DIAGNOSIS, PREVENTIONAND EARLYTHERAPYOF TUBERCULOSIS ROBERT L. MAYOCK ROB ROY MACGREGOR
TABLE
OF
CONTENTS
CHANGE IN PATTERNS OF DISEASE . . PATHOGENESIS AND N A T U R A L H I S T O R Y .
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.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
6
D E L A Y E D H Y P E R S E N S I T I V I T Y TO M Y C O B A C T E R I A L A N T I G E N .
10
EPIDEMIOLOGY
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
17
MANIFESTATIONS OF TUBERCULOSIS . . . . . . . . Symptoms and Signs . . . . . . . . . . . . . . Roentgenographic Examination . . . . . . . . . . DIAGNOSIS OF PULMONARY TUBERCULOSIS . . . . . . P L E U R A L EFFUSION DUE TO TUBERCULOSIS . . . . . . THERAPY
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.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
PULMONARY TUBERCULOSIS SURGERY
.
.
.
.
IN PULMONARY TUBERCULOSIS
.
. .
. .
24
25 26 27 30
. . .
3~
.
31
.
.
38 39
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
HOSPITALIZATION FOR PULMONARY TUBERCULOSIS . . REST IN TttE TREATMENT OF TUBERCULOSIS . . . . A D R E N O C O R T I C A L STEROIDS IN THE TREATMENT OF
4
39
T R E A T M E N T OF T U B E R C U L O S I S T H A T H A S R E L A P S E D . . . .
40
DISEASE COURSE AND MANAGEMENT ON
THERAPY
41
EXTRAPULMONARY TUBERCULOSIS
. . . .
.
.
.
.
.
.
.
.
.
.
45
TUBERCULOSIS OF THE LYMPH NODES
.
.
.
.
.
.
.
.
.
46
.
.
46
CERVICAL ADENITIS (2%)
.
.
.
.
.
.
.
.
.
.
.
TUBERCULOSIS OF THE K I D N E Y AND G E N I T A L T R A C T (1.2%) . . . . . . . . . . . . . . . . . . TUBERCULOSIS PERITONITIS (Smmindurofionl
ISecond str n th
I
~,n ~ g i
I
---
I
~
iTS, infection, thou~,h
LE_E.:.:::_I
~"...............................................:
I"~:~Yl
i
! ,,Omm ~, mor~ s,ec,r,c i
reoct ii
~;co:
:
;i
i.,fe~tio,', tho,.,g.,-,oti specific, due to ! cross-reoction
! i
\ \
~
.......................................
i'~ugge~ts ~e~
o,',e~'~';'i
~ TB possibte i .....~...................................................... 1 ~Potient not onergic, but non-reactive to imaximum PPD stimulus.
L......~.E.!.".~!!.~
~ '.!.'.Z.~.~!~.."...~!~!.~ ...............
Fig. 2 . - S c h e m e for t u b e r c u l i n testing of patients with s u s p e c t e d active tuberculosis.
the patient responds to the more concentrated PPD, one can say that he is not anergic and that he does have mycobacterial delayed h y p e r s e n s i t i v i t y - n o t specific for M. tuberculosis infection but consistent with it. If the patient fails to respond to second-strength PPD, the results of the anergy panel become critical: failure to react to the other antigens suggests a generalized anergy, s o t h a t the negative response to PPD is not evidence against M. tuberculosis infection. If the patieat does react to one or more of the anergy panel antigens, generalized a nergy is not present. Although the issue is not resolved, isolated anergy to tuberculin (as opposed to nonreactivity as part of a generalized anergy) has rarely been documented in the literature. Thus, a negative second-strength PPD in a patient who shows delayed hypersensitivity to another antigen indicates with very high likelihood that the patient has never been infected with M. tuberculosis. Delayed hypersensitivity to tuberculin can be inhibited by many factors (Table 3): diseases that depress cell-mediated immunity, such as lymphoma, leukemia, sarcoidosis 14
TABLE 3 . - F A I ~ E NEGATIVE TUBERCULIN SKIN TESTS I. Technical A. Improper amount of tuberculin given 1. Dilutions or amount incorrect 2. Loss of potency 3. Absorption on syringes 4. Subcutaneous injection B. Incorrect reading II. Nonspecific decrease in immunity A. Intercurrent infections B. Cachexia C. Hypothyroidism D. Dehydration III. Decrease in delayed hypersensitivity A. Hormonal 1. Late pregnancy and puerperium 2. During steroid therapy B. Nonhormonal 1. Sarcoidosis 2. After viral immunization 3. With diseases of the lymphoid system 4. With irradiation 5. With immunosuppressive therapy IV. Undeveloped hypersensitivity A. Early in tuberculosis V. Immunologic blockade A. Miliary or far-advanced tuberculosis VI. Loss of reactivity A. "Healed" tuberculosis
and chronic renal failure, can impair reaction to the extent of producing generalized anergy; the skin often is unable to inflame normally in patients with cancer and other debilitating diseases, so that even though their T-lymphocytes can be shown by in-vitro lymphocyte transformation to be sensitive to an antigen, it elicits no reaction when injected into the skin. Such patients also fail to respond to nonallergic inflammatory stimuli such as croton oil, 4 and this "inflammatory control" test should be included when such patients are evaluated for delayed hypersensitivity. Failure to respond to croton oil indicates that negative reactions to specific antigens m a y not mean lack of cell-mediated immunity, and that the patient's skin test responses are not indicative of his degree of prior exposure to the antigen. Other causes of suppressed delayed hypersensitivity 15
