Treatment of latent tuberculosis infection contacts of new tuberculosis cases in the United States.

for the Contact Investigation Study Group (*)

Background. Few data are available describing treatment completion rates among recently infected contacts of tuberculosis (TB) cases, a group at high risk for development of active TB.

Methods. Health department records were reviewed for all contacts of 360 culture-positive pulmonary TB cases reported from five health departments in the United States in 1996.

Results. Of 2,267 contacts who completed screening, 630 (28%) had newly documented positive skin tests (121 with skin test conversion). Treatment of latent TB infection was documented to have been recommended for 447 (71%). Among these, treatment was documented to be initiated for 398 (89%). Of these, 203 (51%) were documented to have completed a 6-month course of treatment, and 78 (20%) received directly observed treatment. Treatment was recommended more often for contacts <15 years of age, skin test converters, close contacts, and contacts of smear-positive cases. Treatment completion rates were higher for skin test converters.

Conclusions. In this study, fewer than one third of all persons with newly documented positive skin tests detected during contact investigations were proven to have completed treatment. Achieving high rates of completion of therapy for latent TB infection in recently infected contacts of active cases of pulmonary TB is essential to maximize public health prevention efforts aimed at eliminating TB.

**********

THE ACTIVITY of highest priority for TB control programs in the United States is the detection and cure of all active cases of TB, thereby stopping transmission of Mycobacterium tuberculosis. (1) The next highest priority is the effective investigation of the contacts of infectious TB cases, who are themselves at increased risk of having active TB. (1-3)

Tuberculin skin testing and clinical evaluation of contacts should be done promptly after a suspected case of infectious TB is reported, particularly when young children, immunocompromised persons, or others at greater risk for TB may have been exposed. (3) Repeat skin testing is recommended 3 months after last exposure, since skin test conversion may occur up to 10 weeks after exposure. (4) Health department staff conducting contact investigations assess the probability of recent transmission based on infection rates among persons with the most exposure to the case, as well as certain characteristics of the source case, the exposed contacts, and the environment in which exposure occurred. (5)

The effectiveness of isoniazid therapy in preventing progression from TB infection to active disease is well established. (1,6-8) Recent studies have also shown the effectiveness of several alternative regimens to treat latent TB infection in persons with human immunodeficiency virus (HIV) infection. (9-13) As a result, treatment of latent TB infection is generally recommended for all contacts of active cases of pulmonary TB believed to have been recently infected. (1) Despite the recognized importance of treatment of latent TB infection in TB control, few data describe the proportion of infected contacts who initiate and complete therapy, or how completion of therapy is monitored. This manuscript describes a retrospective evaluation of the initiation and completion of therapy for latent TB infection among contacts of active TB cases identified in 1996 by health departments in parts of five states. A description of contact investigation procedures and results of tuberculin skin test screening for these contac ts has already been described. (14)

METHODS

Study Areas

Five health departments in the United States were selected as study sites from a pool of 11 applicants through a competitive process. Eligibility criteria included (1) reporting [greater than or equal to]50 culture-positive pulmonary TB cases to the Centers for Disease Control and Prevention (CDC) national surveillance system in 1996; (2) a policy in place in 1996 to conduct contact investigations for all infectious tuberculosis cases; and (3) the presence of written records for contact investigations conducted in 1996. Three study sites were large metropolitan areas (sites 1, 2, and 5), one comprised a large metropolitan area and five surrounding counties (site 3), and one comprised 10 counties containing small or medium size cities and surrounding rural areas (site 4).

Study Design

Data were abstracted by study area personnel from existing health department records for 360 culture-positive pulmonary TB cases [greater than or equal to]15 years of age reported to the CDC national surveillance system from the study areas during 1996, and for any identified contact of these cases with a health department record and skin test screening results. A list of contacts identified for each case was made by reviewing case investigation, contact investigation, and contact tuberculin skin test screening records. Standard data collection instruments were used for data abstraction. Since the types of data collected in the course of routine contact investigations varied between study sites, not all of the information was available for all contacts.

Definitions

Close contact. We defined contacts as "close" if they were members, visitors, or workers in the case household, or friends and relatives of the case; "other" if they were workplace, institutional, or public place contacts; and "unknown closeness" if type and place of contact were not specified in the record.

