What is a primary tuberculous infection?
This is the initial infection with Mycobacterium tuberculosis (MTB).
Primary tuberculous infections almost always occur through the ______
True or False: In immunocompetent individuals, most primary infections do not develop into active disease. Instead, such individuals continue to harbor the organisms, resulting in a state of latent tuberculous infection.
What is latent tuberculous infection?
This is when an individual is infected with MTB but has no active disease
True or False: Most active disease of TB are due to reactivation of LTBI
____ people in the world are infected with TB
TB is a global threat and is the number _ or _ killer by an infectious agent
1 or 2
What kind of patients progress to primary (active) TB when exposed?
HIV, infants, elderly, immunocompromised
What are the stages of MTB?
1. Ingestion by resident alveolar macrophages
2. Symbiotic stage - MTB multiplies and macrophages accumulate.
3. Migration of T-cells to the site of infection
4a. Latent tuberculosis infection
4b. Decline in immunity leads to reactivation of TB
When TB is ingested by resident macrophages, it's possible that the macrophage engulfs and kills the MTB. However, if the MTB cannot be killed that way, the macrophage either goes through apoptotic or necrotic cell death. Does MTB get killed in apoptotic or necrotic cell death?
After a macrophage engulfs MTB, if it undergoes apoptotic death, it will kill itself as well as the MTB. If it goes through necrotic death, the MTB survives and is released to be taken up by other macrophages
What happens in the symbiotic stage of MTB?
Blood monocytes migrate into the lungs where the differentiate into macrophages and continue to ingest MTB but is not able to destroy it. MTB multiplies within inactivated macrophages and form the early primary tubercle (nodule)
What happens when T-cells migrate to the site of TB infection?
T-cells begin to activate macrophages to kill or prevent the spread of MTB. Granulomas form and MTB is unable to multiply within the solid caseous material. This contains the infection.
Note that in AIDS patients, CD4+ lymphopenia results in granuloma breakdown, resulting in the inability to control the primary infection or in reactivation of latent infection.
What happens in latent tuberculosis infections at the cellular level?
The solid caseous center of the granuloma remains intact. Any bugs that escape the caseous edge are ingested by highly activated macrophages. LTBI is established if the caseation remains solid and does not liquify.
What happens to LTBI in the event of a decline in immunity?
Reactivation of TB.
If there is immunosuppression (Aids, cancer, anti-TNFalpha, aging, malnutrition, etc), there is a loss of integrity of the granuloma and liquifaction of the caseous material (caseous necrosis). This provides a favorable medium for multiplication of MTB which leads to cavity formation and rupture and spread to other parts of the lung and to other individuals
True or False: Latent TB can look completely normal on CXR
What are ghon and rhanke complexes?
Ghon complex = calcified lung nodule at site of initial TB infection
Ranke complex = ghon complex plus calcified regional hilar and/or mediastinal lymph nodes
Compare and contrast LTBI and active TB in the following ways:
- How much MTB is present
- Tuberculin skin test
- Sputum and cultures
- Infectious or not
- There is only a little MTB
- Tuberculin skin test is positive
- Normal CXR (may have ghon complex)
- Sputum smears and cultures are negative
- No symptoms
- Not infectious
In active TB,
- There is MTB present in large numbers
- Tuberculin skin test is positive
- Abnormal CXR with pneumonia with or without cavitary lesions
- Sputum smears and cultures are positive
- Symptomatic with cough, fever, night sweats, and weight loss
- Often infectious before treatment
How do we make a diagnosis for LTBI?
Tuberculin skin test.
PPD (a culture filtrate of MTB with over 200 different mycobacteria antigens) is injected intradermally creating a wheal 6-10 mm in diameter.
After 48-72 hours, the diameter of the induration is measured (not the erythema).
What is M. bovis-BCG?
This is a vaccine given in most parts of the world that shares the same antigen as many of the PPD antigens used for the tuberculin skin test and by many tuberculous mycobacteria. Patients who were vaccinated by this in other parts of the world will give a false positive result on the tuberculin skin test.
A positive tuberculin skin test is an example of a ______ reaction.
type IV delayed-type hypersensitivity
What is considered a positive test on TST?
The size of the induration as well as patient risk factors need to be considered.
What are the advantages of TST?
It is very familiar to healthcare workers, it's inexpensive, and it can be performed in the field an in resource-poor countries. Studies have shown that treatment of LTBI diagnosed by TST is very effective in preventing reactivation of TB (~90%)
What are the disadvantages of TST?