include concurrent live-virus vaccination or infection and medications that interfere with cell-mediated immunity, such as glucocorticoids and cytotoxic agents. Because of these inhibiting factors, a negative reaction to PPD should not be seen as ruling out infection. If one appreciates the fact that induration to PPD only indicates the presence of cell-mediated immunity to mycobacteria, there are no immunologic causes of false positive reactions. If reaction is viewed as evidence of specific M. tuberculosis infection, there are two major sources of error: (1) Atypical mycobacterial a l l e r g y - a s mentioned above, these organisms usually lead to tuberculin reactions of 5 10 mm. Thus, the use of a 10-ram threshold of "significantly positive" induration will prevent most reactions resulting from prior AM infections from qualifying as positire tuberculin skin tests. However, some of these patients will have >10-ram induration to intermediate-strength PPD (although almost always 1 0 ram. 5 They then are seen as having "significantly positive" tuberculin tests, and as having "converted" their reactions from negative to positive. As will be discussed below, true "conversion" indicates recent M. tuberculosis infection and requires prophylactic therapy; the "conversions" secondary to the booster effect can be differentiated by their prior history of small reactions, and should not be given prophylaxis. (2) Another cause of "false positive" tuberculin tests is vaccination with BCG. Most individuals will show a 5 15-mm tuberculin reaction following successful vaccination. If Jested annually, they will maintain approximately the same size reaction, without increase..However, if not tested for 10 years or more after vaccination, 75% will be tuberculin "negative" on their first rechallenge, but then often may be "positive" on next t e s t i n g - a false positive "conversion." Therefore, it is important to question for prior BCG exposure when interpreting an individual's tuberculin reaction. 6 16
EPIDEMIOLOGY M. tuberculosis is a well-adapted parasite, making the host infective enough by necrosis, liquefaction and chronic cough to promote environmental dissemination; at the same time, the level of illness it provokes usually is mild enough to permit the host to act as a vehicle for spread for months to years. Until recently, virtually the whole population of the urbanized countries developed a primary infection during childhood because of active cases in the community, a lack of treatment that could inhibit contagiousness and a level of public hygiene that promoted spread. Tuberculosis was the leading cause of death in American cities from the time when such data were first gathered until into the twentieth century. For example, in New York City from 1805 to 1808, the death rate from tuberculosis was 550/100,000 population, and 50 years later was 431/100,000, accounting for 20% and 11% of all deaths, respectively. Associated with improved public health and nutrition, the death rate nationwide fell steadily from 200/100,000 population in 1900 to about 40/100,000 in 1950 (Fig. 3.) In contrast, the incidence remained high in physicians, nurses and other health workers, who continued to have extensive exposure to the decreasing number of active cases. This unique occupational exposure m e a n t that, up until the era of chemotherapy, 2 5 - 5 0 % of students who were nonreactive on beginning medical school converted their skin test to positive by the time of graduation and 2 - 3 % developed active disease. 7 Since 1950, the slope of the national curve has turned down more sharply, reflecting the development of antibiotic therapy capable of killing the organisms, in contrast to earlier modes of therapy, which attempted only to bolster the host's resistance to his infection. Chemotherapy has accelerated the downward trend of new infections by rapidly reducing the contagiousness of patients under treatment, thus protecting the uninfected population from exposure. The new active case r a t e has fallen from 53.0 in 1953 to 14.8 in 1973 (Fig. 4). Moreover, primary infection of the young has become quite uncommon, as shown by tuberculin screening of high school
17
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,
,
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,
,
,
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,
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,
t-,_t.
