Targeting Tuberculosis Prevention

Philip C. Hopewell

San Francisco General Hospital, University of California San Francisco, San Francisco, California

	ARTICLE

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Much of tuberculosis control is based on the current understanding of factors that influence transmission of Mycobacterium tuberculosis and that lead to active tuberculosis among persons who acquire the infection (1). One of these activities, contact investigation, is intended to identify persons (contacts) who have acquired tuberculosis infection from a newly discovered active case, thereby enabling targeting of preventive treatment to a group at high risk of developing active tuberculosis, this being the main goal of the activity. The study by Marks and coworkers (2) in this issue of the American Journal of Respiratory and Critical Care Medicine (pp. 2033- 2038) presents an assessment of the current status of contact investigation and treatment of latent tuberculosis infection among contacts in tuberculosis control programs in the United States. The data suggest that programs are only moderately successful in identifying, evaluating, and, when indicated, treating infected contacts. The study also implicitly makes the point that there is still much to learn about this component of tuberculosis control and that both new sociobehavioral insights and technologic innovations are needed to make this intervention most efficient and effective.

The need to focus efforts to prevent tuberculosis in populations and individuals, such as contacts, at high risk for developing the disease is strongly emphasized in the recent Institute of Medicine report, Ending Neglect: The Elimination of Tuberculosis in the United States (3). Even stronger emphasis is provided in the new statement by the American Thoracic Society and the Centers for Disease Control and Prevention (4), "Targeted Tuberculin Testing and Treatment of Latent Tuberculosis Infection."

The principle that underlies the emphasis on contact investigation is that a person is most likely to develop active tuberculosis soon after being infected, although the potential extends throughout the person's lifetime (5). Inferences from epidemiological studies conducted since the early 1990s, using molecular methods, suggest that the risk soon after infection might be greater than was determined to be the case in the early 1960s (6). Molecular epidemiological data also have shown that, especially among persons with human immunodeficiency virus (HIV) infection, outbreaks, including outbreaks of multiple drug-resistant tuberculosis, may occur with frightening speed (9, 10). The implication of these findings is that contact investigation can no longer be undertaken at a leisurely pace but must be accomplished rapidly if it is to have its full benefit. It is encouraging to note that Marks and colleagues reported that the interval between diagnosis and initiation of treatment of latent tuberculosis infection was 30 days. However, the time of diagnosis was not defined, leaving room for unreported delays, and all the patients were in public sector tuberculosis control programs. It would be useful to know if there were differences between public sector and private sector patients, given that it is likely that, increasingly, patients will be managed by private physicians.

It is increasingly evident that "close and prolonged" contact is not necessary for transmission of M. tuberculosis to occur. The weight of evidence is strong that transmission may occur with casual contact, as may be inferred from molecular epidemiological studies (8, 11). In a report from San Francisco, among a group of patients with tuberculosis caused by organisms having the same DNA fingerprint, some had easily found exposures to one another, whereas others had exposures that were identified only after exhaustive review of hospital and clinic records and hotel and shelter registries (8). Findings such as these indicate that the "concentric circle" paradigm for contact investigation is inadequate (12). Yet, in the data from Marks and colleagues, a full one-third of the index cases identified only household contacts. It might be inferred that the fact that such a high proportion had only household contacts identified was a consequence of insufficient probing on the part of the interviewer.

Under current circumstances, in-depth cultural understanding is required to identify the broad group of contacts that might have been infected by a given index case. For example, Marks and coworkers found that, although foreign-born patients did not identify more close contacts, they had more household contacts. This seems contradictory but may be a function of different family and household structures. The finding does, however, clearly indicate that cultural understanding is needed to conduct and interpret contact interviews with foreign-born patients. Given that in 1999, 42% of the new cases nationally were among persons born outside of the United States, competence in conducting interviews with foreign-born patients is and will be increasingly important.

Homeless persons, a group at very high risk of tuberculosis, also serve as an example of the need for specialized contact interviewing. Marks and coworkers found homelessness to be significantly correlated with having no contacts identified. In San Francisco in the early 1990s this was the case as well. However, because of concerns that the contact interview was not being conducted in a way to elicit contacts from homeless persons when in fact there were significant exposures occurring, staff were retrained and provided with information on the homeless lifestyle. The number of new cases with no contacts identified decreased from 25 to 5% between 1990 and 1997 (13).

A number of studies have shown that index patients having acid-fast bacilli in their sputum, cavitation on chest films, and severe cough are more infectious for their contacts than patients who do not meet these criteria. Rarely do children have these characteristics (1). Priority in contact investigation is generally given to the contacts of more highly infectious patients (12). Reports, however, have described tuberculosis in an embalmer who handled the body of a person who died of tuberculosis, an outbreak the source for which was a 9-year-old child, and an assessment that estimated approximately 20% of the new tuberculosis cases in San Francisco resulted from transmission from a sputum-negative source case (14- 16). Each of these studies calls into question the traditional approaches to priority assignment in contact investigation and suggests that the investigative base must be broadened, a recommendation contained in the Institute of Medicine report (3).

