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Chemoprophylaxis for tuberculosis
Respiratory
Medicine
(1993) 87,81-83
Editorial
Chemoprophylaxis Is tuberculosis epidemic in 1992? Not as defined in Dorland’s Medical Dictionary as ‘attacking many people in any region at the same time, widely diffused and rapidly spreading’ (1). The century long decline in TB morbidity and mortality has slowed in the United States, but the disease is not widely diffused and rapid decline continues in other advanced countries. According to the Oxford English Dictionary (2), an epidemic is an illness ‘prevalent among a people or community at a special time and produced by some special causes not generally present in the affected locality’. Since the recent recrudescence of tuberculosis is localized and a consequence of recognized unique causes, it may, by latter definition, be reviewed as epidemic. Epidemic or not, fear of TB has reached panic proportions in the United States. Witness the call in the Philadelphia Inquirer (May 17, 1992) for surveillance of all cruise ship personnel largely because two ship employees in Miami were found to have TB. Should we resume mass X-ray surveys of school teachers, restaurant workers, and many others, a practice abandoned as unproductive in societies where TB morbidity and mortality have declined and continue to decline? The New York Times (April 26, 1992), in a lead editorial entitled ‘The Tuberculosis Failure’, called for renewed efforts and funds to cope with the alarming epidemic which has afflicted New York City for much of the past decade. The editorial cites a rise of reported cases in the city from 1300 in 1978 to an estimated 3700 in 199 1 as well as a rise nationally over the same period. It is worth noting, however, that if cases reported in New York City are subtracted from national figures, TB morbidity in the rest of the United States fell from 2753linl978to2200linl99l.Ifcasesinothermajor metropolitan areas (Newark, Miami, Atlanta, Tampa and San Francisco) are also subtracted, the decline of TB has obviously not remitted but in fact continues on for those living elsewhere in the United States. TB is epidemic in these metropolitan centres not because Mycobacterium tuberculosis has become more virulent. Rather, factors that favoured the spread and progression of tuberculosis in the past have resurfaced anew in larger American cities in recent decades: (1) malnutrition, largely due to drug addiction, alcoholism and homelessness; and (2) congestion in crowded 0954-61 I1/93/020081
f03
SOS.OO/O
for tuberculosis prisons and shelters for the homeless. To these urban ills have been added a third catastrophic blow; the acquired immunodeficiency syndrome (AIDS). It is unlikely that tuberculosis control efforts by medical and public health workers can reverse the rise without correction of these root causes. Such efforts, some argue, many prove futile. Worse, such efforts might also prove harmful to the extent that they advocate preventive isoniazid (INH) therapy. The latest published American guidelines for preventive INH therapy recommend its unrestricted use in tuberculin reactors below the age of 35 years in the belief that hepatitis is uncommon and fatal hepatitis extremely rare below this age (3). Circumstances justifying a treatment of reactors above the age of 35 are so numerous in these guidelines that, as generally interpreted, they encourage physicians to frequently administer INH to older reactors. Consequently, 95 000 Americans received preventive INH therapy in 1987 compared to less than 25 000 given curative medication (4). The wisdom of INH prophylaxis has been evaluated in numerous cost-benefit studies since the hepatitis hazard was recognized. Studies employing low estimates of hepatitis mortality and high estimates of tuberculosis prevalence have predictably concluded that benefits outweigh risks of preventive therapy (5). A smaller number of publications using opposite risk estimates have found a lower risk:benefit ratio (6). Nevertheless, the latter studies have failed to influence the federal Centers for Disease Control and the American Thoracic Society advocacy of preventive INH therapy as the mainstay of TB control in the United States (7). In the past 2 years, however, important reports concerning fatal INH-associated hepatitis have been published. Moulding and associates compiled reports of 20 such deaths in California, 19 of which occurred during preventive therapy (8). Eight deaths occurred in persons starting INH before the age of 35. We have reported three additional cases of fatal INH-associated hepatitis (9). One was a 17-year-old who was interviewed monthly by a public health nurse as he received his allotment of pills. He received his sixth and final allotment even though he reported malaise and anorexia to the nurse; within a month he died of hepatic failure. Another fatality, a 77-year-old @ 1993 Baillidre Tindall
82
Editorial
man, was given preventive INH because his wife, under treatment for ovarian cancer, developed ascites and diagnostic paracentesis revealed acid fast bacilli; it was subsequently ascertained that her peritonitis was due to M. avium-intracellulare. The third case was a 68-year-old woman who was given preventive INH therapy because a friend, who died of respiratory failure after a long hospital stay, for another illness, had a single isolation of M. TB during her illness. Snider and Tabas (10) have reported a compilation of 177 deaths in the United States from INH-associated hepatitis due to preventive use of this drug. They noted, in contrast to earlier studies, that a significant proportion of the mortality (46 of the deaths) occurred among persons less than 35 years of age. Nevertheless, they recommended no change in preventive INH policy because they calculated the fatality rate from hepatitis to be less than from future TB, estimating that 5% of untreated