.
)
~,
t"~
~jL c" -~_ E)
0
.a o = ~ . e a - ~
r
,-'~ 9
o
~l O~a3 0 1 o
u~ ~
C.__.;
0
)~ o_-).} o ~ _c: . , . ~
o- o
'oo . ,=-~.
.
o
e-
,n
~
e-"
0
(D e= ~ > ' * ~
O
9 Oe='~ co "Z O ~,O~
~ (D O
~ Oi)
O O
o "-": " - -
~;
~,-~
0
(2)
0 - ~
.
.- > , ~ , o E o . o ~ o N ~_ . ; . - ~_ ~6 E,-.
-',~.
-~
m-$
o > o,--~
0
>'.O
o O)'=-
o,
g c~ 0
!
0
(~
(u,-0~
z~
o ow-,~
_;'z h '-
-).E I
O) O t~
"
~_=~ ~'~
~_ ~~,
~ "-''F ~ ~; ~."~ o o 0
.0
~
r-O~ --- T -
~.--
o " ~ r"
n
~
e=,,,4 ~
u._~'~ o or" m-~ )-.- ~O 0.) r" 0~ ' ~ O (2.) O ~ . r "=) ' ~ ~: ~, L/, :::3:I~ ~ I--
~
0
,,a o.)
0
(tO 0 e=.
--
uo!l~176 000'001 ~ld ;))0~
18
,_
0
" 0 ,)., 0
u~,
e=" . - -
I oo?g~ (~3
RATE
80 60 40
CASE RATE~
----....
20
I0
8
1953
1955
1960
1965
1970
1973
Fig. 4 . - C a s e rate and death rate, United States, 1953-1973.
students: 53% of 16-year-olds were positive in 1928, falling to 16.4% by 1948 (pre-chemotherapy); only 5.9% were positive in 1958 and 1.4% in 1968. s Thus, young people no longer are being recruited into the infected reservoir from which comes the cases of adult reactivation tuberculosis. A consequence of this is the development of the primary form of disease in the adult population; formerly, this group developed their first infection in childhood, so that adult primary disease was rare. W h a t are the epidemiologic factors associated with increased risk of developing a primary infection? In contrast to reactivation, which is potentiated predominantly by host factors, development of primary infection is dependent on environmental exposure. Therefore, tuberculin reactivity (the index of primary infection) is more common in geographic areas and among ethnic groups with higher new 19
active case rates and thus opportunity for exposure; for example, black high school students in Philadelphia have a 2.6% reaction rate and whites 0.9%. 8 Rates are high in areas of h u m a n crowding, especially if associated with poor ventilation, because such conditions allow close, prolonged exposure of uninfected individuals to people with active tuberculosis. Thus, household contacts of active cases are at major risk of infection, as are their classmates, friends and fellow workers, especially when exposure is prolonged and occurs in a small enclosed area. Classic examples of such conditions are school epidemics secondary to a diseased classmate or teacher, shipboard outbreaks (particularly on vessels with recirculated air, such as submarines) and those in mine workers. To be an organism disseminator, the patient with active disease usually must have enough organisms in his sputum to be seen on ZiehlNeelsen stain, since studies show t h a t close contacts of smear-negative patients haqe the same rate of tuberculin sensitivity as in the general population. 9 The smear-positive active patient appears to become noninfectious within 1 - 2 weeks of starting chemotherapy even if still smearpositive (see below); therefore, the risk of contagion applies principally to the undiagnosed, untreated patient. Moreover, infection is more common when exposure is prolonged for days to weeks r a t h e r t h a n a chance, casual event. Once infected, the individual is at risk of developing clinical tuberculosis for the rest of his life. This risk is greatest during the first 5 years of infection (recent tuberculin test converters) and correlates positively with the size of the tuberculin induration: individuals with > 15-mm induration have up to 5 times the incidence of disease as those with
TABLE
OF
CONTENTS
CHANGE IN PATTERNS OF DISEASE . . PATHOGENESIS AND N A T U R A L H I S T O R Y .
