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Beware
EDITORIAL Beware*
I
ministration of drugs to tub e r cui i nconverters of any age or to all tuberculin reactors, each ph)sician and organization should
WAS ASKED TO SPEAK TODAY ON THE
impact modern treatment has had on epidemiology and case finding. However, the impact epidemiologY and case finding have had on tuberculosis must first be considered. Prior to 1947 (the pre-antituberculosis d ru g era) epidemiology and case finding in both people and animals with management of clinical cases constituted the bulk of the attack on tubercle bacilli. The lion's share of our victory over tuberculosis to date was accomplished before the antituberculosis drug era. I What the entire impact of modern treatment has been since 1947 is not easy to evaluate because epidemiology and case finding have continued. However, there is one area where it apparently ha~ been enormous, namely: the suppressive effect of drugs on clinical lesions which is so definite as to cause tubercle bacilli to di appear at least temporarily from excretions of lesions and to cause lesions to recede so they are controlled by nature or can be extirpated. Thus, the dissemination of tubercle bacilli in homes and communities has been decreased. In a life-time disease the ultimate effectiveness of suppressive drugs cannot be determined in a quarter of a century. We alreadv know that drugs are not a panacea as they were earlier thought to be. There is extant a world-sweeping wave of enthusiasm for administration of drugs to children of three years and younger who react to tuberculin and to persons of all ages who have recently had tuberculin conversion. It is being recommended that such persons receive drugs for at least one year. It is even being proposed that persons of all ages found to react to tuberculin be given drugs. Before adopting or continuing the ad-
Dr. C. B. McCreary" working in Karunalaya Hospital, Wandoor, in the state of Kerala, India, found the difficult problem in the domiciliary chemotherapy of tuberculosis is to secure the cooperation of the patients. ''''hen patients were to call at the dispensary for a supply of tablets every few
*Presented in part before a Round .Table Lur:cheon discussion, 33rd An.nual Meeu~g, ~mcrlcan College of Chest PhysiCians, Atlantic City, June 17, 1967.
373
374
J.
A. MYERS
weeks, there was no assurance they were taking them regularly or at all. Some were irregular about calling for drugs and others completely disappeared. A system was devised whereby 200 outpatients are visited twice each week by a pharmacist who in a Jeep van travels 120 miles each time to see all 200 of them. The van travels the main road on schedule and the patients assemble at the nearest stop which may be a tea shop or some other convenient place. Some patients live nearby and others come from homes some distance off the main road. Twice each week the van arrives at t~ese pre-arranged stops and the pharmacist gives each one ~n injection of streptomycin and watches him swallow isoniazid and pyridoxine tablets. A record is made in the attendance book and the van speeds on to the next outpatient clinic. To make such visits to or near each patient's home is the only way that has been found to be sure t~e. d ru gs are .administered regularly. A slmllar method IS being em ploy e d on a large scale in Madras. If drugs are to be administered regularl\' ~ver a sufficient period of time, many pa'tlents need to take them in the presence of physicians, nurses, or other qualified persons. In the United States, the number of clinical cases is small enough that the provision of personal supervision is within the realm of physical possibility. Moreover, the obtainable therapeutic result in clinical cases justifies the effort. It is common knowledge that apparently well people are reluctant to take or administer drugs for more than brief periods of time. This applies especially to infants and children. Novak· has commented editorially on a study conducted by M. R. Lichenstein on 1,257 children under four years of age. Even though their parents or guardians were provided with drugs gratis, analysis at the end of a year revealed that 15 per cent did not have the d ru gs administered; of those who started, 38 per cent failed to complete the year. Among the remainder who presumably completed the course many admitted that they did not admin~
Disuses of the Chest
ister isoniazid regularly. In 1965, the Health Department of Puerto Rico' dispensed isoniazid tablets to 672 Puerto Rican families' contacts of active cases of tuberculosis with instructions on how to take the drug. Each one was ac;ked to I' e t urn for more tablets in six months. However, only 14 returned. Contrary to the former belief that a high percentage of infants who became infected prior to the antituberculosis drug era died from acute forms of tuberculosis, welldocumented studies revealed that rarely did more than 1 or 2 per cent of such infants develop these forms of the disease. Among children up to the age of 12 years whose tuberculin reaction converts, so few develop clinical tuberculosis during this age period as to make the administration of isoniazid to all a most