Skin test converter. A contact with a negative tuberculin skin test at the time of initial evaluation (or within the 2-year period before screening, if documented in health department records) and a subsequent positive skin test ([greater than or equal to]5 mm induration and an increase in induration of [greater than or equal to]5 mm compared with the initial test).

Data Analysis

Statistically significant differences in variables were assessed with Mantel-Haenszel chi-square tests or chi-square for trend using Epi-Info software.

RESULTS

Study Population

A total of 2,270 contacts with health department records and tuberculin skin test screening results were identified for the 360 active pulmonary TB cases. Of the contacts, 1,385 (61%) had negative tuberculin skin tests, 232 (10%) had a history of previous TB or positive tuberculin skin test, 23 (1%) had active TB, and 630 (28%) had newly documented positive TB skin tests (121 with skin test conversion and 509 with positive skin tests and no previous test result) and no evidence of active disease. Table 1 presents demographic characteristics of the 630 contacts with newly documented positive skin tests. The median age of these contacts was 37 years and 53% were male.

Treatment Initiation and Completion Rates

Among 630 contacts with newly documented positive skin tests, treatment of latent TB infection was recommended for 71% and not recommended for 16%; recommendation was not documented in health department records for 13%. Among those for whom treatment of latent infection was recommended, it was initiated for 89%, not initiated for 8%, and not documented for 3%. Of those known to have initiated treatment of latent infection, 51% completed a 6-onth course, 22% completed <6 months (median, 3 months; range, 0 to 5 months), and there was no documentation of completion for 27%. Of those known to have initiated treatment of latent infection, 20% received directly observed therapy, 48% did not receive directly observed therapy, and 32% had no documentation of directly observed preventive therapy.

Of the 429 contacts for whom treatment of latent TB infection was either not recommended, not initiated, not completed, or not documented, 67 were skin test converters, 18 others were <15 years of age, 185 others were part of investigations with one or more active TB cases or converters among other contacts of the same case, 111 others were part of investigations with overall transmission rates to contacts [greater than or equal to]25%, 16 were the only contact screened for a given case, and 32 were part of investigations with transmission rates to contacts <25%. Thus, most (>90%) of these contacts appear to have been eligible for therapy on the basis of having newly documented positive skin tests in contact investigation settings where the probability of recent transmission was high or could not be adequately assessed.

Characteristics of Contacts Treated for Latent TB Infection

Table 2 presents the number and proportion of skin test-positive contacts for whom there was written documentation that treatment of latent TB infection was recommended, initiated, and completed. Treatment of latent TB infection was more likely to be recommended for skin test converters, contacts <15 years of age, close contacts, and contacts of smear-positive cases. The proportion of contacts for whom treatment of latent TB infection was documented to have been recommended also increased with increasing skin test induration (in millimeters). Treatment of latent TB infection was equally likely to be recommended for US-born and foreign-born contacts and less likely for contacts whose birthplace was not recorded. Recommendation rates varied widely (from 46% to 83%) by study area. The proportion of contacts documented to have initiated treatment of latent TB infection did not differ significantly by study area, skin test conversion status, age group, birthplace, contact type, or case smear status, but increased with increasing skin test induration.

Documented completion of treatment of latent TB infection was more likely for skin test converters. Therapy was equally likely to be completed for US-born and foreign-born contacts, and less likely for contacts whose birthplace was not recorded. Completion rates varied widely (from 20% to 69%) by study area.

Directly observed treatment of latent TB infection (DOPT) was more likely for skin test converters (36% vs 15%; P< .001), contacts <15 years of age (42% vs 17% for older ages; P< .001), US-born contacts (33% vs 13% for foreign-born vs 13% for unknown birthplace; P < .001 for both comparisons), and contacts of smear-positive cases (21% vs 10%; P< .05). Directly observed treatment was equally likely for close and other contacts (20% and 23%, respectively).

