954

TUBERCULOSIS COMMENTARY

How Contagious Is Tuberculosis?

Kent A. Sepkowitz
From the Infectious Disease Service, Memorial Sloan-Kettering Cancer Center, New York HospitalCornell Medical Center, New York, New York

There are many questions related to the contagiousness of tuberculosis, and unfortunately they are not simply answered. In this review, Dr. Kent Sepkowitz analyzes the literature on factors associated with contagiousness of this condition. He reminds us of the many elegant laboratory and epidemiologic studies conducted all over the world that have helped answer some of these questions. In addition, he highlights the urgent need for future studies to address the many remaining perplexing questions. The availability of molecular techniques holds promise for a clearer understanding of how contagious tuberculosis is.
Wafaa El-Sadr Chair, Tuberculosis Committee, Infectious Diseases Society of America

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One of the many lessons learned in the course of the nowpassing resurgence of tuberculosis in the United States is how little about Mycobacterium tuberculosis we really understand. In the 1970s, with tuberculosis apparently poised on the brink of eradication, basic investigation ranging from drug development to inquiry into pathogenesis and immunologic responsemore or less ceased. After all, reliable 6-month treatment courses for cure had been established, and case numbers were dropping. The scientific community therefore was caught flat-footed as tuberculosis reemerged in the 1980s and affected a new population those with HIV infection with startlingly high rates of disease and death. Researchers realized it was time to go back to the drawing board but found there was relatively little on the drawing board to explain the current events. Recent articles in the "Tuberculosis Commentary" series published in Clinical Infectious Diseases (see box on next page) have sought to refamiliarize physicians with pertinent information (much of it from older studies) about M. tuberculosis. Despite the large numbers of studies and reports, it is readily evident that large gaps in our basic information remain. Among the areas incompletely understood is the transmission of M. tuberculosis. Careful, large-scale studies have defined the transmission rates of infections such as those due to hepatitis B and C viruses and HIV W. There is even knowledge of

how many bacilli must be ingested to contract shigellosis and salmonellosis [2]. However, similar studies are lacking with regard to transmission of tuberculosis, as noted in previous reviews [3-6]. To further complicate matters, the existing studies rely on the tuberculin skin test to define infection, a test that is notably unreliable and difficult to interpret [7]. Indeed, many "classic" studies were performed before standardized tuberculin, PPD-S, was available. Thus, much of what has been accepted as well studied in the area of tuberculosis transmission is, on closer inspection, a bit of wishful thinking based on few scant facts. This paper will review the basis of our current understanding regarding the transmission of tuberculosis. Five factors influencing transmission will be considered, including (1) the source case; (2) the environment, including ventilation; (3) the duration and intensity of exposure; (4) the contact; and (5) the tubercle bacillus itself The Source Case Styblo estimated that about 10 secondary infections arise annually from one untreated smear-positive case [8], although rare outbreaks have been reported with _^-200 secondary infections [9]. Several factors bear on the infectiousness of the source case, including the acid-fast bacilli (AFB) smear status, treatment status, and frequency of cough.
AFB Smear Status

Received 20 March 1996; revised 12 April 1996. Reprints or correspondence: Dr. Kent A. Sepkowitz, Infectious Disease Service, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, Box 288, New York, New York 10021.
Clinical Infectious Diseases 1996; 23:954-62
1996 by The University of Chicago. All rights reserved. 1058-4838/96/2305 0002$02.00

Numerous well-conducted community-based studies have examined the prevalence of tuberculin reactivity in families and among other contacts of tuberculosis cases [10-30]. Many

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Tuberculosis Commentaries previously published in

Clinical Infectious Diseases:

