Our study found that 29% of TB case pairs identified in contact investigations in seven sites during the course of 5 years were not confirmed as linked by using DNA fingerprinting. We used a restricted definition for considering a case pair to be epidemiologically linked: direction of transmission had to be identified as a result of the epidemiologic investigation. Despite the differences in methodology between our research and a California study (9), which used a less restrictive definition (an epidemiologic case pair was an index case and contact case), both studies found a similar percentage of unconfirmed case pairs.

The fact that case pairs in which transmission was unconfirmed were no less likely to be found in the same household than case pairs in which transmission was confirmed suggests that apparent household transmission should not be taken at face value. Marks et al., in a review of U.S. contact investigations (7), report that 33% of contact investigations focused only on the household of the index case. Veen, however, suggests that a modern day stone-in-the-pond approach should focus first on the places and groups frequented by the person classified as the index case, which may not only be the household (4). Onorato notes that as TB in the United States becomes less prevalent, forms and settings of transmission previously considered unusual will appear relatively more common (13). Many public health departments have designed contact investigation formats to focus on places frequented by persons newly diagnosed with TB and the persons with whom they have had contact during the infectious period, rather than focusing only on the household (S. Sharnprapai, pers. comm.). Our findings suggest that this strategy may be useful, even when an apparent source case has been located in the same household.

Unconfirmed transmission between an epidemiologically linked case pair has two interpretations: either the secondary case actually has a reactivation of a latent, remotely acquired TB infection or the transmission was recent, but the source case has not been identified. The progression of a latent, remotely acquired infection to active TB implies that an opportunity to identify infection and apply appropriate preventive measures may have been missed. Failure to correctly identify the source of a recent transmission suggests that contact-tracing procedures may have been inadequate or that an unusual setting or mode of transmission may have been associated with the infection. The significant associations found in our study suggest that either explanation could apply to many of the unconfirmed transmissions we identified.

Few secondary cases in the study reported previous active TB, and prevalence of previous TB was equal among the confirmed and unconfirmed transmission groups. However, previous TB infection could still be an important factor among some foreign-born persons classified as secondary cases in case pairs in which transmission was unconfirmed. Foreign-born persons from countries with high TB prevalence are likely to have had multiple opportunities for exposure to TB before arrival in the United States (3), diminishing the likelihood that any one identified exposure, such as the source case identified in the contact investigation, is the source of transmission. Screening new arrivals from countries with a high prevalence of TB and scheduling additional screening of persons from such countries were both given a high priority in the Institute of Medicine’s recent recommendations for eliminating TB in the United States (3). The Institute noted that such screening is currently inadequate and warrants expansion, as well as follow-up to ensure that foreign-born persons with positive tuberculin skin tests receive treatment. Much of the active TB among the 133 foreign-born persons classified as secondary cases in this study, as well as some of the TB among the 139 foreign-born persons classified as source cases, might have been prevented if such screening and follow-up were more widely implemented.

Another major finding in this survey is the significant positive association between a smear-negative source case and unconfirmed transmission. This finding suggests that identifying a smear-negative source case for an index case should not preclude ongoing investigation of other possible sources.

On the other hand, the study does not suggest that transmission from smear-negative cases does not occur. Contact investigations of smear-negative cases generally have a low priority in most public health departments. Given that contact investigations were not likely to have been conducted for many smear-negative cases in the network, the fact that 19% of confirmed case pairs had a smear-negative source case suggests that transmission from smear-negative source cases is not negligible. This proportion is similar to that found in a DNA fingerprinting study of two types of epidemiologic clusters, those with smear-negative source cases and those with smear-positive index cases (14). Twenty percent of case pairs with confirmed transmission had a smear-negative index case.

Eighty-nine percent of case pairs with a secondary case <15 years of age were confirmed by genotyping. The shorter incubation of TB in children than in adults and the more limited social circles of children increase the likelihood that children with TB were infected within the circle of present contacts located in a contact investigation. These same factors make TB in children preventable. If TB in the 55 adult source cases who transmitted the infection to these children had been diagnosed and treated promptly and contact tracing had resulted in timely and complete treatment for latent TB infection, latent TB infection in most of these children would have been prevented or would not have progressed to TB.

We hypothesized that secondary cases >65 years of age might have had a greater risk for unconfirmed transmission, given longer lives which included the era of relatively high TB rates before the availability of TB drugs. However, case pairs with unconfirmed transmission were no more likely to include an elderly person as a secondary case than pairs with confirmed transmission. TB in an elderly person should not be assumed to be a reactivation, and contact investigations should attempt to identify a possible source case.

Nearly half the workplace case pairs did not have transmission confirmed by DNA fingerprinting, although the number of case pairs was small. When active TB is diagnosed in a person in a workplace, screening is often not confined to close contacts. Casual contacts may be screened because of anxiety on the part of management and staff. Including nonclose contacts in the screening increases the likelihood that if an additional case is found, transmission did not occur from the index case.

Our hypothesis that secondary cases with HIV are more likely to be part of a confirmed case pair than other secondary cases, since their compromised immune status predisposes them to a quicker progression to active TB once infected, was not borne out in this study. Persons with HIV are also more likely to reactivate previous TB infections than persons not dually infected, which may explain the relatively equal proportions of confirmed and unconfirmed transmissions from the identified source among HIV-positive persons. HIV may also be underreported in the TB surveillance system, and the numbers reported may not represent the real numbers of persons with HIV.

Although DNA fingerprinting provided helpful research information in our study, we think the tool should not be considered a routine contact investigation tool. Contact investigations should ideally be undertaken, and often will be completed, before the isolates from the index case are available. Since early identification of TB cases and prevention of further cases is the highest priority, DNA fingerprinting methods will not be relevant to most contact investigations in a TB control program. If TB cases are identified early and appropriate preventive measures taken for latent TB infection seen in contacts, transmission of TB and progression of latent TB infection to TB in infected contacts should be rare. As noted earlier, other studies report a secondary case rate of between <1% and 4% in contact investigations; as programs progress towards TB elimination, this rate may be further reduced. DNA fingerprinting is most likely to be relevant when a case is suspected of being part of a larger outbreak, for which fingerprints could confirm extensive transmission. This survey suggests that DNA fingerprinting could also be used when an apparent source for an index case is sputum smear-negative, to evaluate whether the smear-negative case could be the true source case, or whether further investigation is needed.