Tuberculosis is the leading cause of death globally from an infectious agent. In 2017, an estimated 10 million people developed TB disease and an estimated 1.6 million died¹. A recent study demonstrated that <57% of internal medicine housestaff across 7 academic institutions in the U.S. correctly answered 9 out of 10 questions assessing knowledge of assessment and diagnosis of tuberculosis². This post addresses these questions and to helps clarify latent vs. active TB in a clinical setting.

The primary focus for this blog post is pulmonary TB. Be aware that although the most common presentation of TB is with pulmonary symptoms, TB can present anywhere in the body and sometimes can present without pulmonary symptoms.

But first, definitions.

Definitions

Latent infection – the bacteria lies dormant in the body and does not cause any symptoms, typically tests for latent infection (see later section) will be positive

Active disease – the individual is experiencing symptoms due to the infection in the body, typically with characteristic imaging findings and microbiological confirmation

Primary disease – immediate onset of active disease after infection

Reactivation disease – onset of active disease after a period of latent infection

Extra-pulmonary disease – presence of bacteria outside of the lungs (the primary organ of infection)

Disseminated disease – two or more noncontiguous sites resulting from lymphohematogenous dissemination

Miliary disease – lesions in the lung that resemble millet seeds; seen in some cases of disseminated TB

Step 1: Risk stratification

Risk factors for TB exposure

• having close contact with individuals who have active tuberculosis (roommates, family, friends, caregivers)
• living/had lived in a country that is endemic for TB
• living/working in a prison
• living/working in a homeless shelter
• injecting drugs
• living/working in any other facility/institution that has high rate of TB (hospitals, nursing homes, residential homes for HIV patients) 

*USPSTF gives a grade B recommendation for screening those at increased risk (see list above) for latent tuberculosis infection⁴

Risk factors for TB reactivation

A. Normal host

• 5-10% of reactivating TB in a lifetime^6,13
• 50% of that 5-10% is within the first 2-5 years of infection^6,13

B. Age – immunity weakens in the elderly

C. Immunosuppression

• HIV
• End stage renal disease
• Diabetes mellitus
• Lymphoma
• Corticosteroid or TNF-alpha inhibitor use
• Cigarette smoking

Step 2: Why is it important to distinguish latent TB from active TB?

The two syndromes are treated completely differently. Latent TB is non-infectious and does not require treatment to prevent progression of disease or transmission to others, but instead to prevent future reactivation. Active TB is infectious and needs to be treated to prevent spread of TB to others. The medications, doses and duration of therapy to treat these syndromes are also different from each other.

Active TB

A. Clinical symptoms

• fevers/chills, night sweats, weight loss, SOB and/or cough
• depending on site of TB disease, can have extrapulmonary symptoms (GI, CNS, spine, etc)
• subacute to chronic onset of symptoms (typically > several weeks)

B. Imaging

• will typically have active pulmonary abnormalities seen on imaging (this can be any type of abnormality – infiltrates, cavitary lesions, effusions, or solitary nodules)
• although the most common cause of apical lung scarring is prior TB infection, lung abnormalities DO NOT have to be in the apices of the lungs (they can be anywhere)

Latent TB
(make diagnosis ONLY after you have excluded active TB)

A. Clinical symptoms

• the patient is asymptomatic (= NO symptoms of active TB)

B. Imaging

• there is no active lung abnormality on chest imaging
• (calcified granulomas/nodules or anything that is deemed old, healed scarring is excluded)

*If there are any signs suggestive of active TB, then the patient should undergo active TB evaluation (discussed below). If there is no evidence of active TB, then treatment can be based on latent TB diagnostics (discussed below).

