Latent Tuberculosis

Latent tuberculosis (LTB), also called latent tuberculosis infection (LTBI), is when a person is infected with ''Mycobacterium tuberculosis'', but does not have active tuberculosis (TB). Active tuberculosis can be contagious while latent tuberculosis is not, and therefore it is not possible to get TB from someone with latent tuberculosis. Various treatment regimens are in use for latent tuberculosis. They generally need to be taken for several months.

Epidemiology

As of 2023, it is estimated that one quarter of the world's population has latent or active TB, with TB estimated to have newly infected 10.8 million people per year.

The spread of TB is uneven throughout the world, with approximately 80% of the population in many Asian and African countries testing positive on tuberculin tests, while only 5–10% of the US population tests positive.

Transmission

Latent disease

It is not possible to catch TB from someone with LTB. In people who develop active TB of the lungs, also called pulmonary tB, the Mantoux test will often be positive. They are contagious and capable of passing the bacteria to others. TB can be transmitted by exhalation. Tiny droplets exhaled by someone with active TB can remain suspended in the air for several hours based on environmental conditions. Another person could then inhale the droplets and potentially become infected with TB. However, this is unlikely to occur, as infection generally requires longer exposure. This includes brief exposures which happen when one is exposed to TB during brief social contact; prolonged exposure (over a couple of months, for example, by living with a relative with TB) is generally required for TB infection.

Statistics show that approximately one-third of people exposed to pulmonary TB become infected with the bacteria, but only one in ten of these infected people develop active TB disease during their lifetime. People with latent TB are not contagious and will not feel sick. However, latent infections can become active TB infections, which are contagious, in the future.

In some countries like Canada and the United States of America, people have medical privacy or "confidentiality" and do not have to reveal their active TB diagnosis to family, friends, or co-workers. A person will know they have been exposed to TB only through required testing for some jobs, developing symptoms of active TB, and visiting and testing by a medical doctor. Because TB is not common in the US, doctors may not suspect TB; therefore, they may not test for the infection. If a person has symptoms of TB, it is wise to be tested.

Persons with diabetes have a significantly higher chance of converting from latent to active TB, and mortality from TB may be greater in diabetic patients. Persons with both human immunodeficiency virus (HIV) and LTB have a 10% chance of developing active TB every year. "HIV infection is the greatest known risk factor for the progression of latent ''M. tuberculosis'' infection to active TB. In many African countries, 30–60% of all new TB cases occur in people with HIV, and TB is the leading cause of death globally for HIV-infected people."

Reactivation

Once a person has been diagnosed with LTBI and a medical doctor confirms no active signs of infection or identifiable ''M. tuberculosis'' bacteria in the body, the person should remain alert to symptoms of active TB for the remainder of their life. Even after completing the full course of medication, there is no guarantee that all of the ''M. tuberculosis'' bacteria have all been killed. "When a person develops active TB (disease), the symptoms (cough, fever, night sweats, weight loss, etc.) may be mild for many months. This can lead to delays in seeking care, and results in the transmission of the bacteria to others."

TB bacteria may exist in the latent form both inside and outside of the lungs. In many cases, they may be latent in another organ, without any remaining bacteria in the lungs. If the reactivation of TB occurs in the brain, organs, kidneys, joints, or other areas, the symptoms are often slow to progress, frequently being ignored by patients until they become severe. Extrapulmonary tuberculosis (TB outside of the lungs) can affect virtually any organ, with distinct manifestations depending on the site: TB in the spine causes back pain and potential paralysis; lymph node involvement presents as painless or occasionally painful swelling in the neck or armpits; meningeal infection triggers persistent headaches and altered consciousness; while urogenital tuberculosis leads to painful urination, blood in urine, and infertility. All of these may feature generalized symptoms like fever, night sweats, and weight loss, which, combined with their nonspecific presentation and lower amounts of bacteria, make them more difficult to diagnose than the classic pulmonary disease.

