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Tuberculin Skin Test Survey in a Pediatric Population with High BCG Vaccination Coverage -- Botswana, 1996

Tuberculosis (TB) causes more deaths worldwide than any other infectious disease: in 1995, TB caused an estimated 3 million deaths, of which 170,000 (6%) occurred among children aged less than 15 years (1,2). Diagnosing TB in children often is difficult and relies on clinical judgement and use of algorithms that include chest radiography and the tuberculin skin test (TST). However, interpretation of TST reactivity can be complicated by many factors other than infection with Mycobacterium tuberculosis. For example, previous Bacille Calmette-Guerin (BCG) vaccination or exposure to nontuberculous mycobacteria can result in positive TST reactions indistinguishable from those caused by M. tuberculosis (3). In contrast, such factors as human immunodeficiency virus (HIV) infection, poor nutritional status, and recent viral or bacterial infections or vaccination with live virus can reduce response to the TST (4). To assess the use of the TST for diagnosing pediatric TB in a population with high BCG coverage, a TST survey was conducted during July-August 1996 among children aged 3-60 months in Botswana (1991 population: 1.3 million) (Figure_1). The findings indicate that most positive TSTs (induration greater than or equal to 10 mm) among children in Botswana can be attributed to TB infection rather than previous BCG vaccination and that the TST remains useful for diagnosing pediatric TB in Botswana.

The rate of TB in Botswana in 1996 was high (444 cases per 100,000 population) compared with that in the United States (eight per 100,000), and approximately 90% of children in Botswana are vaccinated at birth with BCG. This survey and analysis assessed the prevalence of and risk factors for a positive TST reaction (e.g., BCG vaccination, crowding, symptoms of TB, and exposure to persons with TB) and the potential associations between TST reactivity and recent measles vaccination or oral poliovirus vaccination and poor nutritional status.

A multistage cluster survey was conducted in two urban and two rural districts using a modification of the Expanded Program on Immunization method (5). The survey protocol was approved by the institutional review boards of CDC and the Health Research Development and Ethical Committee of the Botswana Ministry of Health. After obtaining informed consent from a parent or guardian, a questionnaire was administered to the parent or guardian of eligible children aged 3-60 months, and the child's vaccination card was reviewed, weight and height were obtained, and arms were examined for a BCG scar. Study nurses then administered 0.1 cm3 of RT23 tuberculin intradermally (equivalent to 5 tuberculin units of purified protein derivative-standard, Mantoux method). Induration was measured independently by two study nurses at 48-72 hours, and an average of these two readings was used in data analysis (mean inter-reader variability was less than 0.3 mm). Data were weighted to account for the probability of selection. Comparisons and associations between categorical variables were evaluated using the chi-square test, and prevalence rate ratios (PRRs) with 95% confidence intervals (CIs) were calculated by the Mantel-Haenszel method.

Of the 1593 households visited, an adult occupant was contacted in 1484 (93%); at least one child aged 3-60 months was identified in 691 (47%) of these households. An adult respondent in 620 (90%) of the 691 households (representing 821 eligible children) agreed to allow at least one child to participate in the study. TSTs were administered to and read for 783 (95%) of the 821 children. The median age of participants was 28 months; 53% were female. The TSTs for the 783 children yielded indurations of zero for 617 (79%) children, 1-9 mm for 108 (14%), 10-14 mm for 43 (5%), and greater than or equal to 15 mm for 15 (2%) (range: zero to 21 mm). Of the 724 children for whom vaccination cards were available, 721 had received BCG vaccine; BCG scars were observed in 524 (73%) children with documented BCG vaccination and in 34 (58%) without vaccination cards.

Children with BCG scars were twice as likely as those without scars to have a TST reaction greater than or equal to 5 mm (95% CI=1.4-2.7); however, the rate of TST positivity (at the 10-mm cutoff) did not differ significantly between those with and without BCG scars (PRR=1.6, 95% CI=0.9-2.9) (Table_1). The prevalence of a positive TST was greater among children with reported contact with any person with active TB than among those without reported contact (PRR=1.9, 95% CI=1.0-3.6). In addition, the prevalence was greater among children with reported contact with a mother (PRR=5.1, 95% CI=2.1-12.4) or aunt (PRR=5.3, 95% CI=2.0-14.0) with TB than among those without any reported contact. The prevalence of TST positivity increased directly with the number of reported TB contacts (chi-square test for trend=0.03). TST positivity was not associated with other factors (e.g., age, interval since BCG vaccination, nutritional status, district, household crowding, or receipt of measles or oral poliovirus vaccine during the preceding 2 months). Although nine children had received anti-TB treatment previously, laboratory confirmation of TB disease in these children was not available; of these nine, TSTs were positive for two (among those with history of TB treatment, the PRR for positive TST was 3.2, 95% CI=1.3-8.0).

