DNA Fingerprinting of Mycobacterium tuberculosis
DNA Fingerprinting of Mycobacterium tuberculosis
DNA fingerprinting was used to evaluate epidemiologically linked case pairs found during routine tuberculosis (TB) contact investigations in seven sentinel sites from 1996 to 2000. Transmission was confirmed when the DNA fingerprints of source and secondary cases matched. Of 538 case pairs identified, 156 (29%) did not have matching fingerprints. Case pairs from the same household were no more likely to have confirmed transmission than those linked elsewhere. Case pairs with unconfirmed transmission were more likely to include a smear-negative source case (odds ratio [OR] 2.0) or a foreign-born secondary case (OR 3.4) and less likely to include a secondary case <15 years old (OR 0.3). Our study suggests that contact investigations should focus not only on the household but also on all settings frequented by an index case. Foreign-born persons with TB may have been infected previously in high-prevalence countries; screening and preventive measures recommended by the Institute of Medicine could prevent TB reactivation in these cases.
Investigating persons who have had close contact with tuberculosis (TB) cases is an essential element of public health programs to control and eliminate TB. These contact investigations are done primarily to discover persons who may require treatment for latent TB infection and also to find and treat additional persons with TB. While not usually highly contagious, TB is generally transmitted to persons who have shared indoor air space frequently or for a long period of time with a person who is infectious. Factors that may influence transmission include prolonged hours of contact during the infectious period, close proximity to the person with TB, and lack of ventilation and ultraviolet light in a shared environment. Generally, close contacts who live with a person identified with active TB or who habitually spend time indoors in close proximity to this person are investigated first. If no evidence of TB transmission is found in these close contacts, the investigation ceases. If transmission has occurred, the investigation may be extended. The "stone-in-the-pond" principle, a technique in which concentric circles of contact persons around the case are sequentially investigated, is practiced in many countries.
If one or more additional persons with TB are identified among the contacts of a person with TB, the person is labeled as the index case for the purpose of the investigation; those subsequently identified are classified as source cases, secondary cases, or unlinked cases. An active TB case found in a contact investigation may be classified as the source of infection to the index case, a secondary case infected by the index case, or a case who neither infected nor was infected by the index case (with a strain of TB unrelated to the strain of the index case). Information about the start and duration of symptoms for the index and the contact cases, and the start and duration of contact between them, facilitates categorization. Categorizing a contact with active TB as a source case, a secondary case, or an unlinked case, based on epidemiologic evidence, helps to direct further investigation. If the source case is known to have drug-resistant TB, establishing epidemiologic links may also aid in choosing an appropriate drug regimen for the contact before cultures and sensitivity test results are available.
The chief priority of TB-control programs is to identify and treat active cases of TB before transmission can occur. If an index case is identified and treated soon after symptoms begin, the time during which TB could be transmitted can be minimized, and active secondary cases are unlikely to be found in contact investigations. If contact investigations are carried out soon after the index case is identified, the time is minimized during which infected persons could progress to disease before receiving treatment for latent TB infection to prevent progression. In a low-prevalence country, a well-resourced and active TB-control program would not expect to find a high proportion of active TB cases among contacts in investigations.
Systematic evaluations of contact investigations are infrequent. In an Australian study, of 1,142 close contacts of 231 cases diagnosed in 1991, a mean of 4.9 contacts per case were identified, but only 3 (0.3%) of the contacts had active TB. However, the authors stated that the screening of these contacts was inadequate so TB may have been underdiagnosed. A 1996-1997 U.S. study of contact investigations of 1,080 pulmonary, smear-positive TB patients found a median of four close contacts per patient. Thirty-six percent of contacts were tuberculin skin-test positive, and 2% had active TB. A systematic review of health department records for all contacts of 349 patients with culture-positive TB in five study areas in 1996 revealed that 13% had not identified contacts. Although 3,824 contacts were identified, only 2,095 (55%) completed screening; of these, 1% had active TB.
DNA fingerprinting has been used to support contact investigations of large clusters of cases in institutional settings and to suggest possible connections among cases without obvious epidemiologic links. This technique is also used, though rarely, to evaluate epidemiologic links found in contact investigations. In San Francisco, culture-positive TB cases previously identified as contacts to active TB cases were evaluated along with their index cases; a median of four contacts was investigated for each of the 1,308 culture-positive index cases reported from 1991 to 1996. Of 11,211 contacts evaluated, 108 (1%) had active TB. Of 94 pairs of index and contact cases with active TB, 66 had positive cultures; of these, 54 had restriction fragment length polymorphism results for both strains. Transmission was confirmed (that is, the same strain was identified in both cases) in 38 (70%) of the 54 pairs.
Between 1996 and 2000 in the United States, the National Tuberculosis Genotyping and Surveillance Network collected information on contacts with culture-confirmed TB identified during the course of contact investigations and medical record reviews in seven sentinel areas (the states of Arkansas, Massachusetts, Maryland, Michigan, and New Jersey and selected sites in California and Texas). These data, combined with the results of DNA fingerprinting, were analyzed to evaluate the proportion of epidemiologically linked cases in which transmission was confirmed by matching fingerprints and to investigate the characteristics of case pairs with unconfirmed transmission (unmatched fingerprints).