Although persons receiving DOPT were more likely to complete treatment (64% vs 48% for persons not receiving or not documented to be receiving DOPT), this difference was not statistically significant. Compared with contacts not receiving or not documented to be receiving DOPT, DOPT was associated with significantly higher completion rates for contacts <15 years of age (75% vs 47%; P< .05), US-born contacts (75% vs 57%; P< .05), and contacts not residing in the case household (62% vs 45%; P< .05). Although persons of the black race receiving DOPT were more likely to complete treatment (67% vs 52% for those not receiving or documented to be receiving DOT), this difference was not statistically significant. Completion of treatment for latent TB infection was equally likely for foreign-born contacts receiving DOPT (43%) and not receiving DOPT (55%).

Treatment of Latent TB Infection for High-Risk Groups 

Treatment of latent TB infection recommendation and initiation results were also evaluated for 141. contacts <6 years of age (14 with positive skin tests and 127 with negative skin tests done <10 weeks after exposure), a group at high risk for progression of disease. Compared with skin test-negative children, skin test-positive children were more likely to have documentation that treatment of latent TB infection was recommended (93% vs 40%; P< .001). Of these, skin test-positive and skin test-negative children were equally likely to have treatment initiated (100% vs 98%). Of the skin test-negative children, contacts of smear-positive cases and smear-negative cases were equally likely to have documentation that treatment of latent infection was recommended (45% vs 38%).

Among 24 skin test-positive contacts with other risk factors for rapid progression to TB disease (4 with HIV infection and 20 with diabetes mellitus, renal failure, or gastrectomy), 83% had written documentation that treatment of latent TB infection was recommended. Of these, 90% were documented to have initiated treatment. Among these, 44% were documented to have completed [greater than or equal to]6 months of treatment.

DISCUSSION

Achieving high rates of completion of treatment of latent TB infection for recenly infected contacts of active cases of pulmonary TB is essential to maximize public health prevention efforts aimed at eliminating TB. (2) In our study, we found that fewer than one third of all persons with newly documented positive skin tests detected during contact investigations had documentation of completed treatment. Indeed, fewer than one half of contacts with skin test conversions and fewer than two thirds of those less than 15 years of age--groups with a high probability of recent infection, and thus at high risk for progression to TB disease--had written documentation that therapy was completed. These findings have important implications for TB control efforts in the United States.

Based on a 10% lifetime risk of progression to TB disease for immunocompetent persons with TB infection (4) and an expected efficacy for a 6-month course of treatment of latent TB infection of 50% to 100%, (68) approximately 10 to 20 cases of active TB were prevented in our study areas as a result of therapy completion by 201 contacts. If all 630 contacts with newly documented positive skin tests were recently infected, as many as 30 to 60 cases of disease might have been prevented if all had received and completed therapy.

Contact investigations are labor intensive and require significant health department time and resources. (5) These investigations are conducted with two major goals in mind: (1) identifying persons with TB infection among contacts of the index case and (2) finding additional active TB cases within that group so that they can be treated. (3,5) To make these efforts most worthwhile, it is important that all recently infected contacts who are identified receive and complete treatment of latent TB infection as an integral part of the contact investigation process.

Current CDC guidelines state that treatment of latent TB infection should be considered for all infected contacts of TB cases, regardless of birthplace, age, previous BCG vaccine administration, skin test conversion, or other factors. (2,3) In our study, therapy was not recommended for at least 16% (and possibly up to 29%) of infected contacts of infectious TB cases in our study areas. Since this study was retrospective, patients and clinicians were not interviewed to determine why therapy was not recommended. Previous TB infection also results in initial or boosted positive skin test results; thus, there may have been uncertainty about whether certain contacts with no previous skin test results were recently infected. For other contacts, health department risk assessment may have suggested either that the source case was not infectious or that the exposure was too brief for transmission to have occurred. Contacts with smaller diameter skin test induration, those with baseline positive skin tests, contacts of smear-negative TB cases, other than close contacts, and high-risk contacts with initial negative skin tests--ie, groups with a lower likelihood of true or recent infection--were less likely to have documentation that treatment of latent TB infection was recommended. Persons [greater than or equal to] 35 years of age--a group at higher risk of adverse reactions to preventive isoniazid therapy--were also less likely to have therapy recommended. These data suggest that perceptions about the likelihood of true or recent infection and the likelihood of adverse reactions to medication entered into health care providers' decisions to recommend or not recommend therapy, as is appropriate.