Risk factors

Situations in which TB may become reactivated are:
* if there is onset of a disease affecting the immune system (such as acquired immunodeficiency syndrome IDS or a disease whose treatment affects the immune system (such as chemotherapy in cancer or systemic steroids in asthma or Enbrel, Humira, or Orencia in rheumatoid arthritis);
* malnutrition (which may be the result of illness or injury affecting the digestive system, a prolonged period of not eating, or disturbance in food availability such as during famine or residence in a refugee or concentration camp);
* degradation of the immune system due to aging;
* certain systemic diseases such as diabetes,
* other conditions such as debilitating disease (especially hematological and some solid cancers), use of long-term steroid medication, end-stage renal disease, silicosis, gastrectomy, and jejuno-ileal bypass;
* being elderly; and
* young age.

Concomitant immunity

Compared to uninfected individuals, people with LTB appears to have some (35–80%) protection against developing active TB after being exposed to ''M. tuberculosis'' in the environment. This kind of protection is called concomitant immunity. It seems to be due to the presence of tissue-resident memory T cells.

Diagnosis

There are two classes of tests commonly used to identify patients with LTB: tuberculin skin tests and Interferon-gamma(IFN-γ) tests.

The two tuberculin skin tests currently include the following:

:* Mantoux test
:* Heaf test

The three IFN-γ tests include the following:
:* T-SPOT.TB
:* QuantiFERON-TB Gold
:* QuantiFERON-TB Gold In-Tube

Tuberculin skin testing

The tuberculin skin test (TST) in its first iteration, the Mantoux Test, was developed in 1908. Tuberculin (also called purified protein derivative or PPD) is a standardized dead extract of cultured TB, injected into the skin to measure the person's immune response to the bacteria. If a person has been exposed to the bacteria previously, they should express an immune reaction to the injection, usually a mild swelling or redness around the site. There have been two primary methods of TST: the Mantoux test and the Heaf test. The Heaf test was discontinued in 2005 because the manufacturer deemed its production to be financially unsustainable, though it was previously preferred in the United Kingdom (UK) because it may require less training to administer and involved less inter-observer variation in its interpretation than the Mantoux test. The Mantoux test was the preferred test in the US, and is now the most widely used TST globally.

Mantoux test

:''See: Mantoux test''
The Mantoux test is now standardized by the World Health Organization ( WHO). Tuberculin at 0.1 milliliter (mL; 100 units/mL), which delivers a dose of 5 units, is given by intradermal injection into the surface of the lower forearm (subcutaneous injection results in false negatives). A waterproof ink mark is drawn around the injection site so as to avoid difficulty of finding it later if the level of reaction is small. The test is read 48 to 72 hours later. The area of induration (NOT of erythema) is measured transversely across the forearm (left to right, not up and down) and recorded to the nearest millimeter (mm).

Heaf test

:''See: Heaf test''

The Heaf test was first described in 1951. The test uses a Heaf gun with disposable single-use heads; each head has six needles arranged in a circle. There are standard heads and pediatric heads: the standard head is used on all patients aged 2 years and older; the pediatric head is for infants under the age of 2 years old. For the standard head, the needles protrude 2 mm when the gun is actuated; for the pediatric heads, the needles protrude 1 mm. Skin is cleaned with alcohol, then tuberculin (100,000 units/mL) is evenly smeared on the skin (about 0.1 mL); the gun is then applied to the skin and fired. The excess solution is then wiped off and a waterproof ink mark is drawn around the injection site. The test is read 2 to 7 days later.
* Grade 0: no reaction, or induration of three or fewer puncture points;
* Grade 1: induration of four or more puncture points;
* Grade 2: induration of the six puncture points coalesce to form a circle;
* Grade 3: induration of 5 mm; or more
* Grade 4: induration of 10 mm or more, or ulceration

The results of both tests are roughly equivalent as follows:
* Heaf grade 0 & 1 ~ Mantoux less than 5 mm;
* Heaf grade 2 ~ Mantoux 5–14 mm;
* Heaf grade 3 & 4 ~ Mantoux 15 or greater

Tuberculin conversion

''Tuberculin conversion'' is said to occur if a patient who previously had a negative tuberculin skin test develops a positive tuberculin skin test at a later date. It indicates a change from negative to positive, and usually signifies a new infection.

Boosting

The phenomenon of boosting is one way of obtaining a false positive test result. Theoretically, a person's ability to develop a reaction to the TST may decrease over time – for example, a person is infected with latent TB as a child and is administered a TST as an adult. Because there has been such a long time since the immune responses to TB has been necessary, that person might give a negative test result. If so, there is a fairly reasonable chance that the TST triggers a hypersensitivity response in the person's immune system and the body overreacts to what it perceives as a re-infection. In this case, when that person is given the test again (as is standard procedure, see above), they may have a significantly greater reaction to the test, giving a very strong positive; this can be commonly misdiagnosed as Tuberculin Conversion. This can also be triggered by receiving the BCG vaccine, as opposed to a proper infection. Although boosting can occur in any age group, the likelihood of the reaction increases with age.