May 1993

Wolinsky E. Statement of the Tuberculosis Committee of the Infectious Diseases Society of America. Clin Infect Dis 1993; 16:627-8. December 1993 Huebner RE, Schein MF, Bass JB Jr. The tuberculin skin test. Clin Infect Dis 1993; 17:968-75. September 1994 Wolinsky E. Conventional diagnostic methods for tuberculosis. Clin Infect Dis 1994; 19:396-401. December 1994 Comstock GW. Variability of tuberculosis trends in a time of resurgence. Clin Infect Dis 1994; 19:1015-22. January 1995 Fine PEM. Bacille Calmette-Guerin vaccines: a rough guide. Clin Infect Dis 1995; 20:11-4. February 1995 Shinnick TM, Good RC. Diagnostic mycobacteriology laboratory practices. Clin Infect Dis 1995;20:291-9. March 1995 Earnest MA, Sbarbaro JA. Defining the issues: returning patients with tuberculosis to institutional settings. Clin Infect Dis 1995; 20:497-500. July 1995 Ad Hoc Committee of the Scientific Assembly on Microbiology, Tuberculosis, and Pulmonary Infections. Treatment of tuberculosis and tuberculosis infection in adults and children. Clin Infect Dis 1995; 21:9-27. September 1995 McGowan JE Jr. Nosocomial tuberculosis: new progress in control and prevention. Clin Infect Dis 1995; 21:489 505.

of these studies date from the first half of the century, when tuberculin preparations were variable and community rates of tuberculosis infection and disease were much higher than they are today. The many studies have been performed in similar fashion: the tuberculin status of an entire community, often in excess of 200,000 persons, is ascertained and all cases of pulmonary tuberculosis identified. Disease in the source case is then categorized according to smear and culture status (table 1), and the prevalence of tuberculin reactivity among home contacts (or casual contacts) is determined. The tuberculin reactivity rates of young children (usually aged 0-4 years) are commonly used to demonstrate transmission rates, since these children are unlikely to have additional exposures beyond the known source case.

The findings in these studies are relatively consistent, demonstrating that among household contacts of smear-positive cases the rates of tuberculin positivity are 30%-50% above those among age-matched community controls. The data for contacts of smear-negative, culture-positive cases are more variable, but in general they show that for contacts of smearnegative source cases the tuberculin reactivity rate is 5% above that for community controls. Smear-negative, culturenegative clinical cases are associated with a variable increase in reactivity, ranging from zero to 8%. It may be that with modern fluorescein-labeled microscopy techniques, many smear-negative patients from these old studies would be found to have smear-positive disease. Thus, the implications of these older studies with regard to current infection control approaches are uncertain. At most hospitals, smear status is the basis on which respiratory isolation for patients with possible tuberculosis is continued or discontinued. In most series, however, 50% of all cases of pulmonary tuberculosis, regardless of HIV status, are smear-negative for AFB [31]. In many cases of pulmonary tuberculosis, therefore, respiratory isolation is discontinued before a response to therapy is established. Despite this, the AFB smearbased approach to isolation has proven successful in interrupting nosocomial outbreaks. This suggests that the current smear technique is sufficient to diagnose most infectious cases, even those involving severely immunocompromised patients. However, at least two outbreaks have been associated with a smear-negative source case [32, 33], demonstrating the need for continued caution. In addition, several investigators have reported on the rates of progression to active disease among tuberculin-positive contacts. In some studies [20, 24, 28], tuberculosis was significantly more common among tuberculin-positive contacts of smear-positive cases than among tuberculin-positive contacts of smear-negative source cases (table 2). As Grzybowski et al. wrote, "the risk of an infected individual developing tuberculous disease does not only depend on . . . the age of the individual and the time elapsing since infection; it also depends on the bacteriologic status of the source" [28]. This factor may also relate to the finding of Loudon et al. that "a higher proportion of contacts were . . . strongly positive [to tuberculin]" when the source case was AFB smearpositive than when the source case was AFB smearnegative and/or culture-negative [23].
Treated vs. Untreated Source Case

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Smear-positive persons expectorate 10 8 -10 10 bacilli daily [34], or about 10 6 -10' AFB per mL of sputum [35], while smear-negative sputum contains <10 3 bacilli per mL of sputum [35]. Treatment of tuberculosis decreases contagiousness, regardless of smear and culture status, by decreasing the number of bacilli expectorated as well as by introducing antibiotic into the infectious droplet nuclei [35-38]. This has important impli-