Step 3: Evaluating for TB – diagnostic tests

A. Active TB tests (pulmonary TB)

• obtain 2-3 sputum samples, ideally at least 8 hours apart, may require sputum induction if patient is not able to cough up sputum.
• one ideally should be in the morning (highest burden of TB in the morning due to pooling of secretions overnight)
• obtaining a bronchoscopy sample only counts for one sample
• send a nucleic acid amplification test (NAAT) on the 1^st sputum sample

1. AFB smear – fluorochrome stain of the clinical specimen

• sensitivity = 67.5% (95% CI, 60.6 to 73.9)⁸
• specificity = 97.5% (95% CI, 97.0 to 97.9)⁸

2. AFB culture – the gold standard test for tuberculosis diagnosis

• can take up to 6 weeks to grow for solid culture versus ~ 2 weeks for liquid culture

3. PCR = NAAT (nucleic acid amplification test) – this is a DNA test using amplification methods

• GeneXpert MTB/RIF assay is a brand test that combines the NAAT with rapid test for rifampin resistance sensitivity and specificity are high in pulmonary tuberculosis but is lower when used on specimens other than sputum.
  • sensitivity: 98% (for smear-positive, culture-positive specimens in HIV-negative patients)⁹
  • specificity: 99%⁹
• this test can be run on both AFB smear negative and positive specimens (although sensitivity is lower on AFB smear negative specimens)
• more specific than the smear because it tests directly for tuberculosis genes, whereas positive AFB smears can be due to non-tuberculous mycobacteria or other acid-fast staining bacteria (i.e. Nocardia)
• positive result → TB diagnosis
  negative result → does not rule out TB

B. Latent TB tests

1. Tuberculin Skin Test (TST) = Purified Protein Derivative (PPD)

• intradermal injection of tuberculin material (many different materials available)
• causes a delayed-type hypersensitivity response in individuals whose immune system has been exposed to TB before
• positive test = induration at the injection site within 48-72 hours
• negative test = no induration

Threshold for treatment

TB, tuberculosis; CXR, chest X-ray; HIV, human immunodeficiency virus; IBW, ideal body weight

*individuals who have received the BCG vaccine in the past may also test positive with this test since their immune systems have been exposed to TB via the vaccine (although immunity tends to wane within 10 years if vaccine is administered in infancy)

2. Interferon Gamma Release Assay (IGRA) = QuantiFERON-TB Gold or Plus  OR T-SPOT.TB

• blood test for detection of cell-mediated immune response to TB antigen
• not affected by BCG vaccine or BCG treatment
• 80-90% sensitivity, >95% specificity (sensitivity is diminished in immunocompromised hosts)⁵
• the QuantiFERON-TB Gold test is made up of 3 tubes:
  • negative control (everyone should not react)
  • positive control (everyone should react), and the
  • TB antigen that is recognized by CD4 cells
• **QuantGold-PLUS (a new test) has added a 4^th tube with TB antigen that binds to CD8 cells thereby increasing sensitivity of the test¹²
• positive test → patient’s blood reacted to the TB antigen and positive control but not the negative control
• negative test → patient’s blood did not react to the TB antigen but did react to the positive control
• indeterminate test → patient’s blood did not react to the positive control so test is invalid (this typically happens when the patient is immunocompromised and cannot mount an immune response to the positive control and thus would not react to the TB antigen either – even if they were exposed to TB)

*Indeterminate result DOES NOT mean it is in the middle between negative and positive. It means the test cannot provide a valid result.

*all latent diagnostic tests can cross-react in individuals infected with non-tuberculous mycobacteria (TST more so than the IGRA)

*Neither test is 100% sensitive and specific – if the patient has high pre-test probability for TB exposure and for future TB reactivation, ID physicians will sometimes treat for latent TB despite the negative tests 

Step 4: Treating TB

Treatment is complex and both choice of medication and duration depends on a variety of clinical and microbiological factors. Here is a basic overview of the difference in treatment between latent and active TB.

A. Latent TB (CDC)

*This is a useful calculator to determine the risks and benefits of TB reactivation vs. side effects from treatment in an individual patient. 

            a) Isoniazid – daily for 6 to 9 months

            b) Rifampin – daily for 4 months

            c) Rifapentine and isoniazid – weekly for 3 months

B. Active TB
— depends on susceptibility of bacteria and clinical syndrome
— RIPE therapy is the standard first-line therapy for fully-susceptible pulmonary TB infection with 2 months of all four drugs followed by 4 months of rifampin and isoniazid.