The shortcomings of our current diagnostic tools for identifying latent tuberculosis infection were also illustrated in the foreign-born contacts as reported by Marks and coworkers. High rates of initial tuberculin skin test positivity and skin test conversions from an initially negative to a positive test at the time of follow up were found among foreign-born contacts. As the authors note, it cannot be determined whether the initial positive test was the result of recent or prior infection with M. tuberculosis that occurred in their country of origin, cross-sensitization caused by bacillus Calmette-Guèrin (BCG) vaccination, or infection with nontuberculous mycobacteria. Likewise, the apparent conversions could be due to "boosting" of a waned reaction but being indistinguishable from a new infection. The need for new tools with which to make a more accurate diagnosis of latent tuberculosis infection is a point emphasized strongly in the Institute of Medicine report (3). The inefficiency and inaccuracy of the tuberculin skin test limit the usefulness of the whole prevention strategy.

There is no value in identifying infected contacts if there is not a good mechanism for ensuring that treatment of latent infection is provided. In the report by Marks and colleagues, only 56% of those who started treatment completed it. Given the high-risk status of close contacts (all of those in the study were close contacts), this is a sorry result. Perhaps the completion rate would have been better if the newly recommended 2-month regimen of rifampin and pyrazinamide had been used, although its effectiveness has been documented only in persons with HIV infection (4). With a short-course regimen, treatment could be administered under direct observation to ensure completion of therapy as in treating active tuberculosis.

In summary, data from the assessment conducted by Marks and coworkers suggest that many improvements are needed if contact investigation is to provide a major contribution to tuberculosis elimination in the United States. The data also suggest that we are addressing only the "easy" parts of contact investigation and are doing that only moderately well. To realize the potential of this crucial element of tuberculosis control there must be increased emphasis on eliciting contacts in a more comprehensive way, completing the evaluation more rapidly, and being more effective in completing treatment of latent infection. At the same time there needs to be intensified research to identify a more accurate test for the diagnosis of latent tuberculosis infection. Advances such as these will provide the wherewithal to move more rapidly toward the elimination of tuberculosis in the United States, as called for in the Institute of Medicine report.

	References

TOP ARTICLE REFERENCES

1. Hopewell PC. Factors influencing the transmission and infectivity of Mycobacterium tuberculosis: implications for clinical and public health management. In: Sande MA, Hudson LD, Root RK, editors. Respiratory infections. New York: Churchill Livingstone; 1986. p. 191-216.

2. Marks SM, Taylor ZT, Qualls NL, Shrestha-Kuwahara RJ, Wilce MA, Nguyen CH. Outcomes of contact investigations of infectious tuberculosis patients. Am J Respir Crit Care Med 2000; 162: 2033-2038 [Abstract/Free Full Text].

3. Institute of Medicine. Ending neglect: the elimination of tuberculosis in the United States. Washington DC: National Academy Press; 2000.

4. American Thoracic Society/Centers for Disease Control and Prevention. Targeted tuberculin testing and treatment of latent tuberculosis infection. Am J Respir Crit Care Med 2000;161:S221-S247.

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8. Small PM, Hopewell PC, Singh SP, Paz EA, Parsonnet J, Ruston DC, Schechter GF, Daley CL, Schoolnik GK. The epidemiology of tuberculosis in San Francisco: a population-based study using conventional and molecular methods. N Engl J Med 1994; 330: 1703-1709 [Abstract/Free Full Text].

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11. Dwyer B, Jackson K, Raios K, Sievers A, Wilshire E, Ross B. DNA restriction fragment analysis to define an extended cluster of tuberculosis in homeless men and their associates. J Infect Dis 1993; 167: 490-494 [Medline].

12. Etkind SC, Veen J. Contact follow-up in high- and low-prevalence countries. In: Reichman LB, Hershfield ES, editors. Tuberculosis: a comprehensive international approach. New York: Marcel Dekker; 2000. p. 377-399.

13. Jasmer RM, Hahn JA, Small PM, Daley CL, Behr MA, Moss AR, Creasman JM, Schechter GF, Paz EA, Hopewell PC. A molecular epidemiologic analysis of tuberculosis trends in San Francisco, 1991- 1997.  Ann Intern Med 1999; 130: 971-978 [Abstract/Free Full Text].

14. Sterling TR, Pope DS, Bishai WR, Harrington S, Greshon RR, Chaisson RE. Transmission of Mycobacterium tuberculosis from a cadaver to an embalmer. N Engl J Med 2000; 342: 246-248 [Free Full Text].

15. Curtis AB, Rizdon R, Vogel R, McDonough S, Hargreaves J, Ferry J, Valway S, Onorato IM. Extensive transmission of Mycobacterium tuberculosis from a child. N Engl J Med 1999; 341: 1491-1495 [Abstract/Free Full Text].

16. Behr MA, Warren SA, Salamon H, Hopewell PC, Ponce de Leon A, Daley CL, Small PM. Transmission of Mycobacterium tuberculosis from acid-fast bacilli smear-negative patients. Lancet 1999; 353: 444-449 [Medline].