Latent tuberculosis

1/4 of the worlds population is infected with mycobacterium tuberculosis, the causative agent of tuberculosis.

In 2020 the US tuberculosis incidence was 2.2 per 100,000 persons.

Approximately 13 million people in the US have latent tuberculosis infection.

Approximately 30% of persons exposed to mycobacterium tuberculosis will develop latent TB infection, and if left untreated, approximately 5 to 10% of healthy  immunocompetent persons will progress to have active tuberculosis disease.

Latent TB occurs when a person has the TB bacteria within their body, but the bacteria are present in very small numbers.

Latent tuberculosis is defined as people who are infected with mycobacterium tuberculosis, who do not have symptoms and do not transmit the disease.

Without treatment approximately 5 to 10% of immunocompetent persons with latent tuberculosis infection develop active TB in their lifetimes.

They are kept under control by the body’s immune system and do not cause any symptoms.

Latent tuberculosis infection is a state of persistent immune response to stimulation by M.Tuberculosis antigens without evidence of clinically manifested active tuberculosis and with bacillary replication absent or below some undefined threshold as a result of immunologic control.

Latent TB is one of the two types of TB.

The other type is TB disease.

This is sometimes known as active TB.

People with latent TB do not feel sick and are not infectious.

They cannot pass the TB bacteria on to other people.

In addition they will usually have a normal chest x-ray and a negative sputum test.

Most patients with latent tuberculosis infection never become sick with tuberculosis, however 5-15% may progress to tuberculous disease.

Tuberculosis disease results from bacterial replication and induces tissue damage and inflammation, which lead to clinical manifestations.

Common signs and symptoms of tuberculosis include: fever, sweats, fatigue, and weight loss as well as cough if the lungs are affected.

Tuberculosis can involve any tissue an organ system with diverse manifestations.

Latent tuberculosis is a reservoir for incident tuberculosis disease.

Infection with tuberculosis requires previous exposure to someone with tuberculosis disease.

In addition for a person to be infected with M tuberculosis, the risk of progression to tuberculosis  disease is determined by their immune competence and the time since initial infection.

It is often only known that someone has latent TB because they have had a TB test, such as the TB skin test.

Testing for latent TB

There are two types of test that can be used.

These are the TB skin test (TST) and the newer IGRA blood test.

In countries where there is a high level of TB (such as the high burden TB countries) the majority of people may have latent TB.

Interferon gamma release assays (IGRAs) and tuberculin skin testing provide indirect assessment of infection through detection of cell mediated immune responses to stimulation by M. Tuberculosis antigens.

These test cannot discriminate latent tuberculosis from tuberculosis disease and cannot be used to monitor treatment efficacy because immunological response is detected by the test so long lasting, even after effective treatment.

Guidelines give preference to the use of IGRAs in adults and older children, but tuberculin skin test are considered acceptable.

IGRAs  or more specific than tuberculin skin testing for the detection M. Tuberculosis infection

BCG vaccination can cause a positive tuberculin skin test owing to shared antigenic components, although the effect is minimal after 10 years or more after vaccination.

IGRAs results are unaffected by previous BCG vaccination.

IGRA testing has the sensitivity of approximately 90%, whereas the tuberculin skin test is approximately 80%.

Host immunocompromise status can  be associated with falsely negative skin test and IGRA results.

At risk individuals for IGRA assay include those with TB endemic regions and those who are immunocompromised or are starting on immunosuppressive medication, such as tumor necrosis factor antagonists with systemic corticosteroids at a dose of at least 15 mg of prednisone per day, or take immunosuppressive drugs after organ transplant.

Latent TB treatment

It is not recommended that everyone with latent TB infection (LTBI) should have TB treatment.

Rather it is recommended that certain “target” groups should receive treatment.

The main “target” groups considered by the World Health Organisation (WHO) to be most at risk from progressing from latent to active TB include people in low TB burden countries:

who have had recent contact with an infectious patient;

with silicosis;

infected with both TB and HIV;

who have been or who are in prison;

who are immigrants to a low burden country from a high burden country;

who are homeless;

who are an illicit drug user;

who have certain clinical conditions, or conditions which compromise their immune system, such as people with diabetes, and people with chronic renal failure.

In high TB burden countries the populations that are most strongly recommended for the treatment of latent TB infection are people living with HIV, and children under five who are household contacts of pulmonary TB cases.

Close contact with a person with infections tuberculosis is a risk factor, and the risk of progression to active tuberculosis disease is highest in the first two years after infection.

Individuals with immunosuppressive conditions, and HIV typically have substantially increased risk of progression from latent tuberculosis to tuberculosis, and as such indicates that routine testing for latent tuberculosis is indicated.

Treatment regimens:

Rifamycin-based regimen for four months is the preferred therapy, because they are effective, safe, and associated with a higher adherence rate, fewer hepatotoxic events, than longer isoniazid regimens.

Since the 1950s many studies have been carried out to assess the effectiveness of the TB drug isoniazid in treating latent TB.

In some of the trials the people taking part took the drug for six months, whilst in other trials the drug was taken for twelve months.

There were also trials with people taking the drug daily being compared with people taking the drug five times a week.

Any adverse effects of taking the drug were also noted and compared. There was a then long period of follow up to see who developed active TB.

The initial human studies of isoniazid  preventative therapy established that prolonged therapy with isoniazid was effective in reducing subsequent active TB infections.

The optimum length of treatment was however unclear but the most common recommendation was for a treatment length of nine months.

Recommended regimens

Currently the American CDC recommends one of the following three regimens for the treatment of latent TB.

Isoniazid daily or twice weekly for nine months

Isoniazid plus rifapentine once weekly for 12 weeks

Rifampicin (or rifabutin) daily for 4 months.

The WHO also recommends two other regimens of 3 or 4 months of isoniazid plus rifampicin daily and six months of isoniazid daily.

For drug resistant tuberculosis, six months of oral only regimes such as bedaquiline, Pretomanid, and linezolid or these  drugs plus moxifloxacin could replace the 24 month standard regimen.

For a drug sensitive tuberculosis in adults, four months with the rifapentine based regimen containing  moxifloxacin was non-inferior to the standard six month regimen.

Isoniazid for 6 to 9 months is in alternative to rifamycin regimens for individuals at risk for drug interactions, or those experiencing adverse effects.

The five-year risk of developing TB is associated with a reduced risk by 21% with a three month treatment yuduration, 65% with a six month duration and 75% with a 12 month duration of isoniazid.

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