Reported by: D Rumisha, MPH, Communicable Diseases Section, Ministry of Health, Botswana; J Baratedi, N Chimidza, C Hirschfeld, M Reed, M Notha, J Phatshwane, M Makhoha, K Mudongo, A Mahala Oteng, L Clay, V Nkwe, R Muzila, MA, T Mavunga, BOTUSA TB Project, Gaborone, Botswana. International Activities Br, Div of Tuberculosis Elimination, National Center for HIV, STD, and TB Prevention, CDC.

Editorial Note

Editorial Note: The increasing rates of reported TB in many countries in which BCG is administered underscore the importance of judicious interpretation of TSTs in children who have received BCG (6). In the United States, this consideration is important for many health-care workers who must interpret TSTs in BCG vaccinees, even though BCG vaccine is not administered in the United States. For example, TSTs are frequently administered to assist in contact tracing and screening efforts among foreign-born persons in the United States; in 1996, foreign-born persons accounted for 36% of all U.S. TB cases, and many of these persons had received BCG (7,8).

WHO recommends BCG vaccination of infants in countries with high TB rates, and an estimated 71% of infants worldwide born in 1989 received BCG. Mean TST size in BCG-vaccinated children varies with factors including the strain and dose of BCG used, interval since vaccination, number of BCG vaccinations administered, subsequent TST placement, and age and nutritional status of the child at the time of vaccination; previous reports indicate the mean size of induration in such children may range from 3 mm to 18 mm (9). In addition, previous studies indicate that TST induration attributed to BCG cross-reactivity decreases with increasing time since BCG administration (10) and that BCG efficacy does not correlate with postvaccination TST induration (9).

The findings of this survey suggest that, in Botswana, a TST with induration greater than or equal to 10 mm can be attributed to TB infection rather than previous BCG vaccination. Of 783 children studied, 617 (79%) had zero reactivity after a TST, indicating that BCG vaccination did not result in TST induration in most study participants. The higher prevalence of positive TST reactions in children who had a reported TB contact and the direct relation between positivity and increasing number of TB contacts suggests that the positive reactions probably resulted from infection with M. tuberculosis rather than BCG vaccination. In addition, presence of a BCG scar was not associated with a positive TST, and TST size did not vary inversely with age, suggesting the continued usefulness of TST for diagnosing pediatric TB in Botswana.

Factors potentially causing false-negative TSTs in this study included HIV seropositivity, altered potency of the tuberculin agent, and malnutrition. However, in Botswana, an estimated 7% of children aged 3-60 months are HIV-positive, which would not account for the large proportion of children with an induration of zero. In addition, the potency of the tuberculin used in the study was confirmed at the Statens Serum Institute in Copenhagen, Denmark. Finally, poor nutritional status (based on low height-for-age and weight-for-weight Z scores) was not associated with TST negativity.

Although BCG vaccination can cause a TST reaction that is indistinguishable from reactivity caused by M. tuberculosis infection, a history of BCG vaccination is not a contraindication to skin testing (10). Factors associated with an increased probability that a positive TST reaction is caused by M. tuberculosis infection rather than BCG vaccination include 1) large reaction size; 2) history of previous contact between the reactive person and a patient with TB; 3) a family history of TB; 4) country of origin with a high prevalence of TB; and 5) longer interval between BCG vaccination and TST administration (10). Health-care workers should be encouraged to use the TST in pediatric TB diagnosis and in screening high-risk populations for tuberculous infection, even in persons who have received BCG vaccine.

References

  1. Dolin PJ, Raviglione MC, Kochi A. Global tuberculosis incidence and mortality during 1990-2000. Bull World Health Organ 1994;72:213-20.

  2. World Health Organization. Groups at risk: WHO report on the tuberculosis epidemic. Geneva, Switzerland: World Health Organization, 1996.

  3. Edwards LB, Acquaviva FA, Livesay VT, Cross FW, Palmer CE. An atlas of sensitivity to tuberculin, PPD-B, and histoplasmin in the United States. Am Rev Respir Dis 1969;99(suppl):S1-S132.

  4. Huebner RE, Schein MF, Bass JB Jr. The tuberculin skin test. Clin Infect Dis 1993;17:968-75.

  5. Turner AG, Magnani RJ, Shuaib M. A not quite as quick but much cleaner alternative to the Expanded Programme on Immunization (EPI) Cluster Survey design. Intern J Epidemiol 1996;25:198-203.

  6. Global Tuberculosis Program, World Health Organization. Global tuberculosis control: WHO report, 1997. Geneva, Switzerland: World Health Organization, 1997; publication no. WHO/TB/97.225.

  7. Zuber PLF, McKenna MT, Binkin NJ, Onorato IM, Castro KG. Long-term risk of tuberculosis among foreign-born persons in the United States. JAMA 1997;278:304-7.

  8. CDC. Reported tuberculosis in the United States, 1996. Atlanta, Georgia: US Department of Health and Human Services, Public Health Service, CDC, July 1997.

  9. CDC. Use of BCG vaccines in the control of tuberculosis: a joint statement by the ACIP and the Advisory Committee for Elimination of Tuberculosis. MMWR 1988;37:663-4,669-75.

  10. CDC. Screening for tuberculosis and tuberculosis infection in high-risk populations: recommendations of the Advisory Council for the Elimination of Tuberculosis. MMWR 1995;44(no. RR-11):3-17.



