met by cells which are hypersensitized to them and are prepared to attack them. The result is an allergic response. The more highly sensitized the cells are, the greater their reaction. Orteil²⁵ has recently been able to show a different body chemistry in those suffering from so-called allergic diseases, indicating a different physicochemical tissue composition.

Sensitization to allergens is a property which may be possessed by all cells of the body, but it affects different cells to a different degree. Consequently allergic reactions in different tissues differ. This is evident in the location of different allergic diseases. It is also shown in the variation of skin tests on different portions of the body surface of the same individual when given simultaneously.

In tuberculosis, heredity seems to play no such part in infection as it does in the entrance of nonbacterial allergens to the body, for infection has long been recognized as being all but universal in the human family (Hamburger²⁶) and still is, according to Opie and his coworkers,^27,28,29 at least in the city population. On the other hand, heredity plays a very important role in the patient’s resistance to the spread of infection after bacilli have once gained entrance to the tissues. There may be something in the character of the tissues; in fact, I am inclined to think there is, which makes certain individuals who harbor a primary infection within their bodies more prone to break down with tuberculous disease than others who harbor what seems to be a similar infection.

Whenever tubercle bacilli or bacillary protein escape from an existing focus into new tissues, or reenter the body from without, allergy manifests itself within a few hours. It has been determined experimentally that this occurs in from four to forty-eight hours. In nonbacterial allergy the reaction comes on much more quickly. I have seen a major attack of hay fever precipitated within a fraction of a minute on a sensitive child putting a daisy to its nose.

The tissues of one already infected with tuberculosis manifest resistance to further entrance of bacilli. In fact, while a few bacilli will inoculate the noninfected, and pass through the tissues with great rapidity; when a person suffers from advanced tuberculosis, countless numbers of bacilli may pass over the mucous membranes of his bronchi daily without producing local lesions; and, we assume, without producing infection at all in most instances, because the patient may go on to a recovery regardless of their presence in large numbers.

From these two examples we see that there is apparently a fundamental difference in the behavior of the sensitized body cells toward the entrance of bacteria (tubercle bacilli), on the one hand, and of nonbacterial substances, on the other hand. The former are prevented from entering or hindered in their entrance, while the latter are apparently aided. This, however, may be only apparent. Possibly we are thinking of conditions as similar which are very different. Possibly minute quantities of nonbacterial allergen contact local cells of higher sensitization, while the tubercle bacilli contact cells of lower sensitization.

 

Difference in Reaction of the Body to Bacterial and to Nonbacterial Substances

There are differences in the allergic reactions produced by bacterial products as observed in tuberculosis and in that produced by nonbacterial substances, as seen in so-called allergic diseases which may be set forth with advantage to our discussion. These manifest themselves in quickness of response, character of response, and persistence of response.

As previously stated, the reaction of the allergic diseases may come on very quickly, after contact with certain allergens, while that in tuberculosis is much slower in developing. Zinsser,^30,31 and Enders³² have shown that there are two distinct fractions in tuberculin, one of which acts like other coagulable proteins and quickly produces cell sensitization and anaphylaxis; the other, a noncoagulable protein which also sensitizes cells but produces a slower allergic reaction. This latter they consider as being connected with the immunity mechanism. We undoubtedly are discussing two somewhat related yet different phenomena in bacterial and nonbacterial allergy. Progress demands that these two reactions be compared and contrasted until they are understood. Difference in nomenclature in the two reactions would probably facilitate their study.

The character of the response to bacterial and to nonbacterial allergens, both local and general, is vastly different. In nonbacterial sensitization the local blood vessels dilate rapidly, their walls become permeable, and an exudation quickly takes place. There is little or no tendency to destruction of tissue or formation of new tissue. In asthma and hay fever the mucous membranes become so edematous that the air passages are markedly encroached upon, yet all will disappear in a short time if the attacks are relieved. It is only when the condition becomes chronic that structural changes occur (Huber and Koessler³³ and Hansel³⁴). The reaction in tuberculosis, in contrast to this, is particularly marked in the tissues with which the bacilli or escaping undiluted tuberculoprotein come in contact; and less marked in other tissues which are the seat of unhealed tuberculous infection and which contact the tuberculoprotein in a very dilute form after it has been diluted by the entire volume of blood; and still less in other cells of the body (Pottenger^11,35,36,37). Tuberculo-allergy is likewise accompanied by an exudation, either mild or severe; but one which persists, often for weeks and months. In tuberculosis, too, the allergic reaction leads to two opposite phenomena–the destruction of tissue and the formation of new tissue; while neither of these pathologic processes becomes a prominent part in acute nonbacterial allergy, although structural changes follow chronic manifestation.