questionable procedure. Moreover, for the few who do develop clinical disease, excellent treatment is now available when the lesions appear. Well-documented studies on 1,886 children who reacted to tuberculin between the ages of 6 and 12 veal'S revealed that 15 developed clinical l~sions during that age period. Although this was in the pre-antituberculosis drug era, 11 of these children made good recoveries, three died from tuberculosis and one from surgical shock 6 during an operation on the spine. Such knowledge of the natural history of tuberculosis among children of this age group would seem to emphasize the lack of need for drug treatment of tuberculin reactors. The conditions from which three died are now treated successfully by antituberculosis drugs. Each physician must decide for himself whether he prefers to prescribe antituberculosis drugs for a year or more for children in this age period who become t~berculin positive, or to refrain from speCific drug therapy for these children until evidence of clinical disease appears. Contrary to a former belief, acute fatal forms of tuberculosis are rare among adults who become positive to tuberculin. In the pre-antituberculosis drug era, among 2,137
Volume 53. No.3 March, 1968
BEWARE
375
sive studies on rodents and concluded "that students of nursing and medicine and recent graduates who experienced tuberculin isoniazid is an acceptable risk when used conversion, none developed an acute fatal as a curative drug for tuberculosis in man, form of tuberculosis.' Here again, each but that it should not be used prophylacphysician must decide whether he prefers tically in healthy babies." to prescribe antituberculosis drugs to medToming's'O studies on "Isoniazid and ical and paramedical students and graduloss of memory" were so carefully made ates who become tuberculin reactors. and so well-documented that the results should command attention of all physicians. If the 30 million to 40 million persons He pointed out that in the usual therain the United States who are now infected peutic doses of 200 to 300 milligrams daily, but have no evidence of clinical tubercuisoniazid often provokes unwanted psycholosis were to have antituberculosis drugs adHe had observed that palogic side-effects. ministered, the time, effort and drugs would tients with pulmonary tuberculosis during be wasted on 95 per cent (28,500,000 to treatment with isoniazid and para-aminosal38,000,000) since it has been estimated icylic acid often had impairment of memory that only 5 per cent of infected people ulduring treatment. From this observation a timately develop clinical disease. The total , ' speCial memory test was improvised which number would need to have drugs adminrevealed a statistically significant impairistered for the remainder of their lives bement of memory at the re-examination durcause the recrudescent lesions which might ing treatment compared with examinations develop would be interspersed throughout before and after treatment. Taming says: the years. "While the reported psychological side(5) Complacency is the most vicious effects do not contraindicate the use of enemy of tuberculosis eradication. It has isoniazid in tuberculous patients, we feel been increased many fold among our citithat they speak in favor of a certain cauzenry, including physicians, since antitubertion in using isoniazid prophylactically on culosis drugs became available. When the a large scale in healthy people." diagnosis of tuberculosis is now made, it is In summary, isoniazid is only bacterionot unusual for the patient to say, "I only static, may cause resistant mutants to need to take pills." Some such persons reemerge, cannot reach bacilli in avascular fuse hospitalization and isolation because lesions, is rejected by 50 to 75 per cent of they have no fear of the disease and do not persons without professional supervision of consider their human and animal associates each dose, offers little to school age chilin danger. dren among whom clinical tuberculosis (6) Several investigators have observed rarely develop, is wasted on 95 per cent that isoniazid in large doses results in neoof the total number of tuberculin reactors plasms of the lungs, especially adenomas in in the nation, and would reach very few of a certain strain of mice. However, Ham8 the 5 per cent who would develop lesions mond, Selikoff and Robitzek traced three any time during the remainder of their groups of people who had received isoniazid. lives. In addition, overconfidence in drug Their findings give no indication that this therapy has developed dangerous compladrug in d ai 1y doses of 4 milligrams per cency in the patient and the public regardkilogram of body weight increases the risk ing tuberculosis eradication. of cancer occurring in human beings with. Recent :vidence shows that isoniazid sigin a period of IOta 15 years after starting mficantly Imp airs memory. Most careful treatment. This study and others are in consideration is justified before this drug is progress, but it may be several years before recommended for use during any phase of a final conclusion can be drawn. tuberculosis except in the presence of clinical lesions. Peacock and Peacock" conducted exten-
J.