Boosting is only likely to be relevant if an individual is beginning to undergo periodic TSTs (health care workers, for example). In this case, the standard procedure is called two-step testing. The individual is given their first test and in the event of a negative, given a second test in 1 to 3 weeks. This is done to combat boosting in situations where, had that person waited up to a year to get their next TST, they might still have a boosted reaction, and be misdiagnosed as a new infection.

There is a difference in US and UK guidelines. In the US, testers are told to ignore the possibility of false positive due to the BCG vaccine, as the BCG is seen as having waning efficacy over time. Therefore, the Centers for Disease Control and Prevention (CDC) urges that people be treated based on risk stratification regardless of BCG vaccination history, and if a person receives a negative and then a positive TST, they will be assessed for full TB treatment beginning with an X-ray to confirm that TB is not active and proceeding from there. Conversely, the UK guidelines acknowledge the potential effect of the BCG vaccination, as it is mandatory and therefore a prevalent concern. Though the UK shares the procedure of administering two tests, 1 week apart, and accepting the second one as the accurate result, they also assume that a second positive is indicative of an old infection (and therefore, certainly LTBI) or the BCG itself. In the case of BCG vaccinations confusing the results, Interferon-γ (IFN-γ) tests may be used as they will not be affected by the BCG.

Interpretation

According to the US guidelines, there are multiple size thresholds for declaring a positive result of LTB from the Mantoux test: For people from high-risk groups, such as those who are HIV positive, the cutoff is 5 mm of induration; for medium risk groups, 10 mm; for low-risk groups, 15 mm. The US guidelines recommend that a history of previous BCG vaccination should be ignored. For details of tuberculin skin test interpretation, please refer to the CDC guidelines (reference given below).

The UK guidelines are formulated according to the Heaf test: In people who have had BCG previously, LTB is diagnosed if the Heaf test is grade 3 or 4, and people have no signs or symptoms of active TB. If the Heaf test is grade 0 or 1, then the test is repeated. In people who have not had BCG previously, latent TB is diagnosed if the Heaf test is grades 2, 3, or 4, and have no signs or symptoms of active TB. Repeat Heaf testing is not done in patients who have had BCG (because of the phenomenon of boosting). For details of tuberculin skin test interpretation, please refer to the BTS guidelines (references given below).

Given that the US recommendation is that prior BCG vaccination be ignored in the interpretation of tuberculin skin tests, false positives with the Mantoux test are possible as a result of: (1) having previously had a BCG vaccine (even many years ago), or (2) periodical testing with tuberculin skin tests. Having regular TSTs boosts the immunological response in those people who have previously had BCG, so these people will falsely appear to be tuberculin conversions. This may lead to treating more people than necessary, with the possible risk of those people developing adverse drug reactions. However, as Bacille Calmette-Guérin vaccine is not 100% effective, and is less protective in adults than pediatric patients, not treating these people could lead to a possible infection. The current US policy seems to reflect a choice to focus infection control.

The US guidelines also allow for tuberculin skin testing in immunosuppressed people (those with HIV, or who are on immunosuppressive drugs), whereas the UK guidelines recommend that tuberculin skin tests should not be used for such people because it is unreliable.

Interferon-γ testing

The role of IFN-γ tests is undergoing constant review and various guidelines have been published with the option for revision as new data becomes availabl
CDC:MMWRHealth Protection Agency:UK

There are currently two commercially available interferon-γ release assays (IGRAs): QuantiFERON-TB Gold and T-SPOT.TB. These tests are not affected by prior BCG vaccination, and assess the body's response to specific TB antigens not present in other forms of mycobacteria and BCG ( ESAT-6). Whilst these tests are new, they are now becoming available globally.

CDC:

HPA Interim Guidance:

Drug-resistant strains

It is usually assumed by most medical practitioners that in the early stages of a diagnosis, a case of LTB is the normal or regular strain of TB. It will therefore be most commonly treated with Isoniazid (the most used treatment for LTB.) Only if the TB bacteria does not respond to the treatment will the medical practitioner begin to consider more virulent strains, requiring significantly longer and more thorough treatment regimens.