reactors would develop clinical TB with a 5% case fatality rate. These projections are at issue because they appear to exaggerate the current risks of morbidity and mortality from tuberculosis in developed countries. With regard to disease incidence in tuberculosis reactors, a study in Great Britain in the 1960s showed an annual incidence of 2% for the first 2.5 years, then falling to 0.7% at the end of a decade (11). Studies in the United States showed occurrence rates of 0.54.8%, while in Danish studies annual disease occurrence fell from 0.3% to 0.2% (11). These observations were made at a time when reactors may have had considerable additional exogenous infection (12). Although no comparable recent studies have been reported, a lower current morbidity is suggested by a 5-year follow-up study of 78 1 British contacts in which only one individual developed disease requiring treatment (13). The 5% case fatality rate from TB projected by Snider and Tabas (10) may also be misleading insofar as it bundles the high rates observed in patients debilitated by homelessness, addictions and AIDS with very low rates observed in the rest of the population. A recent Danish report is illustrative: 65 cases were reported in children below the age of 15 between 1977 and 1987; 25 were Danes and 40 were immigrants from poorer countries whose disease was often more severe and disseminated. No deaths occurred in the 65 cases and all were considered cured by therapy (14). Widespread use of INH to prevent future development of a treatable and curable disease seems difficult to justify when experience demonstrates considerable risk of fatal hepatitis. The report (15) of the British Thoracic Society has recommended INH chemoprophylaxis for BCG unvaccinated contacts under the age of 16 who have
Table
I
Tuberculosis deaths: rate of decline 198tL-1990
Country Great Britain Japan France Denmark Canada U.S.A.
1980*
1990*
Decline (%
1.3 5.5 3.0 1.4 0.6 0.8
0.7 3.0 1.7 I.0 0.5 0.7
46.2 45.5 43.3 28.5 16.7 12.5
*Rate per 100 000 population. strong Heaf test reactions and states that it should a be considered in Asian reactors under the age of. and for all adults in whom recent tuberculin conv sion has been noted. Strict adherence to these polici particularly those restricting preventive INH to adu having documented conversion within a year, v undoubtedly keep the number treated small, and, effect, avoid the large number of drug-related fatalit encountered in the United States. That then prophylaxis is indeed uncommonly practiced in t United Kingdom is indicated by the study of 78 1 cc tacts, where preventive INH was given to only thl children (13). A recent workshop on TB elimination in Euro and other industrialized countries concluded the PI ventive chemotherapy was inefficient if used ind criminantly (16). Preventive INH was recommend only for persons with recently acquired infection a for reactors who are contacts or who have conditio which enhance TB risk such as silicosis; haemodialys diabetes mellitus; carcinomas, especially of the he and neck; immunosuppressive treatment; gastrecton underweight; jejunoileal bypass; and HIV infectic Contraindications related to age or measures to co with the hazard of hepatic toxicity are not mentiom Moreover, these recommendations take no notice INH toxicity problems encountered in the Unit’ States as a result of similar policies. Since TB mc bidity and mortality have continued to decline developed nations worldwide other than the Unit1 States (Table 1) the risk-benefit aspects of IN prophylaxis merit thoughtful consideration as appli to the general population. Preventive INH programmes encounter serio compliance difficulties in providing 6 months of tree ment to groups who are at high risk of fatal TB. MO important, there is no evidence as yet to suggest th preventive INH therapy is effective in preventing infe tious TB in those immunocomprised by AIDS. The problems and the recent emergence of drug-resista TB has led the U.S. Centers for Disease Control
Editorial
form a task force to consider such issues. With regard to the spectrum of spread of drug-resistant TB to health workers and the population at large, it is worth noting that a London study of TB in AIDS patients showed organisms fully sensitive to standard drugs in 14 of 15 patients (17). Moreover, an American study (18) showed increased nosocomial transmission of TB from HIV-infected patients, but all secondary cases tested had drug susceptible organisms. The efforts of tuberculosis control workers should focus on treatment of patients with clinical tuberculosis. High case fatality rates continue among patients debilitated by alcoholism, drug addiction, AIDS, and homelessness. For such patients, directly observed twice-weekly administration has been effective (19), and the U.S. Public Health Service national action plan announced in 1992 places major emphasis on directly observed therapy to cope with the threat of multi-drug resistant TB. In 1935, at a time when there were long waiting lists for crowded sanatoria and no (in retrospect) effective treatment for the disease, Wade Hampton Frost, a Johns Hopkins University epidemiologist astonished TB workers by predicting an indefinitely continued decline of TB (20) because progressive, transmissable disease occurs in only a limited number of infected persons, and because of ‘man’s ability to maintain the present or a higher degree of environmental control’. He did not anticipate the AIDS pandemic. One may predict in 1992 that if AIDS comes under control, the decline of TB will resume, and that if the spread of AIDS is not averted, TB will not be the major problem. In either event, other advanced countries should think twice before adopting the American practice of widespread preventive therapy lest they encounter more fatalities from the ‘friendly fire’ of INH. H.L. ISRAEL Thomas Jefferson Philadelphia,
University, PA, U.S.A.
