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The therapeutic use of tuberculin
1913. THE
PUBLIC
THERAPEUTIC TUBERCULIN.
USE
OF
By CECIL WALL, M.D., F.R.C.P, Assistant Physician, Hospital for Consumption, Brompton.
' T R E A T M E N T in clinical medicine is very largely based upon hypotheses. If the hypotheses are sound the treatment is likely to be good, but unfortunately they are not infrequently built upon a somewhat insecure foundation. It behoves us, therefore, at frequent intervals to examine our hypotheses lest we should be led astray in an interpretation of our therapeutic results. The discordant opinions With regard to t h e use of tuberculin in the treatment of tuberculosis seem largely due to thedifferent hypotheses held with regard to the nature of the resistance of the body against tile infection by the tubercle bacillus. T h e general principle of the treatment of tuberculosis by tuberculin is based upon the hypothesis which may be crudely stated as assuming that resistance against infection by the tubercle bacillus, a n d the establishment of cure after infection, are brought about by the development in the tissues and blood stream of certain specific anti-bodies: probable as this hypothesis appears, t h e evidence experimentally and clinically is by no means conclusive. The resistance against infection byl the typhoid bacillus seems undoubtedly due: to the presence of specific anti-bodies, but when we review our knowledge of the nature of the resistance against typhoid and tuberculous infections respectively, we are struck by the fact that the conditions determining susceptibility or immunity are of a different order. Experimentally, it is possible to immunize an animal against the typhoid baciilus; it does not seem as yet that it has been possible artificially to protect an animal against tuberculous infection. Cliniealty,-we expect typhoid fever in a person who h a s been infected by Eberth's bacillus, unless he has b e e n m a d e specifically resistant by previous infection. : In tuberculosis, on the other hand, while we agree that the disease is not possible without the presence of the tubercle bacillus, we recognise as contributing causes, numerous other conditions, s u c h . a s poor physique, overwork, worry, alcoholic excess, debilitating disease, and the like, which cannot influence directly the content of the specific anti-bodies in the individual. Moreover, if a person has had a tuberculous lesion in the body in the past and recovered, he seems to
HEALTH.
223
remain more liable than a previously healthy person to a recrudescence of the disease or to a fresh infection in another part of the body. If the resisting power against the tubercle bacillus can be proved to be due to the presence in the tissues of certain specific anti-bodies, it seems probable that before long an ideal antigen will be discovered, the introduction of which into the organism will lead to the formation of such anti-bodies, and so to the cure of the disease. It does not seem, however, that at the present time any of the tub~rculins in use fulfil the requiremer~ts of an ideal antigen. It has been fairly definitely established that the disease tuberculosis is partly due to the mechanical effect of the growth of the tubercle bacilli, an d partly due to the biochemical effect of the toxins derived from the bacilli. The clinical study of tuberculous patients leads to the conclusion that many of the symptoms, such as fever, wasting, malaise, and the like, are, directly or indirectly, of toxic origin. In certain cases a power of resistance against this toxsemia develops, and this resistance is associated with the development in the blood of certain recognisable substances, such as opsonins, agglutinins, and complement fixing substances, which are not present in uninfected individuals. The various tuberculins, when injected into the body of an infected person in suitable doses. produce symptoms very similar to those of tuberculosis, and by their administration similar new and recognisable substance s may be caused to develop in the blood. The hypothesis that these new substances indicate the presence of anti-bodies to the tuberculo-toxin is the basis of the tuberculin treatment of tuberculosis. Clinically, we find that by injecting gradually increasing doses of tuberculin it is often possible to immunize the patient against it, and it seemsthat if this is done in certain tuberculous persons they develo p fewer symptoms in their disease. It seems doubtful, however, whether this increase:of resisting power against the tuberculo-toxin is associated with much, if any, increase of resisting power against the local mechanical effects of the growing tubercle bacilli; that is to Say, though the patient has been immunized against tuberculin, yet it does not o f necessity follow that he has become immunized against tuberculosis. To meet this objection it has been urged that if the symptoms •caused by the tuberculo-toxins be checked, the body will be in a better position to deal with the tubercle bacilli, even though it has not acquired F, t