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
6
D E L A Y E D H Y P E R S E N S I T I V I T Y TO M Y C O B A C T E R I A L A N T I G E N .
10
EPIDEMIOLOGY
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
17
MANIFESTATIONS OF TUBERCULOSIS . . . . . . . . Symptoms and Signs . . . . . . . . . . . . . . Roentgenographic Examination . . . . . . . . . . DIAGNOSIS OF PULMONARY TUBERCULOSIS . . . . . . P L E U R A L EFFUSION DUE TO TUBERCULOSIS . . . . . . THERAPY
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
PULMONARY TUBERCULOSIS SURGERY
.
.
.
.
IN PULMONARY TUBERCULOSIS
.
. .
. .
24
25 26 27 30
. . .
3~
.
31
.
.
38 39
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
HOSPITALIZATION FOR PULMONARY TUBERCULOSIS . . REST IN TttE TREATMENT OF TUBERCULOSIS . . . . A D R E N O C O R T I C A L STEROIDS IN THE TREATMENT OF
4
39
T R E A T M E N T OF T U B E R C U L O S I S T H A T H A S R E L A P S E D . . . .
40
DISEASE COURSE AND MANAGEMENT ON
THERAPY
41
EXTRAPULMONARY TUBERCULOSIS
. . . .
.
.
.
.
.
.
.
.
.
.
45
TUBERCULOSIS OF THE LYMPH NODES
.
.
.
.
.
.
.
.
.
46
.
.
46
CERVICAL ADENITIS (2%)
.
.
.
.
.
.
.
.
.
.
.
TUBERCULOSIS OF THE K I D N E Y AND G E N I T A L T R A C T (1.2%) . . . . . . . . . . . . . . . . . . TUBERCULOSIS PERITONITIS (Smmindurofionl
ISecond str n th
I
~,n ~ g i
I
---
I
~
iTS, infection, thou~,h
LE_E.:.:::_I
~"...............................................:
I"~:~Yl
i
! ,,Omm ~, mor~ s,ec,r,c i
reoct ii
~;co:
:
;i
i.,fe~tio,', tho,.,g.,-,oti specific, due to ! cross-reoction
! i
\ \
~
.......................................
i'~ugge~ts ~e~
o,',e~'~';'i
~ TB possibte i .....~...................................................... 1 ~Potient not onergic, but non-reactive to imaximum PPD stimulus.
L......~.E.!.".~!!.~
~ '.!.'.Z.~.~!~.."...~!~!.~ ...............
Fig. 2 . - S c h e m e for t u b e r c u l i n testing of patients with s u s p e c t e d active tuberculosis.
the patient responds to the more concentrated PPD, one can say that he is not anergic and that he does have mycobacterial delayed h y p e r s e n s i t i v i t y - n o t specific for M. tuberculosis infection but consistent with it. If the patient fails to respond to second-strength PPD, the results of the anergy panel become critical: failure to react to the other antigens suggests a generalized anergy, s o t h a t the negative response to PPD is not evidence against M. tuberculosis infection. If the patieat does react to one or more of the anergy panel antigens, generalized a nergy is not present. Although the issue is not resolved, isolated anergy to tuberculin (as opposed to nonreactivity as part of a generalized anergy) has rarely been documented in the literature. Thus, a negative second-strength PPD in a patient who shows delayed hypersensitivity to another antigen indicates with very high likelihood that the patient has never been infected with M. tuberculosis. Delayed hypersensitivity to tuberculin can be inhibited by many factors (Table 3): diseases that depress cell-mediated immunity, such as lymphoma, leukemia, sarcoidosis 14
TABLE 3 . - F A I ~ E NEGATIVE TUBERCULIN SKIN TESTS I. Technical A. Improper amount of tuberculin given 1. Dilutions or amount incorrect 2. Loss of potency 3. Absorption on syringes 4. Subcutaneous injection B. Incorrect reading II. Nonspecific decrease in immunity A. Intercurrent infections B. Cachexia C. Hypothyroidism D. Dehydration III. Decrease in delayed hypersensitivity A. Hormonal 1. Late pregnancy and puerperium 2. During steroid therapy B. Nonhormonal 1. Sarcoidosis 2. After viral immunization 3. With diseases of the lymphoid system 4. With irradiation 5. With immunosuppressive therapy IV. Undeveloped hypersensitivity A. Early in tuberculosis V. Immunologic blockade A. Miliary or far-advanced tuberculosis VI. Loss of reactivity A. "Healed" tuberculosis
and chronic renal failure, can impair reaction to the extent of producing generalized anergy; the skin often is unable to inflame normally in patients with cancer and other debilitating diseases, so that even though their T-lymphocytes can be shown by in-vitro lymphocyte transformation to be sensitive to an antigen, it elicits no reaction when injected into the skin. Such patients also fail to respond to nonallergic inflammatory stimuli such as croton oil, 4 and this "inflammatory control" test should be included when such patients are evaluated for delayed hypersensitivity. Failure to respond to croton oil indicates that negative reactions to specific antigens m a y not mean lack of cell-mediated immunity, and that the patient's skin test responses are not indicative of his degree of prior exposure to the antigen. Other causes of suppressed delayed hypersensitivity 15