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Table 1. Summary of data from studies examining rates of tuberculin reactivity among young contacts (aged 0-4 years, unless otherwise indicated) of patients with smear-positive, smear-negative, and clinical tuberculosis.
No. (%) of tuberculin-reactive contacts/total contacts studied, per disease category Site of study [reference] Time of study 1930s 1940-53 1948-52 1954-5 1967-9 1966-71 Smear + Smear /culture + 31/108 (29) 115/368 (31) 11/82 (13) 10/56 (18) 2/43 (5) 1/189 (<1) 1* 11/181 (6) 7/296 (2.3)t Smear /culture 15/71 (21) NA 6/83 (7) 20/159 (13) 4/91 (8) 0.76 1. 8/122 (6.5) 3/142 (2.1)t Control 38/210 (18) 1/61 (2) 12/189 (6) NA <1% <1% 0.7% 0.7%

Philadelphia [11] Oslo [22] Bedfordshire, England [20] Edinburgh [23] Rotterdam, the Netherlands* [29] Saskatchewan, British Columbia [28]

115/145 (79) 375/644 (58) 97/161 (60) 40/127 (31) 20/40 (50) 20/464 (4)t 90/309 (29) 25/527 (4.7)t

NOTE. NA = not applicable; + = positive; = negative. * Persons aged 0-14 years were studied. t Reflects rate among contacts with casual rather than intimate contact. Downloaded from http://cid.oxfordjournals.org/ by guest on April 2, 2012

cations regarding the timing of discharge of patients with tuberculosis and when they should be allowed to return to work. Although traditionally 2 weeks of therapy has been considered adequate to render a patient sufficiently noncontagious, a 1981 review of the topic by Noble questioned the basis of this recommendation: "the evidence is, at best, circumstantial [that 2 weeks of therapy is sufficient] and should not be given inappropriate reverence" [39]. The classic study that led to this doctrine was carried out by Ramakrishnan [40] and Kamat [41] and co-workers in Madras, India, in the late 1950s. They studied attack rates of tuberculosis over 5 years among close family contacts of source cases treated with isoniazid and p-aminosalicylic acid for 1 year. Source cases were randomly assigned to receive therapy either at home or in a sanatorium; their household contacts about 260 contacts per arm were then followed. Contacts underwent chest radiography and tuberculin skin testing every 3 months (regardless of tuberculin status) for 1 year and every 6 months thereafter. Among initially tuberculinnegative contacts (induration, <5 mm), there was no difference

in tuberculin conversion rates or in tuberculosis case rates for contacts of patients treated at home vs. those for contacts of patients treated in the sanatorium (table 3). These findings suggest that transmission occurred before initiation of treatment for the source case. On the basis of these findings, it has been assumed that it is safe for a patient to return home when medically stable, since the period of greatest contagiousness the weeks before diagnosis has passed. However, the study was performed in a city with extremely high rates of infection and disease. The contribution of community transmission rather than home transmission was surely substantial and far in excess of what would be likely to occur in the United States. Furthermore, such an approach may not be acceptable if family members are HIV-infected or otherwise immunocompromised.

intimate contacts who were initially tuberculin (PPD)negative (induration, <5 mm), according to where source case received therapy.
Source case treatment

Table 3. Rates of tuberculin conversion and active disease among

Table 2. Rates of active tuberculosis among tuberculin-positive contacts of cases, graded according to smear and culture status of source case.
Contact population [reference] Children [24]* Children [20] Adults [20] All ages [28] No. (%) of contacts with active tuberculosis/total contacts studied, per status of source case Smear + 71/200 (35.5) 54/374 (14.4) 75/669 (11.2) 181/1,209 (15) Culture + 2/35 (5.7) 6/228 (2.6) 3/408 (0.7) 13/399 (3.3) Smear /culture 4/35 (11.4) 2/221 (0.9) 5/354 (1.4) 3/260 (1.2)

Contact-population variable Contacts initially PPD-negative, all ages Conversion rate after 2 y Conversion rate after 5 y TB case rate after 5 y Conversion rate among contacts y aged TB case rate after 5 y among all contacts, regardless of initial PPD status

Home

Sanatorium

29%-36% 39%-46% 9/86 (10%) 6/43 (14%)*

33%-37% 45%-48% 10/87 (11%) 14/41 (34%)*

24/245 (10%)

38/264 (.14%)

* Secondary cases were diagnosed radiographically, not microbiologically.