3. CDC. The use of preventive therapy for tuberculosis infection in the United States. MMWR 1990; 39 (No RR-8): 9-12. 4. CDC Update. Tuberculosis elimination-United States. MMWR 1990; 39: 15&155. 5. Colice GL. Decision analysis, public healthy policy and isoniazid prophylaxis for young adult tuberculin skin reactors. Arch Int h4ed 1990; 150: 2517-2522. 6. Tsevat J, Taylor WC, Wong JB, Pauker SG. Isoniazid from the tuberculin reactor: take it or leave it. Am Rev Respir Dis 1988; 137: 2 15-220. 7. Iseman MD, Miller B. Editorial. If a tree falls in the middle of the forest. Isoniazid and hepatitis. Am Rev Respir Dis 1989; 140: 575-576. 8. Mouldine TS. Redeker AG. Kane1 GC. Twentv isoniazid associate2 deaths in one state. Am Rev Respi; Dis 1989; 140: 7m705. 9. Israel HL, Gottlieb JE, Maddrey WC. Perspective: preventive isoniazid therapy and the liver. Chesr 1992; 101: 1298-1301. 10. Snider DE, Tabas GJ. Isoniazid associated hepatitis deaths: a review of available information. Am Rev Respir Dis 1992; 145: 494497. 11. Moulding, T. Chemoprophylaxis of tuberculosis: when is the benefit worth the risks and cost? Ann Int Med 1971; 14: 761-770. 12. Israel HL, DeLien H. The relation ofchildhood infection to the development of tuberculosis in early adult life. Am J Pub1 Health 1942; 32: 1146-l 156. 13. Exmonde TFG, Petheram IS. Audit of tuberculosis contact tracing procedures in South Gwent. Respir Med 1991; 85421423. 14. Mortensen J, Lange P, Storm HK, Viskam K. Childhood tuberculosis in a developed country. Eur Respir J 1989; 2: 985-987.
15. Report of subcommittee of the Joint Tuberculosis Committee of the British Thoracic Society. BA4J 1990; 300: 995-997.
16. Clancy L, Rieder HL, Enarson DA, Spinaci S. Tuberculosis elimination in the countries of Europe and other industrialized countries. Eur Respir J 1991; 4: 1288-1295. 17. Helbert M, Robinson D, Buchanan D et al. Mycobacterial infection in patients infected with the human immunodeficiency virus. Thorax 1990; 45: 4548. 18. Doolev. SW. Villarino ME. Lawrence M. el al. Nosocomial transmission of tuberculosis in a hospital unit for HIV-infected patients. JAMA 1992; 267: 26322635. 19.
References 1. Dorland’s
Illustrated
Medical
Dictionary.
26th edn
Philadelphia: W.B. Saunders, 1985. 2. Compact
Edition
of
The
Oxford
oxford: Clarendon Press, 1971.
83
Cohn DL, Catlin BJ, Peterson KL, Judson FL, Sbarbaro JA. A 62-dose, 6 month therapy for pulmonary and extrapulmonary tuberculosis: a twice-weekly, directly observed and cost effective regimen. Ann Int Med 1990; 112: 407415.
English
Dictionary.