include concurrent live-virus vaccination or infection and medications that interfere with cell-mediated immunity, such as glucocorticoids and cytotoxic agents. Because of these inhibiting factors, a negative reaction to PPD should not be seen as ruling out infection. If one appreciates the fact that induration to PPD only indicates the presence of cell-mediated immunity to mycobacteria, there are no immunologic causes of false positive reactions. If reaction is viewed as evidence of specific M. tuberculosis infection, there are two major sources of error: (1) Atypical mycobacterial a l l e r g y - a s mentioned above, these organisms usually lead to tuberculin reactions of 5 10 mm. Thus, the use of a 10-ram threshold of "significantly positive" induration will prevent most reactions resulting from prior AM infections from qualifying as positire tuberculin skin tests. However, some of these patients will have >10-ram induration to intermediate-strength PPD (although almost always 1 0 ram. 5 They then are seen as having "significantly positive" tuberculin tests, and as having "converted" their reactions from negative to positive. As will be discussed below, true "conversion" indicates recent M. tuberculosis infection and requires prophylactic therapy; the "conversions" secondary to the booster effect can be differentiated by their prior history of small reactions, and should not be given prophylaxis. (2) Another cause of "false positive" tuberculin tests is vaccination with BCG. Most individuals will show a 5 15-mm tuberculin reaction following successful vaccination. If Jested annually, they will maintain approximately the same size reaction, without increase..However, if not tested for 10 years or more after vaccination, 75% will be tuberculin "negative" on their first rechallenge, but then often may be "positive" on next t e s t i n g - a false positive "conversion." Therefore, it is important to question for prior BCG exposure when interpreting an individual's tuberculin reaction. 6 16
EPIDEMIOLOGY M. tuberculosis is a well-adapted parasite, making the host infective enough by necrosis, liquefaction and chronic cough to promote environmental dissemination; at the same time, the level of illness it provokes usually is mild enough to permit the host to act as a vehicle for spread for months to years. Until recently, virtually the whole population of the urbanized countries developed a primary infection during childhood because of active cases in the community, a lack of treatment that could inhibit contagiousness and a level of public hygiene that promoted spread. Tuberculosis was the leading cause of death in American cities from the time when such data were first gathered until into the twentieth century. For example, in New York City from 1805 to 1808, the death rate from tuberculosis was 550/100,000 population, and 50 years later was 431/100,000, accounting for 20% and 11% of all deaths, respectively. Associated with improved public health and nutrition, the death rate nationwide fell steadily from 200/100,000 population in 1900 to about 40/100,000 in 1950 (Fig. 3.) In contrast, the incidence remained high in physicians, nurses and other health workers, who continued to have extensive exposure to the decreasing number of active cases. This unique occupational exposure m e a n t that, up until the era of chemotherapy, 2 5 - 5 0 % of students who were nonreactive on beginning medical school converted their skin test to positive by the time of graduation and 2 - 3 % developed active disease. 7 Since 1950, the slope of the national curve has turned down more sharply, reflecting the development of antibiotic therapy capable of killing the organisms, in contrast to earlier modes of therapy, which attempted only to bolster the host's resistance to his infection. Chemotherapy has accelerated the downward trend of new infections by rapidly reducing the contagiousness of patients under treatment, thus protecting the uninfected population from exposure. The new active case r a t e has fallen from 53.0 in 1953 to 14.8 in 1973 (Fig. 4). Moreover, primary infection of the young has become quite uncommon, as shown by tuberculin screening of high school
17
)
,
,
, , , ,
,
,
,
~
,
l
, i , ) ,
,
t-,_t.