PUBLIC
a specific resisting power. Whatever may be the hypothesis which leads us to the administration of tubercu!in in a case of tuberculosis, and however much we may hope to confer benefit we must remember that if there has been tuberculous infection a specific reaction wilt ensue after a sufficient dose, of an intensity varying with the sensitivity of the tissues at the time and the dose of tuberculin injected. All are agreed that such reaction should not be excessive, though there is a considerable difference of opinion as to the degree of reaction which constitutes excess. In the administration of tuberculin to tuberculous persons very careful attention must be paid to the specific reaction; this is usually described as being of a threefold nature--local, focal, and general. The local reaction at the site of the injection is characterised by redness, swelling and pain. It is seldom of serious import, but may cause considerable inconvenience. Patients soon learn to dread the injections if the local reactions are frequent and severe, and great difficulty arises in persuading them to continue the treatment. The local reactions seem to be more intense if the dose given is too large or too rapidly increased, o r if the interval between the injections be unduly long : the local reaction may also be taken as an indication of the approach of a general reaction, and is of considerable importance in the avoidance of an overdose in tuberculin treatment. The focal reaction is manifested by changes of an inflammatory nature at the site of the disease. If the focus be in the lungs, visible evidence of the reaction cannot be obtained; indirect evidence is given by increased cough, increased sputum, possibly associated with h~emoptysis, and, in some instances, a change in the auscultatory phenomena. It is obvious that marked focal reaction is not without some danger to the patient, and it is very seldom that it is intentionally produced. Fortunately, the local reaction is obtained with a smaller dose than the focal response, and consequently by keeping the local reaction within bounds it is possible to avoid danger from exaggerated focal activity. In the treatment of tuberculous persons by graduated exercise in a sanatorium, it is supposed that the good effect may be attributed to the controlled liberation of autogenous tuberculo-toxins. Sometimes in a course of treatment it is found that symptoms due to the focal disease, such as cough and sputum, lessen up to a certain point and then cease to
HEALTH.
MAY,
improve. It is known that occasionally, when the case is stationary, improvement may result if an overdose of exercise be given, leading to a temporary increase in the pulmonary symptoms, and a general febrile reaction. Similarly, in the treatment by tuberculin, occasionally a dose is given sufficient to produce a definite focal response. The focal reaction is associated with considerable hypera~mia in visible lesions, and it is assumed that this is also the case when the disease is in the lungs. Possibly the focal response may be of benefit ia indolent cases, in the same way that the application of a vesicant is beneficial in an indolent ulcer of the leg. The general reaction is also of great importance. In its slighter grades there may be only a little headache, backache, or malaise, or a " far-away" feeling ; when more marked there may be general pain, considerable pyrexia, and possibly vomiting. The danger of an intense general reaction is probably less than that of an intense focal reaction, b u t the two are likely to occur simultaneously, and consequently it is usually considered advisable to avoid both. The inconvenience to the patient of a marked general reaction is obvious, and there seems to be no evidence that it has any therapeutic advantage. The selection of cases for treatment by tuberculin requires great care. If we assume, as seems justifiable, that many, if not most, of the symptoms of pulmonary tuberculosis are due to the absorption of autogenous tuberculotoxins, we must exercise great caution in the injection of old tuberculin, or tuberculins somewhat similarly prepared, to patients suffering from such symptoms. This constitutes one of the great difficulties in the ambulant treatment of pulmonary tuberculosis by tuberculin. Unless the patient is under close observation, it is impossible to arrive at any estimate of the amount of auto-inoculation occurring, and the injection of tuberculin may at times produce unexpected and dangerous reactions. Tile thermometer is usually employed as the simplest indicator of auto-inoculation, and it is a sound rule that injections o f tuberculin should be given with the very greatest caution if the temperature within the previous twenty-four hours has exceeded 99. The cases which are most favourable for ambulant treatment are those in •which the temperature never exceeds normal, and in which the extent and symptoms of the disease are slight. Of course, it is this type of case that is likely to do well under any form of treatment, and this fact constitutes a great
1913.