REFERENCES MYERS, J. A.: Eighty ye.ars after the first . f the tubercle bacillus, DIs. Chest,S I : g )Impse 0 500 · 1967.H D' Outpatient . c h emot herapy f or 2 I RELAND, . .. . 82 7 tuberculosis, Am. Rev. Res p. DIS., : 3 a,
)960. ' con t ro I 'In I n3 MCCREARY, C. B.. : TubercuIOSIS dia Dis. Chest (In press) .. -J. NO~A1{, J. B.: Drug evaSIOn, a headache for . doctors, The Challenge, IS: 2, 1960. 5 RODRIGUEZ PASTOR, J.: Personal communication, 1967. 6 MYERS, J. A., BEA~MAN, J. E. AND. DIXON, H. G.: VI. PrognosIs among tubercuhn reactor children of six to twelve years, Am. Rev.
Resp. Dis., 90:350, 1964.
Dise.sos of the Chesl
A. MYERS
7 MYERS, J. A., BEARMAN, J. E. AND BOTKINS, ALMA: IX. Prognosis among students with tuberculin reaction conversion before, during and after medical school, Dis. Chest, 50: 120, 1966. 8 HAMMOKD, E. C., SEUKOF", 1. J. AND RODITZEK, E. H.: Isoniazid therapy in relation to later occurrence of cancer in adults and in infants, Brit. Med. ]., 2:792, 1967. 9 PEACOCK, A. AND PEACOCK, P. R.: The results of prolonged administration of isoniazid to mice, rats and hamsters, Brit. ]. Cancer, 20: 307, 1966. LO TORNING, K.: Isoniazid and loss of memory, Scalld. ]. Resp. Dis. (in press). J. A. MYERS, M.D., M.C.C.P. Minneapolis, Minnesota
SMOKING CAN BE A SERIOUS HEALTH HAZARD Please do not smoke in the reception room - it may affect other patients
AMERICAN COLLEGE OF CHEST PHYSICIANS
The above placards, measuring aY2 x II, are available without cost for display in reception rooms of physicians' offices. For your copy, please complete the coupon helow:
Executive Director American College of Chest Physicians 112 East Chestnut Street Chicago, Illinois 60611 Please send me a "Smoking can be a health hazard" placard. NAME ADDRESS - - - - - - - - - - - - - -
CITY, STATE - - - - - - - - - - - -
_
ZIP CODE
I
ministration of drugs to tub e r cui i nconverters of any age or to all tuberculin reactors, each ph)sician and organization should
WAS ASKED TO SPEAK TODAY ON THE
impact modern treatment has had on epidemiology and case finding. However, the impact epidemiologY and case finding have had on tuberculosis must first be considered. Prior to 1947 (the pre-antituberculosis d ru g era) epidemiology and case finding in both people and animals with management of clinical cases constituted the bulk of the attack on tubercle bacilli. The lion's share of our victory over tuberculosis to date was accomplished before the antituberculosis drug era. I What the entire impact of modern treatment has been since 1947 is not easy to evaluate because epidemiology and case finding have continued. However, there is one area where it apparently ha~ been enormous, namely: the suppressive effect of drugs on clinical lesions which is so definite as to cause tubercle bacilli to di appear at least temporarily from excretions of lesions and to cause lesions to recede so they are controlled by nature or can be extirpated. Thus, the dissemination of tubercle bacilli in homes and communities has been decreased. In a life-time disease the ultimate effectiveness of suppressive drugs cannot be determined in a quarter of a century. We alreadv know that drugs are not a panacea as they were earlier thought to be. There is extant a world-sweeping wave of enthusiasm for administration of drugs to children of three years and younger who react to tuberculin and to persons of all ages who have recently had tuberculin conversion. It is being recommended that such persons receive drugs for at least one year. It is even being proposed that persons of all ages found to react to tuberculin be given drugs. Before adopting or continuing the ad-
Dr. C. B. McCreary" working in Karunalaya Hospital, Wandoor, in the state of Kerala, India, found the difficult problem in the domiciliary chemotherapy of tuberculosis is to secure the cooperation of the patients. ''''hen patients were to call at the dispensary for a supply of tablets every few
*Presented in part before a Round .Table Lur:cheon discussion, 33rd An.nual Meeu~g, ~mcrlcan College of Chest PhysiCians, Atlantic City, June 17, 1967.
373
374
J.