NOTE. Data are from [40, 41]. TB = tuberculosis. * P = .55 (Yates's correction).

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Table 4. Rates of initial tuberculin (PPD) reactivity (induration, > 10 mm) and of conversion to tuberculin reactivity among household contacts of treated patients, stratified according to smear and culture status at time of hospital discharge.
Smear and culture status of source case at discharge Smear + and culture + 52 180 98 26 91 41 21 Smear and culture + 34 104 46 20 48 18 12 Smear and culture 69 216 108 39 108 41 21

Variable No. of source patients No. of contacts, all ages Initially PPD + Conversion to PPD + No. of contacts aged < 16 y Initially PPD + Conversion to PPD +

(54%) (14%) (45%) (23%)

(44%) (19%)

(50%) (18%) (38%) (19%)

(38%)
(25%)

NOTE. Table was adapted from [42].

The question of when it is "safe" to discharge a patient with tuberculosis also was addressed by Gunnels and co-workers in Arkansas during the late 1960s and early 1970s [42]. In this retrospective study, patients were hospitalized for 35 days and received treatment with isoniazid and ethambutol, with or without streptomycin, prior to discharge. They were then stratified according to smear and culture status on discharge, and the tuberculin reactivity rates of their home contacts were compared (table 4). The authors found that both the prevalence of tuberculin-positivity and the conversion rate were the same for contacts, regardless of the smear and culture status of patients on discharge, again suggesting that most exposure and transmission occur before diagnosis. Additional, smaller studies demonstrated similar findings [43-45], leading to the current view that patients may be discharged to the home while receiving effective therapy (i.e., when they have demonstrated clinical response). It is important to recognize that no studies have been performed in which the source cases have received rifampin and pyrazinamide, two agents with rapid sterilizing properties that are part of the current routine four-drug regimen. Finally, however, as Farer wrote, "there is no way to determine an absolute moment at which a patient on therapy becomes non-infectious. Decisions regarding the infectiousness of an individual patient must be individualized for that patient" [46]. Thus, isolation and discharge decisions should not be made solely on the basis of smear status but should follow consideration of other factors as well.
Coughing, Singing, and Speaking

were counted for three consecutive nights, from 11 P.M. to 7 of tuberculin reactivity among 130 household contacts were then stratified by coughing frequency of the source cases. Contacts of patients who coughed < 12 times per night had a lower prevalence of tuberculin reactivity than did contacts of those coughing >48 times per night (14 of 51 [27%] vs. 25 of 57 [44%]; P = .11). Cough frequency, however, was less associated with tuberculin reactivity rates than was AFB smear status. In other studies, Loudon and Roberts examined types and frequencies of droplet nuclei produced by coughing, speaking, and singing [48, 49]. They concluded that one cough produces as many droplet nuclei as 5 minutes of loud talking and that singing was similar to coughing in terms of the quantity and size of produced droplet nuclei that were still present at 30 minutes. Further evidence that singing may facilitate transmission has arisen from several singing-related outbreaks reported through the years. In a,boarding school outbreak, rates of infection were higher among persons who were in the choir with the index case than among those who shared a dormitory room or meals with the case but were not in the choir (12 of 20 vs. 13 of 107; P < 10 -5 ) [50]. Additional reports have suggested the same conclusion [51, 52].
A.M. Rates
t

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Pulmonary vs. Extrapulmonary Tuberculosis

Occasional reports have described the spread of tuberculosis from patients with exclusively extrapulmonary disease. Most instances appear to be due to aerosolization of abscess material [53, 54], although an additional theoretic concern is that many patients with extrapulmonary disease also may have subclinical pulmonary disease. Tuberculosis uncommonly has been transmitted via the blood, such as through needlestick injuries (socalled prosector's warts) [55]. However, such instances are quite unusual, indicating that patients with exclusively extrapulmonary tuberculosis are unlikely to transmit infection.
HIV Status of Source Case