PUBLIC H E A L T H .
difficulty in forming a judgment with regard to the true value of the treatment by tuberculin. The treatment by tuberculin of patients who have fever, or many symptoms, is sometimes attempted, but it should be reserved for those who can be kept under very close observation at a hospital or other institution. The form of tuberculin selected for the treatment varies according to the theories that appeal most to the physician in charge. Many tubercutins are on the market, but the number in common use in England is comparatively small. In their clinical effects, so far as we can judge at present, the various preparations differ in degree rather than in kind. All, if given in too large doses, are dangerous, and in all we have the. same difficulty in estimating the true therapeutic value~ because in undertaking the treatment we invariably endeavour to remove as far as possible the contributory causes of the disease, and to improve the hygienic surroundings of the patient. With regard to the dosage of tuberculin, it certainly seems wise to begin with a dose not likely to produce a reaction, and to increase gradually until a local reaction occurs. In this way it is possible to determine the sensitivity of the patient, and to keep under control the focal and general response, which may be fraught with so much danger. Individuals vary so much in their sensitivity to tuberculin that it is not possible to draw up a table of doses; each dose nmst be determined by the effect produced by the last. It is extremely difficult to estimate the value of tuberculin treatment : the type of case from which the best results are claimed is that in which a certain number of recoveries may be expected with other forms of treatment. Evidence is accumulating that patients, at all events in the earlier stages of the disease, do better if they receive tuberculin as well as hygienic treatment, but it does not seem probable that tuberculin alone will give satisfactory results without adequate attention to hygiene, o r that it can be expected to lead to the arrest of the disease in advanced cases. On the other hand, there is no doubt that unless it is used with extreme caution tuberculin may lead to disastrous results. STATE A I D FOR A TUBI'.;RCULOSI8 E x t I I B I T . - - T t t e
legislature of the State of Virginia, U.S,A., has appropriated ~9,ooo towards providing a special train carrying tuberculosis exhibits in connection with a tour of the State planned by the West Virginia Anti-tuberculosis Society.
225
T H E PROS AND CONS OF T U B E R C U L I N IN T H E D I A G N O S I S OF TUBERCULOSIS.* BY H . O. W E S T ,
M.D.,
Tuberculosis Officer, County of Kent.
THEREhas been
of late such a rejuvenescence--one might almost say such a resurr e c t i o n - o f tuberculin both as a means of diagnosis and of treatment that an attempt to sum up the position as regards the diagnostic value of tuberculin, particularly as this is now a public health question, may be of value. Historically tuberculin has passed through many vicissitudes. Koch introduced tuberculin as a specific diagnostic and curative agent in i89o. The hopes raised were soon found not to be justified and in a few months the treatment was practically abandoned--I think almost universally abandoned in England. Individual workers, especially Camac Wilkinson in Australia, continued the use of tuberculin, and of late years there has been a resuscitation of its use. Wilkinson in particular in England has called attention to the subject, and it is largely owing to him that the idea of the diagnostic use of tuberculin has been revived. On the other hand the latest pronouncement of the Local Government Board in a general order now in operation (February Ist, I913), shows that the Board is not convinced, this statement being made : - - " Article V I I I . . . . a medical practitioner shall be deemed to have become aware that a person is suffering from tuberculosis . . . . . from evidence other than that derived solely from tuberculin tests applied to that person." Such, then, is roughly the present situation, on one hand a school with a definite sense of its value, and on the other hand a body of moderate opinion awaiting conviction. Camac Wilkinson, in his book " Tuberculin in the Diagnosis and Treatment of Tuberculosis," gives the results of 20 years' experience, which fact in itself justifies his claim to a careful consideration of his statements. His main contention appears to be :-" Koch in his original paper in i89o stated his opinion that tuberculin in future would become an indispensable diagnostic agent. I believe this claim to be true--that the disasters which led to the disuse of the re-agent so soon after its discovery were unfortunate and due to negligence in following Koch's specific directions. Koch was right--tuberculosis means a " '~Paper read before the Home Counties Division, Societyof Medical Officers of Health~ January xsth x9~3.