In our study, a high proportion of contacts for whom treatment of latent TB infection was documented as having been recommended initiated the therapy (at least 89%). Among skin test-positive contacts who initiated therapy, there was a steady dropout rate throughout the course of therapy, however, and only half of all those who initiated therapy were documented to have completed at least a 6-month course. Although reasons for dropout could not be delineated, the fact that patients who initiated but did not complete therapy received a median of 3 months of therapy--together with the high proportion of contacts who initiated therapy--suggests that recently introduced alternative therapy regimens with shorter durations (such as the 4-month rifampin regimen currently recommended for use in the United States) might be associated with higher completion rates. (15)

In our study, persons with initial positive skin tests and no previous result were less likely to receive treatment of latent TB infection than were persons with documented skin test conversions. Since most contacts have already had extensive exposure at the time a TB case is diagnosed and a contact investigation is conducted, many newly infected contacts will already have a positive skin test at the time of initial screening. Thus, although skin test conversions are more clear-cut evidence of recent infection, in the context of a contact investigation, all contacts with newly documented positive skin tests should be considered potentially recently infected and should be assessed for treatment of latent TB infection. This concept is underscored by data from our study: only 1 in 5 contacts with newly documented positive skin tests had an observed conversion, yet the overall infection rate (30%) was consistent with that reported in the literature for other contact investigations. (14,16-20) Thus, treating only converters could result in failure to treat many newly infected individuals.

Tuberculosis infection cannot be excluded for contacts with negative skin tests until results of skin tests applied at least 10 weeks after last exposure to the case are shown to be negative. (3) Since young children are at high risk for rapid progression to TB disease after infection, the CDC recommends that treatment of latent TB infection be administered to those with initial negative skin tests who are contacts of infectious TB cases until infection has been excluded. In our study, only 40% of skin test-negative contacts <6 years of age with an initial negative skin test <10 weeks after exposure were documented to have received therapy in the so-called "window" period. (3,21) This is of concern and suggests that this public health message needs to be more widely disseminated among health care providers.

Directly observed treatment of latent TB infection (DOPT), first introduced in the early 1990s in the aftermath of the highly successful use of directly observed therapy in TB cases, has now been implemented in a number of settings throughout the United States. (22,23) Although no studies document the effectiveness of this delivery strategy in raising completion rates in treatment of latent TB infection, DOPT is believed by many experts to increase the chances that contacts will complete therapy. (1,9,22,23) Although data from our study did not show a statistically significant difference in completion of treatment of latent TB infection overall for persons who received DOPT compared with those who did not, DOPT was associated with higher completion rates in several contact subsets: children <15 years of age, US-born contacts, and contacts residing outside the case household. Further studies are needed to determine whether DOPT can be an effective means of increasing therapy completion rates in other settings. At present, the only groups for whom the CDC recommends DOPT on a routine basis are contacts receiving intermittent treatment regimens and household contacts of active TB cases receiving home-based directly observed therapy. (9) Improving the utilization of DOPT among young children and other groups at high risk for progression to TB disease may be an important step toward raising therapy completion rates, thus bringing us closer to achieving the goal of TB elimination.

Therapy recommendation and completion data were unknown or missing for a substantial number of skin test-positive contacts in our study. Lack of documentation in health department records of other important contact characteristics such as race/ethnicity and birthplace (each missing for a substantial proportion of skin test-positive contacts) and lower treatment of latent TB infection completion rates among persons for whom information about these characteristics was missing suggest that missing information may have contributed at least in part to our findings of low therapy completion rates in our study areas. Written documentation of adherence to treatment of latent TB infection is essential so that health departments can monitor the effectiveness of their TB prevention programs.

Although individual health departments have described aspects of their program activities in this area, this is the first systematic evaluation of the contact investigation process using the same criteria for a number of health departments. Although the methods and definitions used and the information recorded during contact investigations varied considerably between health departments in our study, our data clearly show that there is much room for improvement in the outcome of contact investigations.