20. Frost WH. The outlook for the eradication of tuberculosis. Am Rev Tuberc 1935; 32: 644-650.
Medicine
(1993) 87,81-83
Editorial
Chemoprophylaxis Is tuberculosis epidemic in 1992? Not as defined in Dorland’s Medical Dictionary as ‘attacking many people in any region at the same time, widely diffused and rapidly spreading’ (1). The century long decline in TB morbidity and mortality has slowed in the United States, but the disease is not widely diffused and rapid decline continues in other advanced countries. According to the Oxford English Dictionary (2), an epidemic is an illness ‘prevalent among a people or community at a special time and produced by some special causes not generally present in the affected locality’. Since the recent recrudescence of tuberculosis is localized and a consequence of recognized unique causes, it may, by latter definition, be reviewed as epidemic. Epidemic or not, fear of TB has reached panic proportions in the United States. Witness the call in the Philadelphia Inquirer (May 17, 1992) for surveillance of all cruise ship personnel largely because two ship employees in Miami were found to have TB. Should we resume mass X-ray surveys of school teachers, restaurant workers, and many others, a practice abandoned as unproductive in societies where TB morbidity and mortality have declined and continue to decline? The New York Times (April 26, 1992), in a lead editorial entitled ‘The Tuberculosis Failure’, called for renewed efforts and funds to cope with the alarming epidemic which has afflicted New York City for much of the past decade. The editorial cites a rise of reported cases in the city from 1300 in 1978 to an estimated 3700 in 199 1 as well as a rise nationally over the same period. It is worth noting, however, that if cases reported in New York City are subtracted from national figures, TB morbidity in the rest of the United States fell from 2753linl978to2200linl99l.Ifcasesinothermajor metropolitan areas (Newark, Miami, Atlanta, Tampa and San Francisco) are also subtracted, the decline of TB has obviously not remitted but in fact continues on for those living elsewhere in the United States. TB is epidemic in these metropolitan centres not because Mycobacterium tuberculosis has become more virulent. Rather, factors that favoured the spread and progression of tuberculosis in the past have resurfaced anew in larger American cities in recent decades: (1) malnutrition, largely due to drug addiction, alcoholism and homelessness; and (2) congestion in crowded 0954-61 I1/93/020081
f03
SOS.OO/O
for tuberculosis prisons and shelters for the homeless. To these urban ills have been added a third catastrophic blow; the acquired immunodeficiency syndrome (AIDS). It is unlikely that tuberculosis control efforts by medical and public health workers can reverse the rise without correction of these root causes. Such efforts, some argue, many prove futile. Worse, such efforts might also prove harmful to the extent that they advocate preventive isoniazid (INH) therapy. The latest published American guidelines for preventive INH therapy recommend its unrestricted use in tuberculin reactors below the age of 35 years in the belief that hepatitis is uncommon and fatal hepatitis extremely rare below this age (3). Circumstances justifying a treatment of reactors above the age of 35 are so numerous in these guidelines that, as generally interpreted, they encourage physicians to frequently administer INH to older reactors. Consequently, 95 000 Americans received preventive INH therapy in 1987 compared to less than 25 000 given curative medication (4). The wisdom of INH prophylaxis has been evaluated in numerous cost-benefit studies since the hepatitis hazard was recognized. Studies employing low estimates of hepatitis mortality and high estimates of tuberculosis prevalence have predictably concluded that benefits outweigh risks of preventive therapy (5). A smaller number of publications using opposite risk estimates have found a lower risk:benefit ratio (6). Nevertheless, the latter studies have failed to influence the federal Centers for Disease Control and the American Thoracic Society advocacy of preventive INH therapy as the mainstay of TB control in the United States (7). In the past 2 years, however, important reports concerning fatal INH-associated hepatitis have been published. Moulding and associates compiled reports of 20 such deaths in California, 19 of which occurred during preventive therapy (8). Eight deaths occurred in persons starting INH before the age of 35. We have reported three additional cases of fatal INH-associated hepatitis (9). One was a 17-year-old who was interviewed monthly by a public health nurse as he received his allotment of pills. He received his sixth and final allotment even though he reported malaise and anorexia to the nurse; within a month he died of hepatic failure. Another fatality, a 77-year-old @ 1993 Baillidre Tindall
82
Editorial
man, was given preventive INH because his wife, under treatment for ovarian cancer, developed ascites and diagnostic paracentesis revealed acid fast bacilli; it was subsequently ascertained that her peritonitis was due to M. avium-intracellulare. The third case was a 68-year-old woman who was given preventive INH therapy because a friend, who died of respiratory failure after a long hospital stay, for another illness, had a single isolation of M. TB during her illness. Snider and Tabas (10) have reported a compilation of 177 deaths in the United States from INH-associated hepatitis due to preventive use of this drug. They noted, in contrast to earlier studies, that a significant proportion of the mortality (46 of the deaths) occurred among persons less than 35 years of age. Nevertheless, they recommended no change in preventive INH policy because they calculated the fatality rate from hepatitis to be less than from future TB, estimating that 5% of untreated