  R = rifampin

  I = isoniazid

  P = pyrazinamide

  E = ethambutol

*Ethambutol can be discontinued if drug susceptibility testing confirms a fully susceptible strain

*Patients with extensive disease e.g. cavitation or who remain smear and/or culture positive at 2 months may require a longer duration of therapy.

Don’t forget to:

• give daily Vitamin B6 with isoniazid to prevent peripheral neuropathy
• get baseline eye exam when starting ethambutol to enable monitoring for optic neuritis, particularly in patients with abnormal renal function
• evaluate for other co-morbidities such as HIV, hepatitis B or C, diabetes or substance use

References:

1. Global Tuberculosis Report 2018: Executive Summary. World Health Organization. Published Sept 2018. Accessed Mar 10, 201

2. Chida N, Brown C, Mathad J, et al. Internal Medicine Residents’ Knowlesge and Practice of Pulmonary Tuberculosis Diagnosis. OFID. 2018; 5(7).

3. Tuberculosis (TB). Centers for Disease Control and Prevention. Available from: https://www.cdc.gov/tb. Accessed Feb 13, 2019.

4. US Preventive Services Task Force. Screening for Latent Tuberculosis Infection in Adults. US Preventive Services Task Force Recommendation Statement. JAMA. 2016; 316(9):962-969. doi:10.1001/jama.2016.11046

5. Lewinsohn DM, Leonard MK, LoBue PA, et al. Official American Thoracic Society/Infectious Disease Society of America/Centers for Disease Control and Prevention Clinical Practice Guidelines: Diagnosis of Tuberculosis in Adults and Children. Clin Infect Dis. 2017; 64(2):111-115. doi: 10.1093/cid/ciw778

6. Horsburgh CR. Priorities for the Treatment of Latent Tuberculosis Infection in the United States. N Engl J Med. 2004; 350:2060-2067. DOI: 10.1056/NEJMsa031667

7. Pai M, Behr MA, Dowdy D, et al. Primer: Tuberculosis. Nature Reviews. 2016; 2:1-23.

8. Mathew P, Yen-Hong K, Vazirani B, Eng RHK, and Weinstein MP. Are Three Sputum Acid-Fast Bacillus Smears Necessary for Discontinuing Tuberculosis Isolation? J Clin Microbiol. 2002; 40(9):3482-3484. doi: 10.1128/JCM.40.9.3482-3484.2002

9. Steingart KR, Schiller I, Horne DJ, Pai M, Boehme CC, and Dendukuri N. Xpert® MTB/RIF assay for pulmonary tuberculosis and rifampicin resistance in adults. Cochrane Database Syst Rev. 2014 Jan 21;(1):CD009593. doi: 10.1002/14651858.CD009593.pub3.

10. Zeka AN, Tasbakan S, and Cavusoglu C. Evaluation of the GeneXpert MTB/RIF Assay for Rapid Diagnosis of Tuberculosis and Detection of Rifampin Resistance in Pulmonary and Extrapulmonary Specimens. 2011; 49(12):4138-4141. doi:10.1128/JCM.05434-11.  

11. Menzies D. Use of the tuberculin skin test for diagnosis of latent tuberculosis infection (tuberculosis screening) in adults. UpToDate. Available from: https://www.uptodate.com/contents/use-of-the-tuberculin-skin-test-for-diagnosis-of-latent-tuberculosis-infection-tuberculosis-screening-in-adults#H9. Accessed Feb 13, 2019.

12. QuantiFERON®-TB Gold Plus (QFT®-Plus) ELISA [Package Insert]. Hilden, Germany: Qiagen; 2016.

13. Comstock GW. Epidemiology of tuberculosis. Am Rev Respir Dis. 1982; 125(3 Pt 2):8.