In the 1960s, Loudon and Spohn studied the contribution of coughing to overall infectiousness [47]. Sixty-three patients with pulmonary tuberculosis were identified and their coughs

The relative infectiousness of HIV-infected persons with tuberculosis vs. that of those with tuberculosis who are HIVuninfected is unknown. In Lusaka, Zambia, household contacts of 43 HIV-positive and 28 HIV-uninfected patients with tuberculosis underwent tuberculin testing [56]. Among these, 52% of 207 contacts of the HIV-infected patients vs. 71% of 141 contacts of HIV-uninfected patients were tuberculin-positive (OR, 0.43; P < .001). One explanation of this finding is that HIV-infected persons are less contagious. In a similar study, no difference in tuberculin reactivity rates was found among 1,200 household contacts of HIV-uninfected and HIV-infected patients in Kinshasha, Zaire [57]. However, in another study, more cases of clinical tuberculosis occurred among employees working with HIV-infected patients with

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tuberculosis than among those caring for HIV-uninfected patients with tuberculosis (7 of 85 vs. 2 of 1,079; RR = 44), suggesting that HIV-infected persons may be more infectious [58]. Exposure Due to Closed Ventilation Ventilatory interventions to control the spread of tuberculosis remain a contentious issue, about which cost vs. efficacy is debated. Several thorough reviews of environmental control of tuberculosis have appeared [59-61]. In a series of classic articles about studies of guinea pigs, directed air flow, and patients with newly diagnosed pulmonary tuberculosis, Riley and coworkers contributed significantly to our fundamental understanding of tuberculosis transmission [62-64]. In these studies performed during the late 1950s, several hundred guinea pigs were exposed to air ventilated out of rooms housing patients with tuberculosis. The exposed animals were then systematically tested for evidence of tuberculous infection and disease. The authors concluded that the airborne route could indeed "account for the spread of pulmonary tuberculosis in human beings" [62], the first scientific proof of this now seemingly self-evident principle. These studies verified and extended the work of William Wells, who had postulated the existence of droplet nuclei [65]. Riley et al. also found that a relatively small number of source patients were responsible for the majority of animal infections: 35 of 48 animal cases were attributable to only 3 source patients, although 77 patients had occupied the tuberculosis ward during the observation period. Although these three patients had high numbers of tubercle bacilli in their expectorated sputa, so did other patients who were not associated with transmission. The authors were unable to determine the reasons for the differences in the infectiousness of the cases [63, 64]. The other sources of information regarding ventilation are various reports on "accidents of nature" leading to outbreaks [9]. Most notable among these are outbreaks aboard ships [66-71] and among persons on school buses [72, 73], in poorly ventilated classrooms [74], and in bars [75]. Perhaps the beststudied incident occurred aboard the USS Byrd, where 139 (46%) of 308 crew members tuberculin-converted (i.e., converted to tuberculin positivity) and disease developed in 7 (2.3%) [66-68]. Infection was spread by recirculation of contaminated air along closed ventilatory circuits, and high conversion rates were noted in specific sleeping compartments along a ventilatory system. In one compartment housing 6 crewmen with tuberculosis, 52 (79%) of 66 personnel tuberculinconverted; in the next compartment, which shared ventilation with the first, 46 (57%) of 81 tuberculin-converted. This compared to a rate among new recruits of 3.4%. In their review of several Navy outbreaks, Kent et al. suggested that some infection was perpetuated by tuberculin converters whose chest radiographs were normal [76]. These pa-

Table 5. Rates of tuberculin positivity (PPD +) in relation to time

spent daily on a bus whose driver had cavitary tuberculosis undiagnosed for at least 4 months. Daily duration (min) of bus ride <10 10-39 >40 No. (%) of PPD + riders/total tested 8/37 (22) 58/191 (30) 17/30 (57) No. of cases of tuberculosis* 7 35 9

NOTE. Data are from [9, 72]. Reprinted with permission from [9]. 1996, American Medical Association. * Community prevalence was 2%.