reactors would develop clinical TB with a 5% case fatality rate. These projections are at issue because they appear to exaggerate the current risks of morbidity and mortality from tuberculosis in developed countries. With regard to disease incidence in tuberculosis reactors, a study in Great Britain in the 1960s showed an annual incidence of 2% for the first 2.5 years, then falling to 0.7% at the end of a decade (11). Studies in the United States showed occurrence rates of 0.54.8%, while in Danish studies annual disease occurrence fell from 0.3% to 0.2% (11). These observations were made at a time when reactors may have had considerable additional exogenous infection (12). Although no comparable recent studies have been reported, a lower current morbidity is suggested by a 5-year follow-up study of 78 1 British contacts in which only one individual developed disease requiring treatment (13). The 5% case fatality rate from TB projected by Snider and Tabas (10) may also be misleading insofar as it bundles the high rates observed in patients debilitated by homelessness, addictions and AIDS with very low rates observed in the rest of the population. A recent Danish report is illustrative: 65 cases were reported in children below the age of 15 between 1977 and 1987; 25 were Danes and 40 were immigrants from poorer countries whose disease was often more severe and disseminated. No deaths occurred in the 65 cases and all were considered cured by therapy (14). Widespread use of INH to prevent future development of a treatable and curable disease seems difficult to justify when experience demonstrates considerable risk of fatal hepatitis. The report (15) of the British Thoracic Society has recommended INH chemoprophylaxis for BCG unvaccinated contacts under the age of 16 who have
Table
I
Tuberculosis deaths: rate of decline 198tL-1990
Country Great Britain Japan France Denmark Canada U.S.A.
1980*
1990*
Decline (%
1.3 5.5 3.0 1.4 0.6 0.8
0.7 3.0 1.7 I.0 0.5 0.7
46.2 45.5 43.3 28.5 16.7 12.5
*Rate per 100 000 population. strong Heaf test reactions and states that it should a be considered in Asian reactors under the age of. and for all adults in whom recent tuberculin conv sion has been noted. Strict adherence to these polici particularly those restricting preventive INH to adu having documented conversion within a year, v undoubtedly keep the number treated small, and, effect, avoid the large number of drug-related fatalit encountered in the United States. That then prophylaxis is indeed uncommonly practiced in t United Kingdom is indicated by the study of 78 1 cc tacts, where preventive INH was given to only thl children (13). A recent workshop on TB elimination in Euro and other industrialized countries concluded the PI ventive chemotherapy was inefficient if used ind criminantly (16). Preventive INH was recommend only for persons with recently acquired infection a for reactors who are contacts or who have conditio which enhance TB risk such as silicosis; haemodialys diabetes mellitus; carcinomas, especially of the he and neck; immunosuppressive treatment; gastrecton underweight; jejunoileal bypass; and HIV infectic Contraindications related to age or measures to co with the hazard of hepatic toxicity are not mentiom Moreover, these recommendations take no notice INH toxicity problems encountered in the Unit’ States as a result of similar policies. Since TB mc bidity and mortality have continued to decline developed nations worldwide other than the Unit1 States (Table 1) the risk-benefit aspects of IN prophylaxis merit thoughtful consideration as appli to the general population. Preventive INH programmes encounter serio compliance difficulties in providing 6 months of tree ment to groups who are at high risk of fatal TB. MO important, there is no evidence as yet to suggest th preventive INH therapy is effective in preventing infe tious TB in those immunocomprised by AIDS. The problems and the recent emergence of drug-resista TB has led the U.S. Centers for Disease Control
Editorial
form a task force to consider such issues. With regard to the spectrum of spread of drug-resistant TB to health workers and the population at large, it is worth noting that a London study of TB in AIDS patients showed organisms fully sensitive to standard drugs in 14 of 15 patients (17). Moreover, an American study (18) showed increased nosocomial transmission of TB from HIV-infected patients, but all secondary cases tested had drug susceptible organisms. The efforts of tuberculosis control workers should focus on treatment of patients with clinical tuberculosis. High case fatality rates continue among patients debilitated by alcoholism, drug addiction, AIDS, and homelessness. For such patients, directly observed twice-weekly administration has been effective (19), and the U.S. Public Health Service national action plan announced in 1992 places major emphasis on directly observed therapy to cope with the threat of multi-drug resistant TB. In 1935, at a time when there were long waiting lists for crowded sanatoria and no (in retrospect) effective treatment for the disease, Wade Hampton Frost, a Johns Hopkins University epidemiologist astonished TB workers by predicting an indefinitely continued decline of TB (20) because progressive, transmissable disease occurs in only a limited number of infected persons, and because of ‘man’s ability to maintain the present or a higher degree of environmental control’. He did not anticipate the AIDS pandemic. One may predict in 1992 that if AIDS comes under control, the decline of TB will resume, and that if the spread of AIDS is not averted, TB will not be the major problem. In either event, other advanced countries should think twice before adopting the American practice of widespread preventive therapy lest they encounter more fatalities from the ‘friendly fire’ of INH. H.L. ISRAEL Thomas Jefferson Philadelphia,
University, PA, U.S.A.
