Mycobacterium Tuberculosis What the Primary Care PA Needs to Know

Tony Skaggs, MPAS, PA-C

Dept. of PA Studies, School of Health Professions UT Health Science Center at San Antonio

• Topics of Discussion o Focused on primarily immunocompetent/adult population o Demographics and Etiology o Natural history and pathogenesis o Common Presentations o Diagnosis o Treatment

Drug-resistant disease o LTBI

Diagnosis Treatment

o Miliary and extrapulmonary tuberculosis

• Tuberculosis - Worldwide o Leading cause of death o More than two billion people are estimated to be infected

About 1/3 of the world population o Global incidence peaked around 2003

Appears to be declining slowly o 2014: 9.6 million individuals became ill with TB

1.5 million died o Highest Rates (100/100,000 or higher)

Sub-Saharan Africa, India, and the islands of Southeast Asia and Micronesia o Intermediate rates of TB (26 to 100 cases/100,000)

China, Central and South America, Eastern Europe, and northern Africa

• Tuberculosis in the United States o 2013: 9,582 cases of TB reported in the United States o 1992-2013: substantial decline in the rate of TB o 2013: Historic Low (3.0 per 100,000) o Majority of U.S. TB cases – foreign born individuals emigrating from countries with high

rates of endemic TB 57 percent of United States TB cases in 2006 Case rate is 22 per 100,000 Roughly half occur in individuals residing in the U.S. for ≤5 years most of these cases are due to reactivation of LTBI

o Also a challenge: Increased travel to/from countries with endemic TB

Mycobacterium Tuberculosis What the Primary Care PA Needs to Know 2

Mycobacterium Tuberculosis What the Primary Care PA Needs to Know 3

Mycobacterium Tuberculosis What the Primary Care PA Needs to Know 4

Mycobacterium Tuberculosis What the Primary Care PA Needs to Know 5

• Risk factors for Tuberculosis o Impaired immunity/immune compromise o Increased exposure to infectious person o Substance abuse (drugs, alcohol, and tobacco) o Poor nutritional status o Systemic disease o Age:

Rates highest amongst young adults in developing world Rates highest amongst older adults in the U.S.

o Gender: men o Lower socioeconomic status

• Pulmonary Tuberculosis

o Susceptible person inhales airborne droplet nuclei Contains viable organisms – doesn’t take a lot

o Tubercle bacilli reach the alveolar space (5-10 microns) Ingested by alveolar macrophages

o Infection inoculum escapes macrophage microbicidal activity

Mycobacterium Tuberculosis What the Primary Care PA Needs to Know 6

• Primary Tuberculosis to Primary Progressive Tuberculosis o Immune response is inadequate to contain the primary infection o Primary progressive looks like reactivation tuberculosis o Reactivation vs. primary progressive

Reactivation (historically) considered to be the majority of active TB Current research 5% of patients? – Could be as high as 1/3 of active TB

• Primary Tuberculosis to LTBI

o As noted, viable organism is inhaled o Lymphatic/hematogenous dissemination

Occurs before the development of an effective immune response o Immune system surrounds the organism

T cells/macrophages form granuloma Bacteria is held in check – the spread is limited But infection is only contained – NOT ERADICATED

o Viable organism lies dormant in granuloma Years and decades

• Latent Tuberculosis (LTBI)

o No active disease o Cannot transmit the organism o Lying dormant o Impaired host immune defenses Reactivation o If it affects the immune system, it can trigger reactivation

Diabetes mellitus, HIV infection; corticosteroids, TNF inhibitors, etc. o 5-10% of individuals latent TB will develop active disease

Reactivation Of this 5-10%, half will reactivate within the first 2 years of infection

• Active Pulmonary Disease – Signs and Symptoms

• Primary Progressive • Reactivation • Fever • Pleuritic or retrosternal pain • Pleural effusion • Fatigue • Cough • Arthralgias • Pharyngitis

• Diurnal fever • Night sweats • Cough – scant production • Sputum – foul smelling/blood • Hemoptysis • Pleuritic or retrosternal pain • Dyspnea • Anorexia • Wasting (consumption) • Malaise

• Cough most common pulmonary symptom in both

Mycobacterium Tuberculosis What the Primary Care PA Needs to Know 7

• Active Pulmonary – Physical Findings o Unremarkable – non-diagnostic

Rarely - asymptomatic o Classic finding – posttussive apical rales o Otherwise

Dullness with decreased fremitus • Pleural thickening or effusion

o Signs of consolidation associated with open bronchi o Whispered pectoriloquy o Distant hollow breath sounds over cavities (amphoric) o Extrapulmonary signs – clubbing

• Active Pulmonary – Diagnostic Studies (Imaging)

o Primary pulmonary TB – chest radiograph is often normal Hilar adenopathy Small unilateral infiltrates Segmental atelectasis Pleural effusion

o Reactivation – Abnormal X-ray common, even with no symptoms Fibrocavitary apical disease Discrete nodules Pneumonic infiltrates