According to findings from this study, ways to improve treatment of latent TB infection completion in the United States may include the following: (1) placing greater emphasis on ensuring completion of therapy for persons with M tuberculosis infection identified during contact investigations; (2) monitoring and maintaining written records of contact adherence to therapy; (3) making further efforts to inform health care providers about the need to recommend treatment of latent TB infection for all infected contacts of TB cases; (4) improving the utilization of DOPT, particularly for groups at high risk for progression to TB disease; and (5) greater use of short-course regimens recommended by the CDC as alternatives to standard course isoniazid therapy for latent TB infection, such as the 4-month regimen of daily rifampin (15) or, when completion of longer treatment courses is unlikely and patients can be closely monitored, the 2-month regimen of daily rifampin and pyrazinamide. (24)

Treatment completion rates are by no means a complete measure of a successful TB prevention program. If large numbers of contacts are either not detected or not completely screened, the true number of infected contacts could greatly exceed the number of identified contacts who were fully screened and found to have a newly documented positive skin test, the denominator used in this study to estimate therapy completion rates. Thus, looking exclusively at therapy completion rates could inaccurately reflect the effectiveness of TB prevention programs.

Further studies are needed to determine the contribution of lack of documentation to the low rates of completion of treatment of latent TB infection shown in our study, and to determine whether the low rates we observed are a nationwide phenomenon or more geographically limited. A limitation of this study was that it was a retrospective chart review on records that were not designed for such a review. Future studies should be prospective and should attempt to delineate reasons for not recommending and not completing a full course of therapy.

Study Group Members. Centers for Disease Control and Prevention: Ken Dansbury, AA; Denver Public Health: Patty Calixto, RN, and Mohammed Malakouti, BS; Maryland Department of Health and Mental Hygiene: Nancy Baruch, RN, MBA, and Deirdre Thompson, RN; Massachusetts Department of Public Health: Janice Boutotte, RN, Denise O'Connor, RN, and Sue Etkind, RN; Mississippi State Department of Health: J. M. Holcombe, BS, and Ann Jackson, RN; New Jersey Department of Health and Senior Services: Ken Shilkret, MA, and Janet de Graaf, MPA; and New Jersey Medical School National Tuberculosis Center: Mark Wolman, MPH, Sandy Barnes, RN, and Eileen Napoliatano, BA.

TABLE 1

Characteristics of 630 Contacts Who Had Newly Documented Positive
Tuberculin Skin Tests

Characteristic     No. (%)

Age group (years)

  <15               52 (8)
  15-34            221 (35)
  >35              330 (52)
  Unknown           27 (5)

Sex

  Male             333 (53)
  Female           259 (41)
  Unknown           38 (6)

Race/ethnicity

  White             97 (15)
  Black            197 (31)
  Asian             68 (11)
  Hispanic          77 (12)
  Other              9 (2)
  Unknown          182 (29)

Birthplace

  US               175 (28)
  Foreign-born     149 (24)
  Unknown          306 (48)
TABLE 2

Treatment of Latent TB Infection (LTBI) for 630 Contacts With Newly
Documented Positive Tuberculin Skin Tests (TSTs) (*)

                                                Percent Contacts


                                  No.        LTBI          LTBI
Characteristic                  Contacts  Recommended  Initiated (+)

Skin test status

  TST converter                   121         80 (ss)       92
  Initial TST positive            509         69            88

Age group (yr) (II)

  <15                              52         98 (ss)       94
  15-34                           221         82            90
  >35                             330         63            86

Birthplace

  US-born                         175         82            92
  Foreign-born                    149         87            87
  Unknown                         306         57 (ss)       87

Type of Contact

  Close                           280         89 (ss)       92
  Other                           275         57            85
  Unknown                          75         57            86

Case smear status (II)

  Smear positive                  476         73 (ss)       88
  Smear negative                  123         59            86

Skin test size (mm) (II)

  5-9                              42         64            85
  10-19                           400         74            88
  [greater than or equal to]20    158         84 (n)        95 (n)

Study area

  1                               109         62            85
  2                                91         46            98
  3                               194         76            87
  4                               130         83            87
  5                               106         77            91

                                    Percent Contacts

                                   [greater than or
                                equal to]6 months LTBI
Characteristic                      Completed (++)

Skin test status

  TST converter                           61 (ss)
  Initial TST positive                    48

