Tubrculosis: Latent TB Infection (LTBI) or reactivated TB.

Case 1. A 12-year-old boy was brought to the OPD of the Department of MEdicine in a large urban center serving low-income group patients with the facility being funded by the government. It was attached to a medical college as it’s teaching hospital. He had been running a fever of 99-101 degrees for 5 weeks. He came from a small town about a hundred miles away where medical facilities were available but were rudimentary. The boy had been adopted by the father’s elder brother who was a low income farmer but sent the boy to school and had taken him to several doctors during this time. The boy’s natural father lived in the city and had a well running business and he had decided to bring the boy back to his own home. The boy had received artemether for malaria and ciproxin for typhoid fever but continued to run fever. The boy had been given the BCG vaccine at 3 days of age but despite that had developed tuberculosis at the age of 18 months.His adoptive mother had smear positive TB and was also given treatment for 9 months. He received 3 drug therapy for 9 months, became healthy , put on weight and was active and kept up with other children of his age in physical and mental activities. There was no record of his weight and height in his childhood. He was admitted for observation, diagnosis and treatment. No antibiotics were started. He had a mild dry cough, no breathlessness and moderate pain in the left lower part of his abdomen but his bowel habits were normal and there was no dysuria. He was intelligent and cooperative but looked tired and exhausted, was not dehydrated, anemic or jaundiced. His weight was 28 kg, height 4 ft 10 in. Pulse rate was 110/min, temperature 99.4 degrees, BP was 85/60 mm Hg, respiratory rate 16/min. He had no palpable peripheral lymph nodes, the thyroid was not enlarged, JVP was not raised: there was no edema. The lungs were clear and there was no evidence of a pleural effusion. The examination of the heart was unremarkable. The abdomen was not distended, there was no shifting dulness, the edge of the liver was palpable and the spleen was not palpable. Neither kidney was tender or palpable. There was a mild tenderness in the left iliac fossa bot no guarding or a palpable mass. The joints were not swollen or painful and there were no skin lesions. The neurological examination was unremarkable.

  1. Why did this boy get tuberculosis after receiving the BCG vaccine?
  2. Should we give the other family contacts a BCG vaccine?
  3. Why is he likely to have TB and which type of tuberculosis is he likely to have?
  4. How can we investigate this boy for likely reactivated TB tuberculosis now?
  5. Should his adoptive mother be tested for activation of latent tuberculosis?

BCG vaccine does not provide 100% protection from all forms of tuberculosis. BCG vaccine is offered to new-born babies in many countries with a high prevalence of TB like Pakistan and India to prevent childhood tuberculous meningitis and miliary disease. Despite receiving BCG vaccine there is a 6 to 10% incidence of tuberculosis varying from region to region. In many countries like the USA and UK  BCG is not generally recommended for use in infants because of the low risk of infection with Mycobacterium tuberculosis, the variable effectiveness of the vaccine against adult pulmonary TB, and the vaccine’s potential interference with tuberculin skin test reactivity.

The BCG vaccine is not offered to the adult population of countries where the prevalence of the disease is high because it does not prevent adult pulmonary tuberculosis.

Reference for this recommendation is The Bulletin of the World Health Organization, 57 (5): 819-827 (1979).

Trial of BCG vaccines in south India for tuberculosis prevention: first report

TUBERCULOSIS PREVENTION TRIAL 1
The protective effect of BCG vaccination is being evaluated in a controlled community
trial near Madras in south India. After tuberculin and sensitin testing and radiographic and bacteriological examinations, BCG vaccines and placebo were allocated randomly to about 260 000 individuals, of whom 115 000 were definitely tuberculin negative at the time of vaccination. Intensive efforts are being made, by means of regular follow-up surveys, to identify all new cases of tuberculosis occurring in the community. This report presents the findings of the first 7* years of follow-up. Incidence of infection was high in the study population. However, incidence of bacillary disease was more frequent among initial tuberculin reactors, especially among the older persons, than among non-reactors of whom the majority were in the younger age groups. The distribution of new cases of bacillary tuberculosis among those not infected at intake did not show any evidence of a protective effect of the BCG vaccines in the 7 1/2 years of the follow-up period.
The BCG vaccine is offered to a very select group of  persons who meet specific criteria and in consultation with a TB expert e.g. children of parents living in areas where the prevalence of TB is high, to health care workers etc.