PUBLIC
THERAPEUTIC TUBERCULIN.
USE
OF
By CECIL WALL, M.D., F.R.C.P, Assistant Physician, Hospital for Consumption, Brompton.
' T R E A T M E N T in clinical medicine is very largely based upon hypotheses. If the hypotheses are sound the treatment is likely to be good, but unfortunately they are not infrequently built upon a somewhat insecure foundation. It behoves us, therefore, at frequent intervals to examine our hypotheses lest we should be led astray in an interpretation of our therapeutic results. The discordant opinions With regard to t h e use of tuberculin in the treatment of tuberculosis seem largely due to thedifferent hypotheses held with regard to the nature of the resistance of the body against tile infection by the tubercle bacillus. T h e general principle of the treatment of tuberculosis by tuberculin is based upon the hypothesis which may be crudely stated as assuming that resistance against infection by the tubercle bacillus, a n d the establishment of cure after infection, are brought about by the development in the tissues and blood stream of certain specific anti-bodies: probable as this hypothesis appears, t h e evidence experimentally and clinically is by no means conclusive. The resistance against infection byl the typhoid bacillus seems undoubtedly due: to the presence of specific anti-bodies, but when we review our knowledge of the nature of the resistance against typhoid and tuberculous infections respectively, we are struck by the fact that the conditions determining susceptibility or immunity are of a different order. Experimentally, it is possible to immunize an animal against the typhoid baciilus; it does not seem as yet that it has been possible artificially to protect an animal against tuberculous infection. Cliniealty,-we expect typhoid fever in a person who h a s been infected by Eberth's bacillus, unless he has b e e n m a d e specifically resistant by previous infection. : In tuberculosis, on the other hand, while we agree that the disease is not possible without the presence of the tubercle bacillus, we recognise as contributing causes, numerous other conditions, s u c h . a s poor physique, overwork, worry, alcoholic excess, debilitating disease, and the like, which cannot influence directly the content of the specific anti-bodies in the individual. Moreover, if a person has had a tuberculous lesion in the body in the past and recovered, he seems to
HEALTH.
223
remain more liable than a previously healthy person to a recrudescence of the disease or to a fresh infection in another part of the body. If the resisting power against the tubercle bacillus can be proved to be due to the presence in the tissues of certain specific anti-bodies, it seems probable that before long an ideal antigen will be discovered, the introduction of which into the organism will lead to the formation of such anti-bodies, and so to the cure of the disease. It does not seem, however, that at the present time any of the tub~rculins in use fulfil the requiremer~ts of an ideal antigen. It has been fairly definitely established that the disease tuberculosis is partly due to the mechanical effect of the growth of the tubercle bacilli, an d partly due to the biochemical effect of the toxins derived from the bacilli. The clinical study of tuberculous patients leads to the conclusion that many of the symptoms, such as fever, wasting, malaise, and the like, are, directly or indirectly, of toxic origin. In certain cases a power of resistance against this toxsemia develops, and this resistance is associated with the development in the blood of certain recognisable substances, such as opsonins, agglutinins, and complement fixing substances, which are not present in uninfected individuals. The various tuberculins, when injected into the body of an infected person in suitable doses. produce symptoms very similar to those of tuberculosis, and by their administration similar new and recognisable substance s may be caused to develop in the blood. The hypothesis that these new substances indicate the presence of anti-bodies to the tuberculo-toxin is the basis of the tuberculin treatment of tuberculosis. Clinically, we find that by injecting gradually increasing doses of tuberculin it is often possible to immunize the patient against it, and it seemsthat if this is done in certain tuberculous persons they develo p fewer symptoms in their disease. It seems doubtful, however, whether this increase:of resisting power against the tuberculo-toxin is associated with much, if any, increase of resisting power against the local mechanical effects of the growing tubercle bacilli; that is to Say, though the patient has been immunized against tuberculin, yet it does not o f necessity follow that he has become immunized against tuberculosis. To meet this objection it has been urged that if the symptoms •caused by the tuberculo-toxins be checked, the body will be in a better position to deal with the tubercle bacilli, even though it has not acquired F, t
PUBLIC