There are four types of TB recognized in the world today:
* TB
* Multi-drug-resistant tuberculosis (MDR TB)
* Extensively drug-resistant tuberculosis (XDR TB)
* Totally drug-resistant tuberculosis (TDR TB)

Treatment

The treatment of LTBI is essential to controlling and eliminating TB by reducing the risk that TB infection will progress to disease. LTB will convert to active TB in 10% of cases (or more in cases of immunocompromised patients). Taking medication for LTB is recommended by many doctors.

In the US, the standard treatment is 9 months of isoniazid, but this regimen is not widely used outside of the US.

Terminology

There is no agreement regarding terminology: the terms ''preventive therapy'' and ''chemoprophylaxis'' have been used for decades, and are preferred in the UK because it involves giving medication to people who have no disease and are currently well: the reason for giving medication is primarily to prevent people from becoming unwell. In the US, physicians talk about LTB ''treatment'' because the medication does not actually prevent infection: the person is already infected and the medication is intended to prevent existing silent infection from becoming active disease. There are no convincing reasons to prefer one term over the other.

Specific situations

"Populations at increased risk of progressing to active infection once exposed:
* Persons with recent TB infection hose infected within the previous 2 years* Congenital or acquired immunosuppressed patients (in particular, HIV-positive patients)
* Illicit intravenous drug users; alcohol and other chronic substance users
* Children (particularly those younger than 4 years old)
* Persons with comorbid conditions (i.e., chronic kidney failure, diabetes, malignancy, hematologic cancers, body weight of at least 10% less than ideal, silicosis, gastrectomy, jejunoileal bypass, asthma, or other disorders requiring long-term use of corticosteroids or other immunosuppressants)."

Treatment regimens

It is essential that assessment to rule out active TB be carried out before treatment for LTBI is started. To give treatment for LTB to someone with active TB is a serious error: the TB will not be adequately treated and there is a serious risk of developing drug-resistant strains of TB.

There are several treatment regimens currently in use:
* 9H — isoniazid for 9 months is the gold standard (93% effective, in patients with positive test results and fibrotic pulmonary lesions compatible with TBEfficacy of various durations of isoniazid preventive therapy for tuberculosis: five years of follow-up in the IUAT trial. International Union Against Tuberculosis Committee on Prophylaxis. Bull World Health Organ. 1982;60(4):555-64.).
* 6H — Isoniazid for 6 months might be adopted by a local TB program based on cost-effectiveness and patient compliance. This is the regimen currently recommended in the UK for routine use. The US guidance excludes this regimen from use in children or persons with radiographic evidence of prior TB (old fibrotic lesions) (69% effective).
* 6 to 9H₂ — An intermittent twice-weekly regimen for the above two treatment regimens is an alternative if administered under Directly observed therapy (DOT).
* 4R — rifampicin for 4 months is an alternative for those who are unable to take isoniazid or who have had known exposure to isoniazid-resistant TB.
* 3HR — Isoniazid and rifampin may be given daily for 3 months.
* 2RZ — The 2-month regimen of rifampin and pyrazinamide is no longer recommended for treatment of LTBI because of the greatly increased risk of drug-induced hepatitis and death.
* 3HP – 3-month (12-dose) regimen of weekly rifapentine and isoniazid. The 3HP regimen has to be administered under DOT. A self-administered therapy (SAT) of 3HP is investigated in a large international study.

Evidence for treatment effectiveness

A 2000 Cochrane review containing 11 double-blinded, randomized control trials and 73,375 patients examined 6 and 12-month courses of isoniazid (INH) for treatment of LTB. HIV positive and patients currently or previously treated for TBs were excluded. The main result was a relative risk (RR) of 0.40 (95% confidence interval I0.31 to 0.52) for development of active TB over 2 years or longer for patients treated with INH, with no significant difference between treatment courses of 6 or 12 months (RR 0.44, 95% CI 0.27 to 0.73 for six months, and 0.38, 95% CI 0.28 to 0.50 for 12 months).