Recommendation in high prevalence areas like India, Pakistan, Bangladesh is that all infants should be given BCG vaccine within the first three days of birth.

Recommendations in low prevalence areas

Children. BCG vaccination should only be considered for children who have a negative tuberculin skin test and who are continually exposed, and cannot be separated from, adults who

  • Are untreated or ineffectively treated for TB disease (if the child cannot be given long-term treatment for infection); or
  • Have TB caused by strains resistant to isoniazid and rifampicin.

Health Care Workers. BCG vaccination of health care workers should be considered on an individual basis in settings in which

  • A high percentage of TB patients are infected with M. tuberculosis strains resistant to both isoniazid and rifampicin;
  • There is ongoing transmission of such drug-resistant M. tuberculosis strains to health care workers and subsequent infection is likely; or
  • Comprehensive TB infection-control precautions have been implemented, but have not been successful.

Health care workers considered for BCG vaccination should be counseled regarding the risks and benefits associated with both BCG vaccination and treatment of Latent TB Infection (LTBI).

Contraindications

Immunosuppression. BCG vaccination should not be given to persons who are immunosuppressed (e.g., persons who are HIV infected) or who are likely to become immunocompromised (e.g., persons who are candidates for organ transplant).

Pregnancy. BCG vaccination should not be given during pregnancy. Even though no harmful effects of BCG vaccination on the fetus have been observed, further studies are needed to prove its safety.

Testing for TB in BCG-Vaccinated Persons

The tuberculin skin test (TST) and blood tests to detect TB infection are not contraindicated for persons who have been vaccinated with BCG but the TST is likely to give a false positive result.

TB Blood Tests. Blood tests to detect TB infection, unlike the TST, are not affected by prior BCG vaccination and are less likely to give a false-positive result.

 

Standards for testing and treatment are defined below in the WHO recommendations.

The guidelines recommend that either tuberculin skin test or interferon gamma release assays (IGRA) can be use to test for latent TB in high-income and upper middle-income countries with estimated TB incidence less than 100 per 100 000. “Currently, these are the only diagnostic tests available though they are both weak in predicting future development of TB among infected. Development of better diagnostic tools should be priority for research’ said Dr Alberto Matteelli, Medical officer from the TB/HIV and community engagement unit. Consistent with existing WHO recommendations, the guidelines reiterated that interferon gamma release assays should not replace tuberculin skin test in low-income and other middle-income countries.

What are the chances that this boy and his adoptive mother are false positive for tuberculosis?

In most individuals, Mycobacterium tuberculosis infection is contained initially by host defenses, and infection remains latent or is cleared. However, latent infection has the potential to develop into active disease at any time. Identification and treatment of LTBI  (Latent TB Infection) can reduce the risk of development of disease by as much as 90 percent and so has the potential to protect the health of the individuals as well as the public by reducing the number of potential sources of infection.

Since 1988, The World Bank has supported a series of studies (“Health Sector Priorities Review”) on the public health importance of clusters of certain diseases in the developing world and on the costs and effectiveness of technologies for prevention and management of these diseases. Since the 1940s, the number of cases and deaths from tuberculosis (TB) has been decreasing in most developed countries; in developing countries, however, TB remains a major problem. This report summarizes findings of The World Bank’s evaluation of TB in developing countries.

The Average Annual Risk of TB Infection (ARI)

Because reporting of cases and deaths in developing countries is incomplete, for this analysis the burden of TB was estimated indirectly using data on the average annual risk of TB infection (ARI)* (i.e., the probability that any person will be infected or reinfected with Mycobacterium tuberculosis in 1 year), the incidence of sputum smear-positive pulmonary TB, the proportion of all cases of TB that are smear-positive, and case-fatality rates for smear-positive TB and other TB. The ARI is highest in sub-Saharan Africa (1.5%-2.5%) and Asia (1.0%-2.0%). In comparison, the ARI in the Netherlands in 1985 was estimated at 0.012% .

Prevention of TB by Treating Latent TB.