a specific resisting power. Whatever may be the hypothesis which leads us to the administration of tubercu!in in a case of tuberculosis, and however much we may hope to confer benefit we must remember that if there has been tuberculous infection a specific reaction wilt ensue after a sufficient dose, of an intensity varying with the sensitivity of the tissues at the time and the dose of tuberculin injected. All are agreed that such reaction should not be excessive, though there is a considerable difference of opinion as to the degree of reaction which constitutes excess. In the administration of tuberculin to tuberculous persons very careful attention must be paid to the specific reaction; this is usually described as being of a threefold nature--local, focal, and general. The local reaction at the site of the injection is characterised by redness, swelling and pain. It is seldom of serious import, but may cause considerable inconvenience. Patients soon learn to dread the injections if the local reactions are frequent and severe, and great difficulty arises in persuading them to continue the treatment. The local reactions seem to be more intense if the dose given is too large or too rapidly increased, o r if the interval between the injections be unduly long : the local reaction may also be taken as an indication of the approach of a general reaction, and is of considerable importance in the avoidance of an overdose in tuberculin treatment. The focal reaction is manifested by changes of an inflammatory nature at the site of the disease. If the focus be in the lungs, visible evidence of the reaction cannot be obtained; indirect evidence is given by increased cough, increased sputum, possibly associated with h~emoptysis, and, in some instances, a change in the auscultatory phenomena. It is obvious that marked focal reaction is not without some danger to the patient, and it is very seldom that it is intentionally produced. Fortunately, the local reaction is obtained with a smaller dose than the focal response, and consequently by keeping the local reaction within bounds it is possible to avoid danger from exaggerated focal activity. In the treatment of tuberculous persons by graduated exercise in a sanatorium, it is supposed that the good effect may be attributed to the controlled liberation of autogenous tuberculo-toxins. Sometimes in a course of treatment it is found that symptoms due to the focal disease, such as cough and sputum, lessen up to a certain point and then cease to
HEALTH.
MAY,
improve. It is known that occasionally, when the case is stationary, improvement may result if an overdose of exercise be given, leading to a temporary increase in the pulmonary symptoms, and a general febrile reaction. Similarly, in the treatment by tuberculin, occasionally a dose is given sufficient to produce a definite focal response. The focal reaction is associated with considerable hypera~mia in visible lesions, and it is assumed that this is also the case when the disease is in the lungs. Possibly the focal response may be of benefit ia indolent cases, in the same way that the application of a vesicant is beneficial in an indolent ulcer of the leg. The general reaction is also of great importance. In its slighter grades there may be only a little headache, backache, or malaise, or a " far-away" feeling ; when more marked there may be general pain, considerable pyrexia, and possibly vomiting. The danger of an intense general reaction is probably less than that of an intense focal reaction, b u t the two are likely to occur simultaneously, and consequently it is usually considered advisable to avoid both. The inconvenience to the patient of a marked general reaction is obvious, and there seems to be no evidence that it has any therapeutic advantage. The selection of cases for treatment by tuberculin requires great care. If we assume, as seems justifiable, that many, if not most, of the symptoms of pulmonary tuberculosis are due to the absorption of autogenous tuberculotoxins, we must exercise great caution in the injection of old tuberculin, or tuberculins somewhat similarly prepared, to patients suffering from such symptoms. This constitutes one of the great difficulties in the ambulant treatment of pulmonary tuberculosis by tuberculin. Unless the patient is under close observation, it is impossible to arrive at any estimate of the amount of auto-inoculation occurring, and the injection of tuberculin may at times produce unexpected and dangerous reactions. Tile thermometer is usually employed as the simplest indicator of auto-inoculation, and it is a sound rule that injections o f tuberculin should be given with the very greatest caution if the temperature within the previous twenty-four hours has exceeded 99. The cases which are most favourable for ambulant treatment are those in •which the temperature never exceeds normal, and in which the extent and symptoms of the disease are slight. Of course, it is this type of case that is likely to do well under any form of treatment, and this fact constitutes a great
1913.