tients presumably had small areas of infection sufficient to cause both a tuberculin conversion and some transmission but not sufficiently large to be evident on a chest radiograph. This has been suggested by others [77], including Hardy and coworkers, who studied another outbreak on a Navy ship [71]. They identified nine culture-confirmed cases of tuberculosis among new converters whose chest radiographs were normal, representing about one-third of the cases overall in this outbreak. The relative infectiousness of such persons is unknown [71, 77]. Duration and Intensity of Exposure Analysis of several outbreaks in hospitals and in the community has helped define the association between duration of exposure and rates of tuberculin reactivity. In perhaps the most remarkable outbreak, a bus driver in a rural area of New York State was symptomatic for several months before diagnosis [72]. Of 258 children with known duration of exposure who rode his bus, 83 (32%) were tuberculin reactors and 51 acquired tuberculosis (table 5). Stratification of the children's tuberculin reactivity rates according to the daily duration of exposure to the bus driver revealed that 22% of children riding < 10 min/ d were positive, vs. 57% of children riding >40 min/d. Community prevalence of tuberculin reactivity was 2%. Other school outbreaks have demonstrated similar findings. In one, 48% of children whose only exposure was to enter a classroom directly after the index case had left were tuberculin reactors, vs. a community rate of 2.5% [74]. In another, suitemates and social contacts had the highest rates of tuberculin reactivity [78]. It is disturbing that eight tuberculin conversions occurred among classmates with no more than 5 hours of exposure to the source case who had laryngeal tuberculosis. Duration of exposure also was estimated in several hospital outbreaks. In an outbreak in England, cavitary tuberculosis was diagnosed in the mother of a 3-year-old child who was hospitalized for 1 month before diagnosis of a tuberculous abscess in the child [79]. The mother spent at least 9 hours a day with her child. Investigation of 129 exposed children re-

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vealed that 12 (15%) of 82 who had spent 1-2 days as the child's (and mother's) roommate were tuberculin-reactive or acquired tuberculosis, vs. 9 (30%) of 27 with 3-7 days of exposure and 8 (57%) of 14 with >8 days of exposure. In addition, rates of disease were highest among those with the most prolonged exposure. In a remarkable outbreak, an intubated patient with advanced pulmonary tuberculosis was present in the emergency department for only 4 hours and spread infection to 16 (14%) of 112 employees [80]. Factors that may have enhanced transmission included frequent endotracheal suctioning, the failure to filter air or introduce fresh air into the ventilatory system, and the use by workers of four-string surgical masks, which may offer little protection. In Miami, a patient with undiagnosed pulmonary tuberculosis spread infection to 21 (35%) of 60 employees who were exposed for only 57 hours [81]. Evaluation of the ventilation of the unit where the patient had been treated demonstrated circulation of air from patients' rooms into the central-corridor employee area. Another approach to understanding the effect of sustained exposure is to examine the results of "casual" versus "intimate" exposure in the various community-wide surveys that have been conducted (table 1). In these, risk among casual contacts, particularly of smear-positive cases, is reduced, which suggests a "dose-response." Additional evidence comes from older reports regarding rates of tuberculosis among married couples [82-84]. These demonstrated that rates of tuberculosis
among spouses of the source cases exceeded rates in other family members, owing to the degree and intimacy of contact. The Host

tion of latent infection [91] and in development of acute disease Whether establishment of acute infection is influenced by HIV status is unknown, and given the high rates of skin anergy among HIV-infected persons, this question may not be answerable until an alternative means of diagnosing latent M. tuberculosis infection is developed.
Characteristics of the Organism

Several host factors also may influence transmission. Previous infection with M. tuberculosis, reflected by a positive tuberculin test, is believed by some to provide durable immunity against second infection. However, exogenous reinfection among HIV-infected persons [85], veterans [86], and the homeless [87] has previously been described. Older studies found evidence of exogenous reinfection among immunocompetent health care workers: among already tuberculin-positive nurses, more cases of tuberculosis occurred among those working on tuberculosis wards than those rarely caring for patients with tuberculosis [88, 89]. Molecular fingerprinting of M. tuberculosis strains may provide a means to better define how frequently exogenous reinfection occurs. The BCG immunization status of the contact may also influence transmission (as well as complicate outbreak investigation). An often-cited meta-analysis has demonstrated that BCG vaccination decreased rates of tuberculosis by 50% [90]. Thus, extensive transmission may be less likely among BCGvaccinated populations. The HIV status of the host clearly influences the rates of progression from infection to disease, both in cases of reactiva-