A Cochrane systematic review published in 2013 evaluated four different alternatives regimens to INH monotherapy for preventing active TB in HIV-negative people with LTB infection. The evidence from this review found no difference between shorter regimens of rifampicin or weekly, and directly observed how Rifapentine plus INH compared to INH monotherapy in preventing active TB in at-ick HIV-negative people. However, the review found that the shorter rifampicin regimen for 4 months and weekly directly observed Rifapentine plus INH for 3 months "may have additional advantages of higher treatment completion and improved safety." However the overall quality of evidence was low to moderate (as per GRADE criteria) and none of the included trials were conducted in low- to middle-income countries (LMIC) with high TB transmission and hence might not be applicable to nations with high TB transmission.

Treatment efficacy

There is no guaranteed "cure" for LTB. "People infected with TB bacteria have a lifetime risk of falling ill with TB..." with those who have compromised immune systems, those with diabetes and those who use tobacco at greater risk.

A person who has taken the complete course of Isoniazid (or other full course prescription for TB) on a regular, timely schedule may have been cured. "Current standard therapy is isoniazid (INH) which reduces the risk of active TB by as much as 90 percent (in patients with positive LTBI test results and fibrotic pulmonary lesions compatible with tuberculosis) if taken daily for 9 months." However, if a person has not completed the medication exactly as prescribed, the "cure" is less likely, and the "cure" rate is directly proportional to following the prescribed treatment specifically as recommended. Furthermore, "If you don't take the medicine correctly and you become sick with TB a second time, the TB may be harder to treat if it has become drug resistant." If a patient were to be cured in the strictest definition of the word, it would mean that every single bacterium in the system is removed or dead, and that person cannot get TB (unless re-infected). However, there is no test to assure that every single bacterium has been killed in a patient's system. As such, a person diagnosed with LTB can safely assume that, even after treatment, they will carry the bacteria – likely for the rest of their lives. Furthermore, "It has been estimated that up to one-third of the world's population is infected with ''M. tuberculosis'', and this population is an important reservoir for disease reactivation." In areas where TB is endemic, treatment may be even less certain to "cure" TB, as reinfection could trigger activation of LTB already present even in cases where treatment was followed completely.

Controversy

There is controversy over whether people who test positive long after infection have a significant risk of developing the disease (without re-infection). Some researchers and public health officials have warned that this test-positive population is a "source of future TB cases" even in the US and other wealthy countries, and that this "ticking time bomb" should be a focus of attention and resources.

On the other hand, Marcel Behr, Paul Edelstein, and Lalita Ramakrishnan reviewed studies concerning the concept of LTB in order to determine whether TB-infected persons have life-long infection capable of causing disease at any future time. These studies, both published in the ''British Medical Journal'' (''BMJ'') in 2018 and 2019, show that the incubation period of TB is short, usually within months after infection, and very rarely more than 2 years after infection. They also show that more than 90% of people infected with ''M. tuberculosis'' for more than 2 years never develop TB even if their immune system is severely suppressed. Immunologic tests for TB infection such as the tuberculin skin test and IGRAs only indicate past infection, with the majority of previously infected persons no longer capable of developing TB. Ramakrishnan told the New York Times that researchers "have spent hundreds of millions of dollars chasing after latency, but the whole idea that a quarter of the world is infected with TB is based on a fundamental misunderstanding."

Writing in ''The Atlantic'', science journalist Katherine J. Wu explains:

The first BMJ article disputing widespread latency was accompanied by an editorial written by Dr. Soumya Swaminathan, Deputy Director-General of the World Health Organization, who endorsed the findings and called for more funding of TB research directed at the most heavily afflicted parts of the world, rather than disproportionate attention to a relatively minor problem that affects just the wealthy countries.

The WHO no longer endorses the concept that all those with immunologic evidence of past TB infection are currently infected and so are at risk of developing TB some time in the future. In 2022, the WHO issued corrigenda to its 2021 Global TB Report to clarify estimates on the worldwide burden of infected people. These corrigenda deleted "About a quarter of the world's population is infected with ''M. tuberculosis''" and replaced it with "About a quarter of the world's population has been infected with ''M. tuberculosis''." The corrigenda also removed the prior estimate of the lifetime risk of TB of 5 to 10% among those with evidence of past TB infection, indicating that they no longer have confidence in earlier estimates that a substantial percentage of those with positive immunologic test results will develop the disease.

See also

* Silent disease

References

Further reading

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External links

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