Although clinical TB can be secondarily prevented by treating persons with latent tuberculous infection, mass chemoprophylaxis of all such persons cannot be efficiently or economically accomplished. However, selective treatment of high-risk groups (e.g., close family contacts of smear-positive sources) may be feasible. If proven effective in clinical trials, chemoprophylaxis might also play an important role in preventing clinical TB in persons with dual human immunodeficiency virus (HIV) and tuberculous infections.

Reference. Murray CJL, Styblo K, Rouillon A. Tuberculosis in developing countries: burden, intervention, and cost. Bull Int Union Tuberc Lung Dis 1990;65:6-24.

Five treatment options are recommended for the treatment of LTBI in the guidelines:

  • isoniazid daily for 6 or 9 months,
  • the combination of rifapentine and isoniazid once a week for 12 weeks,
  • the combination of rifampicin and isoniazid daily for 3-4 months,
  • rifampicin alone daily for 3-4 months.

The reason that the boy in the case got tuberculosis at the age of 18 months was because he got a high dose of bacterial infection from his sputum positive adoptive mother. The BCG provided imperfect protection. Without the BCG vaccine his chance of developing TB was 50% and with the vaccine about 10%. He should have received prophylactic treatment with at least 2 drugs preferably three drugs,

The risk of disease in the first two years following infection is age dependent. The decline of risk with increasing age reflects greater innate and acquired immunity:

  • Infants (ages ≤1 year): 50 percent
  • Children (ages 1 to 2 years): 12 to 25 percent
  • Children (ages 2 to 5 years): 5 percent
  • Children (ages 5 to 10 years): 2 percent
  • Age >10 years: 1 to 2 percent

The answer to question no 3 is that although this boy was given 3 drug therapy at the age of 18 months and appeared to recover is that he was infected with mostly bacilli that were susceptible to the therapy, however some of the bacilli which were resistant did not die but became dormant because of his increasing innate immunity. They got reactivated because for some reason his immunity reduced i.e some other illness or poor nutrition or he got a fresh dose of bacilli which are likely to be resistant. To answer the next question he is likely to have multi drug resistant TB hence should have a proper culture and sensitivity test done and a diagnosis should not be made only on TST and IGRA and an X-ray chest.His adoptive mother should also be investigated for latent TB and if possible material should be obtained for culture and sensitivity, If she is found to have disease activity she should be treated as MDX TB.

INDICATIONS FOR LTBI (LATENT TB INFECTION) TESTING.

  •  Individuals at risk for new infection due to tuberculosis exposure
  • Individuals with LTBI who are at increased risk of reactivation (ie, progression to active disease) due to underlying condition

Circumstances in which neither TST nor IGRAs should be used include:

  • Testing individuals who have a low risk of infection and a low risk of progression to active TB disease if they are infected. However, low-risk individuals are commonly tested before exposure, when repeat testing is likely. In this situation, TST is recommended (discussed under the third heading below); if the TST is positive, then an IGRA may be useful to confirm a positive TST result to enhance specificity.
  • Diagnosis of active TB
  • Routine or mass screening for LTBI of immigrants
  • Monitoring treatment response to antituberculous therapy

Individuals for whom IGRAs are preferred for testing (but TST is acceptable) include:

  • Individuals who received BCG as a vaccine after one year of age and/or have received BCG vaccination more than once
  • Individuals from groups that have historically poor rates of return for TST reading (such as homeless individuals or illicit drug users)

The TST is recommended for testing (and an IGRA is NOT acceptable) for circumstances in which repeat testing is planned to assess for risk of new infection (ie, conversions); examples include repeat in a contact investigation or serial testing of individuals with potential for ongoing exposure (such as health care workers, corrections staff, or prison inmates).

Routine dual testing with both TST and IGRA is not warranted.

 

 

 

 

 

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shaheenmoin

I am a Professor of Medicine and a Nephrologist. Having served in the Army Medical College, Pakistan Army for 27 years I eventually became the Dean and Principal of the Bahria University Medical and Dental College Karachi from where I retired in 2016. My passion is teaching and mentoring young doctors. I am associated with the College of Physicians and Surgeons Pakistan as a Fellow and an examiner. I find that many young doctors make mistakes because they do not understand how they should answer questions; basically they do not understand why a question is being asked. My aim is to help them process the information they acquire as part of their education to answer questions, pass examinations and to best take care of patients without supervision of a consultant. Read my blog, interact and ask questions so that I can help you more.

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