3. CDC. The use of preventive therapy for tuberculosis infection in the United States. MMWR 1990; 39 (No RR-8): 9-12. 4. CDC Update. Tuberculosis elimination-United States. MMWR 1990; 39: 15&155. 5. Colice GL. Decision analysis, public healthy policy and isoniazid prophylaxis for young adult tuberculin skin reactors. Arch Int h4ed 1990; 150: 2517-2522. 6. Tsevat J, Taylor WC, Wong JB, Pauker SG. Isoniazid from the tuberculin reactor: take it or leave it. Am Rev Respir Dis 1988; 137: 2 15-220. 7. Iseman MD, Miller B. Editorial. If a tree falls in the middle of the forest. Isoniazid and hepatitis. Am Rev Respir Dis 1989; 140: 575-576. 8. Mouldine TS. Redeker AG. Kane1 GC. Twentv isoniazid associate2 deaths in one state. Am Rev Respi; Dis 1989; 140: 7m705. 9. Israel HL, Gottlieb JE, Maddrey WC. Perspective: preventive isoniazid therapy and the liver. Chesr 1992; 101: 1298-1301. 10. Snider DE, Tabas GJ. Isoniazid associated hepatitis deaths: a review of available information. Am Rev Respir Dis 1992; 145: 494497. 11. Moulding, T. Chemoprophylaxis of tuberculosis: when is the benefit worth the risks and cost? Ann Int Med 1971; 14: 761-770. 12. Israel HL, DeLien H. The relation ofchildhood infection to the development of tuberculosis in early adult life. Am J Pub1 Health 1942; 32: 1146-l 156. 13. Exmonde TFG, Petheram IS. Audit of tuberculosis contact tracing procedures in South Gwent. Respir Med 1991; 85421423. 14. Mortensen J, Lange P, Storm HK, Viskam K. Childhood tuberculosis in a developed country. Eur Respir J 1989; 2: 985-987.
15. Report of subcommittee of the Joint Tuberculosis Committee of the British Thoracic Society. BA4J 1990; 300: 995-997.
16. Clancy L, Rieder HL, Enarson DA, Spinaci S. Tuberculosis elimination in the countries of Europe and other industrialized countries. Eur Respir J 1991; 4: 1288-1295. 17. Helbert M, Robinson D, Buchanan D et al. Mycobacterial infection in patients infected with the human immunodeficiency virus. Thorax 1990; 45: 4548. 18. Doolev. SW. Villarino ME. Lawrence M. el al. Nosocomial transmission of tuberculosis in a hospital unit for HIV-infected patients. JAMA 1992; 267: 26322635. 19.
References 1. Dorland’s
Illustrated
Medical
Dictionary.
26th edn
Philadelphia: W.B. Saunders, 1985. 2. Compact
Edition
of
The
Oxford
oxford: Clarendon Press, 1971.
83
Cohn DL, Catlin BJ, Peterson KL, Judson FL, Sbarbaro JA. A 62-dose, 6 month therapy for pulmonary and extrapulmonary tuberculosis: a twice-weekly, directly observed and cost effective regimen. Ann Int Med 1990; 112: 407415.
English
Dictionary.
20. Frost WH. The outlook for the eradication of tuberculosis. Am Rev Tuberc 1935; 32: 644-650.