DNA fingerprinting was used to evaluate epidemiologically linked case pairs found during routine tuberculosis (TB) contact investigations in seven sentinel sites from 1996 to 2000. Transmission was confirmed when the DNA fingerprints of source and secondary cases matched. Of 538 case pairs identified, 156 (29%) did not have matching fingerprints. Case pairs from the same household were no more likely to have confirmed transmission than those linked elsewhere. Case pairs with unconfirmed transmission were more likely to include a smear-negative source case (odds ratio [OR] 2.0) or a foreign-born secondary case (OR 3.4) and less likely to include a secondary case <15 years old (OR 0.3). Our study suggests that contact investigations should focus not only on the household but also on all settings frequented by an index case. Foreign-born persons with TB may have been infected previously in high-prevalence countries; screening and preventive measures recommended by the Institute of Medicine could prevent TB reactivation in these cases.
Investigating persons who have had close contact with tuberculosis (TB) cases is an essential element of public health programs to control and eliminate TB. These contact investigations are done primarily to discover persons who may require treatment for latent TB infection and also to find and treat additional persons with TB. While not usually highly contagious, TB is generally transmitted to persons who have shared indoor air space frequently or for a long period of time with a person who is infectious. Factors that may influence transmission include prolonged hours of contact during the infectious period, close proximity to the person with TB, and lack of ventilation and ultraviolet light in a shared environment. Generally, close contacts who live with a person identified with active TB or who habitually spend time indoors in close proximity to this person are investigated first. If no evidence of TB transmission is found in these close contacts, the investigation ceases. If transmission has occurred, the investigation may be extended. The "stone-in-the-pond" principle, a technique in which concentric circles of contact persons around the case are sequentially investigated, is practiced in many countries.
If one or more additional persons with TB are identified among the contacts of a person with TB, the person is labeled as the index case for the purpose of the investigation; those subsequently identified are classified as source cases, secondary cases, or unlinked cases. An active TB case found in a contact investigation may be classified as the source of infection to the index case, a secondary case infected by the index case, or a case who neither infected nor was infected by the index case (with a strain of TB unrelated to the strain of the index case). Information about the start and duration of symptoms for the index and the contact cases, and the start and duration of contact between them, facilitates categorization. Categorizing a contact with active TB as a source case, a secondary case, or an unlinked case, based on epidemiologic evidence, helps to direct further investigation. If the source case is known to have drug-resistant TB, establishing epidemiologic links may also aid in choosing an appropriate drug regimen for the contact before cultures and sensitivity test results are available.
The chief priority of TB-control programs is to identify and treat active cases of TB before transmission can occur. If an index case is identified and treated soon after symptoms begin, the time during which TB could be transmitted can be minimized, and active secondary cases are unlikely to be found in contact investigations. If contact investigations are carried out soon after the index case is identified, the time is minimized during which infected persons could progress to disease before receiving treatment for latent TB infection to prevent progression. In a low-prevalence country, a well-resourced and active TB-control program would not expect to find a high proportion of active TB cases among contacts in investigations.
Systematic evaluations of contact investigations are infrequent. In an Australian study, of 1,142 close contacts of 231 cases diagnosed in 1991, a mean of 4.9 contacts per case were identified, but only 3 (0.3%) of the contacts had active TB. However, the authors stated that the screening of these contacts was inadequate so TB may have been underdiagnosed. A 1996-1997 U.S. study of contact investigations of 1,080 pulmonary, smear-positive TB patients found a median of four close contacts per patient. Thirty-six percent of contacts were tuberculin skin-test positive, and 2% had active TB. A systematic review of health department records for all contacts of 349 patients with culture-positive TB in five study areas in 1996 revealed that 13% had not identified contacts. Although 3,824 contacts were identified, only 2,095 (55%) completed screening; of these, 1% had active TB.
DNA fingerprinting has been used to support contact investigations of large clusters of cases in institutional settings and to suggest possible connections among cases without obvious epidemiologic links. This technique is also used, though rarely, to evaluate epidemiologic links found in contact investigations. In San Francisco, culture-positive TB cases previously identified as contacts to active TB cases were evaluated along with their index cases; a median of four contacts was investigated for each of the 1,308 culture-positive index cases reported from 1991 to 1996. Of 11,211 contacts evaluated, 108 (1%) had active TB. Of 94 pairs of index and contact cases with active TB, 66 had positive cultures; of these, 54 had restriction fragment length polymorphism results for both strains. Transmission was confirmed (that is, the same strain was identified in both cases) in 38 (70%) of the 54 pairs.
Between 1996 and 2000 in the United States, the National Tuberculosis Genotyping and Surveillance Network collected information on contacts with culture-confirmed TB identified during the course of contact investigations and medical record reviews in seven sentinel areas (the states of Arkansas, Massachusetts, Maryland, Michigan, and New Jersey and selected sites in California and Texas). These data, combined with the results of DNA fingerprinting, were analyzed to evaluate the proportion of epidemiologically linked cases in which transmission was confirmed by matching fingerprints and to investigate the characteristics of case pairs with unconfirmed transmission (unmatched fingerprints).