Age group (yr) (II)

  <15                                     63
  15-34                                   47
  >35                                     53

Birthplace

  US-born                                 62
  Foreign-born                            54
  Unknown                                 38 (ss)

Type of Contact

  Close                                   55
  Other                                   49
  Unknown                                 30 (ss)

Case smear status (II)

  Smear positive                          49
  Smear negative                          48

Skin test size (mm) (II)

  5-9                                     48
  10-19                                   53
  [greater than or equal to]20            47

Study area

  1                                       69
  2                                       20
  3                                       59
  4                                       51
  5                                       39

(*)Percent with indicated characteristic documented in health department
records.

(+)Among those for whom treatment of latent TB infection was
recommended.

(++)Among those for whom treatment of latent TB infection was initiated.

(II)Denominators sometimes differed because information for these
variables was incomplete for some contacts.

(ss)P<.05 compared with other groups.

(n)P<.05 on chi-square for linear trend.

(*.) Study group members are listed after the text.

References

(1.) American Thoracic Society, American Academy of Pediatrics, Centers for Disease Control and Prevention, Infectious Diseases Society of America: Control of tuberculosis in the United States. Am Rev Respir Dis 1992; 146:1623-1633

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(7.) Comstock GW, Baum C, Snider DE: Isoniazid prophylaxis among Alaskan Eskimos: a final report of the Bethel isoniazid studies. Am Rev Respir Dis 1979; 119:827-830

(8.) Snider DE, Caras GJ, Koplan JP: Preventive therapy with isoniazid. cost-effectiveness of different durations of therapy. JAMA 1986; 255:1579-1583

(9.) Centers for Disease Control and Prevention: Prevention and treatment of tuberculosis among patients infected with human immunodeficiency virus: principles of therapy and revised recommendations. MMWR Morb Mortal Wkly Rep 1998; 47(No. RR-20):18-22

(10.) Whalen CC, Johnson JL, Okwera A, et al: A trial of three regimens to prevent tuberculosis in Ugandan adults infected with the human immunodeficiency virus. N Engl J Med 1997; 337:801-808

(11.) Gordin F, Chaisson R, Matts J, et al: A randomized trial of 2 months of rifampin (RIF) and pyrazinamide (PZA) versus 12 months of isoniazid (INH) for the prevention of tuberculosis (TB) in HIV-positive (+), PPD+ patients (PTS) (Abstract). Fifth Conference on Retroviruses and Opportunistic Infections. Chicago, Ill, 1998

(12.) Halsey NA, Coberly JS, Desormeaux J, et al: Randomized trial of isoniazid versus rifampicin and pyrazinamide for prevention of tuberculosis in HIV-1 infection. Lancet 1998; 351:786-792

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(17.) Snider DE, Kelly GD, Cauthen GM, et al: Infection and disease among contacts of tuberculosis cases with drug-resistant and drug-susceptible bacilli, Am Rev Respir Dis 1985; 132:125-132

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RELATED ARTICLE: KEY POINTS

* In a study in five US states, we found that fewer than one third of all contacts to infectious tuberculosis cases with newly detected latent tuberculosis infection were documented to have completed treatment.

* The Centers for Disease Control and Prevention recommends that treatment of latent tuberculosis infection be administered to all young children who are contacts to infectious tuberculosis cases until infection has been excluded.

* Achieving high rates of completion of treatment of latent tuberculosis infection for recently infected contacts to infectious tuberculosis cases is essential to maximize public health prevention efforts aimed at eliminating tuberculosis.

From the Division of Tuberculosis Elimination, National Center for HIV, STD, and TB Prevention, Centers for Disease Control and Prevention, Atlanta, Ga; Denver Public Health, Denver, Colo; the Maryland Department of Health and Mental Hygiene, Baltimore; the Massachusetts Department of Public Health, Jamaica Plain; the Mississippi State Department of Health, Jackson; the New Jersey Department of Health and Senior Services, Trenton; and the New Jersey Medical School National Tuberculosis Center, Newark.

Reprint requests to Mary R. Reichler, MD, Centers for Disease Control and Prevention, Mailstop E-10, DTBE, 1600 Clifton Rd, Atlanta, GA 30333.