A. MYERS
weeks, there was no assurance they were taking them regularly or at all. Some were irregular about calling for drugs and others completely disappeared. A system was devised whereby 200 outpatients are visited twice each week by a pharmacist who in a Jeep van travels 120 miles each time to see all 200 of them. The van travels the main road on schedule and the patients assemble at the nearest stop which may be a tea shop or some other convenient place. Some patients live nearby and others come from homes some distance off the main road. Twice each week the van arrives at t~ese pre-arranged stops and the pharmacist gives each one ~n injection of streptomycin and watches him swallow isoniazid and pyridoxine tablets. A record is made in the attendance book and the van speeds on to the next outpatient clinic. To make such visits to or near each patient's home is the only way that has been found to be sure t~e. d ru gs are .administered regularly. A slmllar method IS being em ploy e d on a large scale in Madras. If drugs are to be administered regularl\' ~ver a sufficient period of time, many pa'tlents need to take them in the presence of physicians, nurses, or other qualified persons. In the United States, the number of clinical cases is small enough that the provision of personal supervision is within the realm of physical possibility. Moreover, the obtainable therapeutic result in clinical cases justifies the effort. It is common knowledge that apparently well people are reluctant to take or administer drugs for more than brief periods of time. This applies especially to infants and children. Novak· has commented editorially on a study conducted by M. R. Lichenstein on 1,257 children under four years of age. Even though their parents or guardians were provided with drugs gratis, analysis at the end of a year revealed that 15 per cent did not have the d ru gs administered; of those who started, 38 per cent failed to complete the year. Among the remainder who presumably completed the course many admitted that they did not admin~
Disuses of the Chest
ister isoniazid regularly. In 1965, the Health Department of Puerto Rico' dispensed isoniazid tablets to 672 Puerto Rican families' contacts of active cases of tuberculosis with instructions on how to take the drug. Each one was ac;ked to I' e t urn for more tablets in six months. However, only 14 returned. Contrary to the former belief that a high percentage of infants who became infected prior to the antituberculosis drug era died from acute forms of tuberculosis, welldocumented studies revealed that rarely did more than 1 or 2 per cent of such infants develop these forms of the disease. Among children up to the age of 12 years whose tuberculin reaction converts, so few develop clinical tuberculosis during this age period as to make the administration of isoniazid to all a most questionable procedure. Moreover, for the few who do develop clinical disease, excellent treatment is now available when the lesions appear. Well-documented studies on 1,886 children who reacted to tuberculin between the ages of 6 and 12 veal'S revealed that 15 developed clinical l~sions during that age period. Although this was in the pre-antituberculosis drug era, 11 of these children made good recoveries, three died from tuberculosis and one from surgical shock 6 during an operation on the spine. Such knowledge of the natural history of tuberculosis among children of this age group would seem to emphasize the lack of need for drug treatment of tuberculin reactors. The conditions from which three died are now treated successfully by antituberculosis drugs. Each physician must decide for himself whether he prefers to prescribe antituberculosis drugs for a year or more for children in this age period who become t~berculin positive, or to refrain from speCific drug therapy for these children until evidence of clinical disease appears. Contrary to a former belief, acute fatal forms of tuberculosis are rare among adults who become positive to tuberculin. In the pre-antituberculosis drug era, among 2,137
Volume 53. No.3 March, 1968
BEWARE
375
sive studies on rodents and concluded "that students of nursing and medicine and recent graduates who experienced tuberculin isoniazid is an acceptable risk when used conversion, none developed an acute fatal as a curative drug for tuberculosis in man, form of tuberculosis.' Here again, each but that it should not be used prophylacphysician must decide whether he prefers tically in healthy babies." to prescribe antituberculosis drugs to medToming's'O studies on "Isoniazid and ical and paramedical students and graduloss of memory" were so carefully made ates who become tuberculin reactors. and so well-documented that the results should command attention of all physicians. If the 30 million to 40 million persons He pointed out that in the usual therain the United States who are now infected peutic doses of 200 to 300 milligrams daily, but