.
)
~,
t"~
~jL c" -~_ E)
0
.a o = ~ . e a - ~
r
,-'~ 9
o
~l O~a3 0 1 o
u~ ~
C.__.;
0
)~ o_-).} o ~ _c: . , . ~
o- o
'oo . ,=-~.
.
o
e-
,n
~
e-"
0
(D e= ~ > ' * ~
O
9 Oe='~ co "Z O ~,O~
~ (D O
~ Oi)
O O
o "-": " - -
~;
~,-~
0
(2)
0 - ~
.
.- > , ~ , o E o . o ~ o N ~_ . ; . - ~_ ~6 E,-.
-',~.
-~
m-$
o > o,--~
0
>'.O
o O)'=-
o,
g c~ 0
!
0
(~
(u,-0~
z~
o ow-,~
_;'z h '-
-).E I
O) O t~
"
~_=~ ~'~
~_ ~~,
~ "-''F ~ ~; ~."~ o o 0
.0
~
r-O~ --- T -
~.--
o " ~ r"
n
~
e=,,,4 ~
u._~'~ o or" m-~ )-.- ~O 0.) r" 0~ ' ~ O (2.) O ~ . r "=) ' ~ ~: ~, L/, :::3:I~ ~ I--
~
0
,,a o.)
0
(tO 0 e=.
--
uo!l~176 000'001 ~ld ;))0~
18
,_
0
" 0 ,)., 0
u~,
e=" . - -
I oo?g~ (~3
RATE
80 60 40
CASE RATE~
----....
20
I0
8
1953
1955
1960
1965
1970
1973
Fig. 4 . - C a s e rate and death rate, United States, 1953-1973.
students: 53% of 16-year-olds were positive in 1928, falling to 16.4% by 1948 (pre-chemotherapy); only 5.9% were positive in 1958 and 1.4% in 1968. s Thus, young people no longer are being recruited into the infected reservoir from which comes the cases of adult reactivation tuberculosis. A consequence of this is the development of the primary form of disease in the adult population; formerly, this group developed their first infection in childhood, so that adult primary disease was rare. W h a t are the epidemiologic factors associated with increased risk of developing a primary infection? In contrast to reactivation, which is potentiated predominantly by host factors, development of primary infection is dependent on environmental exposure. Therefore, tuberculin reactivity (the index of primary infection) is more common in geographic areas and among ethnic groups with higher new 19
active case rates and thus opportunity for exposure; for example, black high school students in Philadelphia have a 2.6% reaction rate and whites 0.9%. 8 Rates are high in areas of h u m a n crowding, especially if associated with poor ventilation, because such conditions allow close, prolonged exposure of uninfected individuals to people with active tuberculosis. Thus, household contacts of active cases are at major risk of infection, as are their classmates, friends and fellow workers, especially when exposure is prolonged and occurs in a small enclosed area. Classic examples of such conditions are school epidemics secondary to a diseased classmate or teacher, shipboard outbreaks (particularly on vessels with recirculated air, such as submarines) and those in mine workers. To be an organism disseminator, the patient with active disease usually must have enough organisms in his sputum to be seen on ZiehlNeelsen stain, since studies show t h a t close contacts of smear-negative patients haqe the same rate of tuberculin sensitivity as in the general population. 9 The smear-positive active patient appears to become noninfectious within 1 - 2 weeks of starting chemotherapy even if still smearpositive (see below); therefore, the risk of contagion applies principally to the undiagnosed, untreated patient. Moreover, infection is more common when exposure is prolonged for days to weeks r a t h e r t h a n a chance, casual event. Once infected, the individual is at risk of developing clinical tuberculosis for the rest of his life. This risk is greatest during the first 5 years of infection (recent tuberculin test converters) and correlates positively with the size of the tuberculin induration: individuals with > 15-mm induration have up to 5 times the incidence of disease as those with