Two visits are required, 2-5 days apart. Measuring the size of the induration is more subjective than you would think. Thus, self-reading is not done.
False-positivity can occur in patients who have received the BCG vaccine because there is cross-reactivity to PPD as late as 15 years after vaccination.
False-positivity can also occur in individuals infected with environmental mycobacteria (in soil and stuff)
False-negativity can occur in individuals who are T cell depleted (e.g. AIDS, organ transplants, patients on chemo, etc). These patients that are immunocompromised don't have the ability to react to the skin test.
What are 2 tests that are starting to be used instead of TST?
INF-gamma release assays:
1. Quantiferon (incubate whole blood over night with antigens specific for MTB)
2. T-spot. TB (add patient's blood to a plate with anti-IFNgamma antibodies. (likely to be more accurate than quantiferon in immunocompromised patients because you're counting individual cells)
In each of these, if a patient has TB, their adaptive immune system will launch an augmented response with greater levels of IFN-gamma released compared to patients who have never had TB.
What are advantages of using INFgamma-release assays instead of TST?
Only one visit is required and the results can be finished quite quickly.
It is also thought that quantifying INFgamma levels is a more reliable and accurate measure that measuring induration.
The sensitivity for LTBI is probably as good or better than TST. In immunosuppressed patients, T-Spot TB may be better than both quantiferon or TST.
Specificity for LTBI is better than TST because MTB antigens used in IGRA are not found in BCG or most NTM. For example, in BCG-vaccinated individuals with low risk of exposure, specificity is 86-99% for T-Spot TB and 96-99% in quantiferon.
A positive test may be more predictive of progression to disease than TST.
What are disadvantages of INFgamma release assays?
There is a high rate of false-positives. So, if you get a false-positive in a patient that has low risk of exposure, you should consider retesting them.
What is the greatest risk factor for TB?
True or False: HIV accelerates TB progression and vice versa
True or False: TB is responsible for 1/3 of all deaths from AIDS
True or False: TB is less prevalent in US born individuals than immigrants.
True. Immigrants account for 65% of all active TB cases in the U.S.
True or False: Vitamin D deficiency can increase risk for TB
How do you treat LTBI?
9 months of isoniazid (INH) daily or BID or
Rifampin daily for 4 months (fewer serious adverse side effects, better adherence, more cost effective than 9mo INH) or
INH + rifampin daily for 3 months or
INH 900mg + rifampin 900mg once weekly for 3 months. This regimen is newer and may be better in some ways. Patients are more likely to adhere due to the 12 total doses. Results have been good with preventing TB activation.
What is a significant adverse effect of isoniazid (INH)?
Risk factors include age, alcohol, pre-existing active liver disease, or use of other hepatotoxic drugs
True or False:
A 50 year old man with a heart transplant is found to have a PPD of 8mm. He has never received treatment for LTBI. He should be started on INH for a total of 9 months.
True. A solid organ transplant recipient is highly immunosuppressed and should receive INH for LTBI if the PPD is greater than or equal to 5mm
True or False:
A 27 year old medical student beginning her 3rd year clinical clerkship has a PPD induration of 7mm. She has no medical problems. She should get 9 months of INH prophylaxis because she will be constantly exposed to patients with TB.
For a healthcare worker who is otherwise healthy, the criteria for positivity is greater than or equal to 10 mm. As for certain healthcare workers with patient contact, she should be tested yearly to monitor for PPD conversion.
True or False:
a 55 y/o alcholic man has a PPD induration of 15mm. He lives in a homeless shelter in NYC and has been incarcerated recently. He is coughing up sputum that is blood streaked. His CXR shows an upper lobe cavitary lesion that is new from 1 year ago. His sputum smear is positive for AFB but the culture at 1 week is negative. He should receive INH for 9 months.
False. This man likely has active TB and should be treated with a multi-drug regimen (with at least 4 drugs)
True or False: Active TB must be treated with a multi-drug regimen
True or False:
A 45 y/o woman with schizophrenia has a PPD induration of 16mm. She is otherwise healthy. Due to her history of non-adherence to her medications, you should prescribe 2 months of rifampin-pyrazinamide rather than the 9 months of INH
rifampin-pyrazinamide combination for LTBI is associated with unacceptable risk of severe hepatitis although a 2 month regimen is easier to adhere to, this regimen should never be used
A and C
BCG = bump
Smallpox = sunken