have no evidence of clinical tubercuisoniazid often provokes unwanted psycholosis were to have antituberculosis drugs adHe had observed that palogic side-effects. ministered, the time, effort and drugs would tients with pulmonary tuberculosis during be wasted on 95 per cent (28,500,000 to treatment with isoniazid and para-aminosal38,000,000) since it has been estimated icylic acid often had impairment of memory that only 5 per cent of infected people ulduring treatment. From this observation a timately develop clinical disease. The total , ' speCial memory test was improvised which number would need to have drugs adminrevealed a statistically significant impairistered for the remainder of their lives bement of memory at the re-examination durcause the recrudescent lesions which might ing treatment compared with examinations develop would be interspersed throughout before and after treatment. Taming says: the years. "While the reported psychological side(5) Complacency is the most vicious effects do not contraindicate the use of enemy of tuberculosis eradication. It has isoniazid in tuberculous patients, we feel been increased many fold among our citithat they speak in favor of a certain cauzenry, including physicians, since antitubertion in using isoniazid prophylactically on culosis drugs became available. When the a large scale in healthy people." diagnosis of tuberculosis is now made, it is In summary, isoniazid is only bacterionot unusual for the patient to say, "I only static, may cause resistant mutants to need to take pills." Some such persons reemerge, cannot reach bacilli in avascular fuse hospitalization and isolation because lesions, is rejected by 50 to 75 per cent of they have no fear of the disease and do not persons without professional supervision of consider their human and animal associates each dose, offers little to school age chilin danger. dren among whom clinical tuberculosis (6) Several investigators have observed rarely develop, is wasted on 95 per cent that isoniazid in large doses results in neoof the total number of tuberculin reactors plasms of the lungs, especially adenomas in in the nation, and would reach very few of a certain strain of mice. However, Ham8 the 5 per cent who would develop lesions mond, Selikoff and Robitzek traced three any time during the remainder of their groups of people who had received isoniazid. lives. In addition, overconfidence in drug Their findings give no indication that this therapy has developed dangerous compladrug in d ai 1y doses of 4 milligrams per cency in the patient and the public regardkilogram of body weight increases the risk ing tuberculosis eradication. of cancer occurring in human beings with. Recent :vidence shows that isoniazid sigin a period of IOta 15 years after starting mficantly Imp airs memory. Most careful treatment. This study and others are in consideration is justified before this drug is progress, but it may be several years before recommended for use during any phase of a final conclusion can be drawn. tuberculosis except in the presence of clinical lesions. Peacock and Peacock" conducted exten-
J.
REFERENCES MYERS, J. A.: Eighty ye.ars after the first . f the tubercle bacillus, DIs. Chest,S I : g )Impse 0 500 · 1967.H D' Outpatient . c h emot herapy f or 2 I RELAND, . .. . 82 7 tuberculosis, Am. Rev. Res p. DIS., : 3 a,
)960. ' con t ro I 'In I n3 MCCREARY, C. B.. : TubercuIOSIS dia Dis. Chest (In press) .. -J. NO~A1{, J. B.: Drug evaSIOn, a headache for . doctors, The Challenge, IS: 2, 1960. 5 RODRIGUEZ PASTOR, J.: Personal communication, 1967. 6 MYERS, J. A., BEA~MAN, J. E. AND. DIXON, H. G.: VI. PrognosIs among tubercuhn reactor children of six to twelve years, Am. Rev.
Resp. Dis., 90:350, 1964.
Dise.sos of the Chesl
A. MYERS
7 MYERS, J. A., BEARMAN, J. E. AND BOTKINS, ALMA: IX. Prognosis among students with tuberculin reaction conversion before, during and after medical school, Dis. Chest, 50: 120, 1966. 8 HAMMOKD, E. C., SEUKOF", 1. J. AND RODITZEK, E. H.: Isoniazid therapy in relation to later occurrence of cancer in adults and in infants, Brit. Med. ]., 2:792, 1967. 9 PEACOCK, A. AND PEACOCK, P. R.: The results of prolonged administration of isoniazid to mice, rats and hamsters, Brit. ]. Cancer, 20: 307, 1966. LO TORNING, K.: Isoniazid and loss of memory, Scalld. ]. Resp. Dis. (in press). J. A. MYERS, M.D., M.C.C.P. Minneapolis, Minnesota
SMOKING CAN BE A SERIOUS HEALTH HAZARD Please do not smoke in the reception room - it may affect other patients
AMERICAN COLLEGE OF CHEST PHYSICIANS
The above placards, measuring aY2 x II, are available without cost for display in reception rooms of physicians' offices. For your copy, please complete the coupon helow:
Executive Director American College of Chest Physicians 112 East Chestnut Street Chicago, Illinois 60611 Please send me a "Smoking can be a health hazard" placard. NAME ADDRESS - - - - - - - - - - - - - -
CITY, STATE - - - - - - - - - - - -
_
ZIP CODE