PUBLIC H E A L T H .
difficulty in forming a judgment with regard to the true value of the treatment by tuberculin. The treatment by tuberculin of patients who have fever, or many symptoms, is sometimes attempted, but it should be reserved for those who can be kept under very close observation at a hospital or other institution. The form of tuberculin selected for the treatment varies according to the theories that appeal most to the physician in charge. Many tubercutins are on the market, but the number in common use in England is comparatively small. In their clinical effects, so far as we can judge at present, the various preparations differ in degree rather than in kind. All, if given in too large doses, are dangerous, and in all we have the. same difficulty in estimating the true therapeutic value~ because in undertaking the treatment we invariably endeavour to remove as far as possible the contributory causes of the disease, and to improve the hygienic surroundings of the patient. With regard to the dosage of tuberculin, it certainly seems wise to begin with a dose not likely to produce a reaction, and to increase gradually until a local reaction occurs. In this way it is possible to determine the sensitivity of the patient, and to keep under control the focal and general response, which may be fraught with so much danger. Individuals vary so much in their sensitivity to tuberculin that it is not possible to draw up a table of doses; each dose nmst be determined by the effect produced by the last. It is extremely difficult to estimate the value of tuberculin treatment : the type of case from which the best results are claimed is that in which a certain number of recoveries may be expected with other forms of treatment. Evidence is accumulating that patients, at all events in the earlier stages of the disease, do better if they receive tuberculin as well as hygienic treatment, but it does not seem probable that tuberculin alone will give satisfactory results without adequate attention to hygiene, o r that it can be expected to lead to the arrest of the disease in advanced cases. On the other hand, there is no doubt that unless it is used with extreme caution tuberculin may lead to disastrous results. STATE A I D FOR A TUBI'.;RCULOSI8 E x t I I B I T . - - T t t e
legislature of the State of Virginia, U.S,A., has appropriated ~9,ooo towards providing a special train carrying tuberculosis exhibits in connection with a tour of the State planned by the West Virginia Anti-tuberculosis Society.
225
T H E PROS AND CONS OF T U B E R C U L I N IN T H E D I A G N O S I S OF TUBERCULOSIS.* BY H . O. W E S T ,
M.D.,
Tuberculosis Officer, County of Kent.
THEREhas been
of late such a rejuvenescence--one might almost say such a resurr e c t i o n - o f tuberculin both as a means of diagnosis and of treatment that an attempt to sum up the position as regards the diagnostic value of tuberculin, particularly as this is now a public health question, may be of value. Historically tuberculin has passed through many vicissitudes. Koch introduced tuberculin as a specific diagnostic and curative agent in i89o. The hopes raised were soon found not to be justified and in a few months the treatment was practically abandoned--I think almost universally abandoned in England. Individual workers, especially Camac Wilkinson in Australia, continued the use of tuberculin, and of late years there has been a resuscitation of its use. Wilkinson in particular in England has called attention to the subject, and it is largely owing to him that the idea of the diagnostic use of tuberculin has been revived. On the other hand the latest pronouncement of the Local Government Board in a general order now in operation (February Ist, I913), shows that the Board is not convinced, this statement being made : - - " Article V I I I . . . . a medical practitioner shall be deemed to have become aware that a person is suffering from tuberculosis . . . . . from evidence other than that derived solely from tuberculin tests applied to that person." Such, then, is roughly the present situation, on one hand a school with a definite sense of its value, and on the other hand a body of moderate opinion awaiting conviction. Camac Wilkinson, in his book " Tuberculin in the Diagnosis and Treatment of Tuberculosis," gives the results of 20 years' experience, which fact in itself justifies his claim to a careful consideration of his statements. His main contention appears to be :-" Koch in his original paper in i89o stated his opinion that tuberculin in future would become an indispensable diagnostic agent. I believe this claim to be true--that the disasters which led to the disuse of the re-agent so soon after its discovery were unfortunate and due to negligence in following Koch's specific directions. Koch was right--tuberculosis means a " '~Paper read before the Home Counties Division, Societyof Medical Officers of Health~ January xsth x9~3.