Experts have long speculated that specific characteristics of the tubercle bacillus or the sputum may influence contagiousness [22, 62-64]. Objective data, however, are limited. On the basis of studies by Riley et al. [62-64] grew the notion of the "dangerous disseminator" and "super-disseminator." As noted above, these patients clinically were similar to other patients seen during the study period, as were the susceptibility profiles of their bacteria, volume of sputum production, and cough frequency. One such disseminator was noted to have "liquid sputum," which the authors thought might aerosolize more easily. Hertzberg attemptedunsuccessfullyto study the question by stratifying households according to whether or not the infection in the source case resulted in rapidly fatal disease (death within 1 year of infection) [22]. Children who were contacts of "lethally disposed" source cases had slightly more morbidity and mortality, but the difference was not statistically significant. On the basis of age-specific mortality rates showing poorest survival among the very young, he concluded that the age of the child is the more important predictor of a fatal outcome, rather than properties of the microorganism. Preliminary work in New York City on restriction fragment length polymorphism (RFLP) analysis of M. tuberculosis demonstrated that one drug-susceptible strain, designated strain C, caused 10% of cases in New York City from 1991 to 1994 [93]. Demographic features and hospitalizations within 5 years prior to diagnosis of tuberculosis were associated with infection with this C strain. Further studies are under way to determine if this strain somehow is more capable than other strains of causing disease in large populations. If this is true, a crucial aspect of tuberculosis epidemiologyisolate-to-isolate variationmay begin to be understood. The relative contagiousness of resistant vs. susceptible tuberculosis is unknown. However, in a case-control study, contacts of cases with resistant tuberculosis had the same rates of infection and disease as contacts of cases with drugsusceptible disease, suggesting little difference in degree of infectiousness [94].
Conclusion

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Public concern [95] and concern among health care workers [96] regarding the potential transmissibility of tuberculosis arose in the late 1980s and early 1990s because of several well-

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publicized urban outbreaks of the disease. However, persons exposed to a source case found that their seemingly simple question, "Am I going to catch TB?", had an extremely complicated and incomplete answer: unlike many other infectious agents, the determinants of transmissibility for tuberculosis remain only partially understood. Incredibly, despite decades of inquiry and hundreds (if not thousands) of reports, it is still not clear why one person with tuberculosis is more contagious than the next. Much of our current understanding of the transmissibility of tuberculosis derives from inference and accident rather than from intentional scientific study. Published reports on various community outbreaks of tuberculosis have been particularly helpful in understanding the transmissibility of tuberculosis [9]; in these reports, investigation of a cluster of cases has elucidated an important principle of disease transmission. In addition, numerous meticulous community-based studies [10-30] have demonstrated repeatedly that a single variable the AFB smear status of the source case strongly predicts which patients are the most contagious. Beyond these observations, however, much has been left to speculation. The group headed by Riley made the most valiant attempts to study the question of tuberculosis transmission scientifically [62-64]. In addition to the points listed above, they also noted that transmission was decreased when the mouth was covered while coughing. This simple intervention is often overlooked as attention is focused on the current elaborate strategies for decreasing transmission [96], such as sophisticated filters on masks, ultraviolet light sterilization of air, and negative pressure ventilation in rooms. Our understanding of the transmission of tuberculosis is further hampered by our reliance on the tuberculin skin test to identify latently infected and newly infected individuals. Numerous investigations of outbreaks have been complicated by the relatively poor sensitivity and specificity of this old test. Improved understanding of the transmission of tuberculosis may await the development of a more reliable test for diagnosing individuals who are infected with M. tuberculosis. Use of RFLP and other molecular techniques may provide the additional technologic advantage needed to better comprehend the principles of transmission. On the other hand, it may be that one more modern technique will fall short of completely unlocking the mysteries of the tubercle bacillus.
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