    1. Figure_1

      Figure_1
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      Table_1
      Note: To print large tables and graphs users may have to change their printer settings to landscape and use a small font size.
      
      TABLE 1. Tuberculin skin test (TST) positivity among children aged 3-60 months, by study characteristics -- Botswana, July-August 1996
      ===================================================================================================================================================
                                                                     Sample size (n=783)               Positive TST (induration >=10mm)
                                                                 -------------------------    ------------------------------------------------------
      Characteristic                                              No.                  (%)    No.               (%)   PRR+    (95% CI &)   p value @
      ---------------------------------------------------------------------------------------------------------------------------------------------------
      Sex
       Male                                                       367                 (47)    30               ( 8)    1.2    (0.8-1.8)       0.05
       Female                                                     416                 (53)    28               ( 7)          (Referent)
      Bacille Calmette-Guórin (BCG) status**
       Vaccinated                                                 721                 (92)    56               ( 8)    2.7    (0.9-8.4)       0.05
       Not vaccinated                                              62                 ( 8)     2               ( 3)          (Referent)
      BCG scar
       Yes                                                        558                 (71)    46               ( 8)    1.6    (0.9-2.9)       0.05
       No                                                         223                 (29)    12               ( 5)          (Referent)
      Measles vaccination during the preceding 2 months
       Yes                                                        228                 (29)    14               ( 6)    0.8    (0.4-1.4)       0.05
       No                                                         555                 (71)    44               ( 8)          (Referent)
      Oral poliovirus vaccination during the preceding
      2 months
       Yes                                                        410                 (52)    27               ( 7)    0.7    (0.3-1.5)       0.05
       No                                                         373                 (48)    31               ( 8)          (Referent)
      Any symptoms suggestive of tuberculosis++
       Yes                                                        353                 (45)    26               ( 7)    1.0    (0.6-1.6)       0.05
       No                                                         430                 (55)    32               ( 7)          (Referent)
      Height-for-age Z score <=2 &&
       Yes                                                        106                 (14)     9               ( 8)    1.3   (0.7- 2.2)       0.05
       No                                                         677                 (86)    49               ( 7)          (Referent)
      Weight-for-height Z score <=2 &&
       Yes                                                         47                 ( 6)     3               ( 6)    0.9   (0.3- 2.6)       0.05
       No                                                         736                 (94)    55               ( 7)          (Referent)
      Age group (mos)@@
        3-12                                                      136                 (17)     9               ( 7)    1.1   (0.4- 2.6)       0.05
       13-24                                                      190                 (24)    16               ( 8)    1.4   (0.6- 3.0)       0.05
       25-36                                                      158                 (20)    12               ( 8)    1.2   (0.5- 2.8)       0.05
       37-48                                                      152                 (20)    12               ( 8)    1.3   (0.6- 2.9)       0.05
       49-60                                                      145                 (19)     9               ( 6)          (Referent)
      TB contact***
       None                                                       690                 (88)    46               ( 7)          (Referent)
       Any                                                         93                 (12)    12               (13)    1.9   (1.0- 3.6)       0.02
         Mother                                                    12                 ( 2)     4               (33)    5.1   (2.1-12.4)      <0.01
         Father                                                     3                 (<1)     1               (33)    4.6   (0.9-25.2)       0.05
         Sibling                                                    5                 ( 1)     0                 --           Undefined
         Aunt                                                      11                 ( 1)     4               (36)    5.3   (2.0-14.0)      <0.01
         Grandmother                                               23                 ( 3)     4               (17)    2.5   (1.0- 6.3)       0.05
      ---------------------------------------------------------------------------------------------------------------------------------------------------
      *   Study participants include only children who had TSTs read. Two categories (scar and age) contain information on only 781 patients because of
          missing data.
      +   Prevalence rate ratio is the rate of TST positivity among children with the characteristic  compared with the rate of TST positivity among
          children without the characteristic.
      &   Confidence interval.
      @   p values are nonweighted; PRRs and corresponding Cis are weighted.
      **  Only considered "vaccinated" if this was documented on a vaccination card. If vaccination card was not available, the child was counted as
          "unvaccinated."
      ++  Cough, fever, or enlarged glands, as reported by the child's parent or guardian.
      &&  Z scores,  or standard deviation (SD) units, have  a normal distribution and SD of 1. Z scores that are at least 2 SD  unitsbelow the
          reference median indicate malnutrition. Low height- for- age indicates chronic malnutrition, whereas low weight- for-  height Z scores
          suggest acute malnutrition or illness.
      @@  PRRs and corresponding Cis for age compare the rate of TST positivity among children of  thespecific age group with the rate of TST positivity
          among the children with the lowest rate of TST positivity (i. e., those aged 49- 60 months). The PRRs for age are  nonweighted.
      *** The referent population is comprised of children for whom no TB contact was reported. PRRs for TB contact represent the ratio of  the risk for
          TST positivity among children with the contact to the rate of TST positivity among children without any TB contact.
      ===================================================================================================================================================
      

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