These two types of allergic reaction are accompanied by a very different general reaction, which is expressed in different components of the vegetative neurocellular mechanism. The general symptoms which accompany the body’s reaction to nonbacterial protein are expressed in a vagus (parasympathetic) syndrome (Pottenger^38,39,40), as is illustrated in asthma, which consists of a bronchial spasm, increased secretion of the secretory glands in the bronchial mucous membrane, increased permeability of blood vessels and local cells, an increase in the normal potassium-calcium ratio (Kylin⁴¹), an increase in alkalinity of tissues, and an eosinophilia. That belonging to other so-called allergic diseases, such as hay fever, urticaria, and angioneurotic edema, is similar, differing though in the location of the reaction.

A genuine toxic syndrome can be brought about by nonbacterial protein when employed in certain ways but this is not the usual syndrome shown in the allergic diseases.

The general symptoms of allergy met in tuberculosis, on the other hand, are expressed in the sympathetic system (Pottenger^40,42,43). It may or may not be accompanied by an increase in the body temperature. If the reaction is severe, it is met by evidence of widespread stimulation of the sympathetics, thus: chill, fever, contraction of the pilomotor muscles, sweating, rapid heart, poor appetite, diminished digestive ability, constipation, malaise, leucocytosis, a decrease in alkalinity of the blood, and anemia. When the allergy is mild, the acute toxic syndrome is absent but some of the symptoms of sympathetic stimulation, such as sweating; rapid heart; malaise; poor appetite; and slow digestion, particularly on exercise; and leucocytosis are present.

There is also a wide difference in the persistence in reaction in these two types of allergy.

Nonbacterial allergy may disappear as by magic, as is so often seen following the administration of adrenalin in an acute attack of asthma or urticaria. Atropine, because of its inhibitory action upon the parasympathetic system, will also combat some of these phenomena, but cannot be given in doses sufficiently large to be effective without at the same time making the patient very uncomfortable. Calcium will strengthen the action of the sympathetics (Pottenger^40,44,45), aid in restoring the calcium-potassium balance, and lessen the permeability of the cells (Lilly,^46,47 Zondek,⁴⁸ and Pottenger^39,40). In patients in whom a deficiency of thyroid is suspected, thyroid preparations may be administered for their effect on the sympathetic nerves and for the purpose of mobilizing bone calcium so that it may be utilized by the body, as shown by Aub.^49,50 Lastly, the toxic syndrome relieves asthma. Asthmatic patients may be relieved by acute temperature reactions, by which the sympathetics are stimulated and adrenalin increased, and the preponderant parasympathetic action in the bronchi is opposed (Pottenger⁴⁰).

Allergic reactions in tuberculosis are slow to disappear. If they are accompanied by marked exudation in the tissues, weeks and often months are necessary for these to disappear; and, if followed by loss of tissue, months and years may be required, or they may never be restored. It may be that the reason why these allergic phenomena do not disappear more quickly is because they are kept up by frequently repeated reinoculations, for the depot of supply is present so long as active infection is present. There is no way of knowing the exact part that this factor of reinoculation plays; but such a thing as the magical disappearance of the exudation and bronchial spasm which may be brought about in asthma by the employment of adrenalin has no parallel in the clearing up of the phenomena of tuberculosis. Our method of attack in tuberculosis is to employ such measures as will limit reinoculations and build up the patient’s physical strength; and then rely on the patient’s specific powers of defense, alone or assisted, to aid in the destruction, retardation of migration, and encapsulation of the bacilli; the desensitization to his own tuberculoprotein; and the clearing of the inflammatory field and restoration of injured tissue.

 

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