• Apical or posterior segments • Visible air-fluid levels

o Difficult to distinguish Primary from Reactivation

o Often discussed, rarely seen – only in a minority of patients Ghon complex

• Calcified primary focus Ranke complex

• Calcified primary focus and calcified hilar lymph node

• Active Pulmonary – Diagnostic Studies (Labs) o Source of sample

Sputum • Obtained by coughing • Has to be sputum – not nasopharyngeal secretions or saliva • Bronchoscopy with bronchoalveolar lavage – only in certain

circumstances o Unsuccessful attempts to obtain adequate expectorated

sputum samples o Negative sputum studies in the setting of a high clinical

suspicion for TB o Potential alternative diagnosis for which diagnostic

bronchoscopy is required o Urgent diagnostic information is needed

Mycobacterium Tuberculosis What the Primary Care PA Needs to Know 8

• Active Pulmonary – Diagnostic Studies (Labs) – Cont. Gastric secretions Pleural effusion Tissue biopsy

o Diagnostic evaluation moderate to high index of suspicion Need three sputum specimens – at least one needs to be morning

• Looking for acid-fast bacilli (AFB) Smear and culture One specimen for nucleic acid amplification (NAA or NAAT-TB) Drug-susceptibility testing for INH, RIF, and EMB on initial positive culture

o Must use medical judgement to interpret o Both AFB and NAA are positive, this confirms the diagnosis o Gets complicated if one is positive & the other is negative o Must be considered in the context of the patient

• Active Pulmonary – Treatment

o Primary goal Eradicating M. tuberculosis infection Preventing development of drug resistance Preventing relapse of disease

o Nonadherence to treatment is a major cause of treatment failure Directly observed therapy (DOT)

o Relapse or treatment failure Early consultation with an expert

o Single drug should never be added to a failing regimen Resistance

o Separated into initial and continuation phase

o Isoniazid (INH) Peripheral neuropathy and hepatic toxicity (pyridoxine)

o Rifampin (RIF) o Pyrazinamide (PZA)

Hepatic injury Hyperuricemia

o Ethambutol (EMB) Optic neuritis

o Rifapentine (RPT) o Fixed dose combinations o INH and RIF (Rifamate) o INH, RIF, and PZA (Rifater)

Mycobacterium Tuberculosis What the Primary Care PA Needs to Know 9

Mycobacterium Tuberculosis What the Primary Care PA Needs to Know 10

• Drug Resistance o Drug resistant TB

Resistant to one of the first-line anti-TB drugs o Multidrug-resistant TB (MDR-TB)

Resistant to at least isoniazid and rifampin and possibly additional agents o Extensively drug-resistant TB (XDR-TB)

Resistant to at least isoniazid, rifampin, and fluoroquinolones as well as either aminoglycosides or capreomycin or both

o Totally drug-resistant (TDR-TB) Resistant to all locally tested medications

o INH-monoresistant TB treated with RIF, PZA, and EMB Six to nine months

o RIF-monoresistant TB INH, PZA, and an injectable agent Nine months

o MDR-TB (empiric regimens) First-line agents plus additional drugs chosen via stepwise selection through the

categories of anti-tuberculous drugs Four active drugs should be included in the regimen Should include a fluoroquinolone and an injectable Intensive (initial) phase – six to eight months

• Four months after culture conversion Continuation phase – 18 to 24 months

Mycobacterium Tuberculosis What the Primary Care PA Needs to Know 11

• Latent TB Infection (LTBI)

o Treatment of LTBI – reduce risk of reactivation by 90% o Two major tests for ID of LTBI

Both tests evaluate cell-mediated immunity • Tuberculin skin test (TST) and interferon gamma release assay (IGRA)

o Tuberculin skin test (TST) Tuberculin material is purified protein derivative (PPD)

• 5 tuberculin units (0.1 mL) • Intradermal injection of tuberculin material on the inner surface of the

forearm Measure the transverse diameter of the induration

o Recorded in millimeters

• Latent TB Infection (LTBI)

o Interferon Gamma Release Assay (IGRA) QuantiFERON-TB Gold In-Tube Test Cannot distinguish between LTBI and active tuberculosis IGRAs have specificity >95 percent for diagnosis of LTBI Not affected by Bacille Calmette-Guérin (BCG) vaccination status Preferred over TST for:

• Individuals that have Received BCG o Either as a vaccine or for cancer therapy

• Individuals that have poor rates of return for TST reading o Routine testing with both TST and IGRA is not recommended o Positive TST or IGRA = XRAY

Mycobacterium Tuberculosis What the Primary Care PA Needs to Know 12

• Miliary Tuberculosis o Hematogenous dissemination of Mycobacterium tuberculosis

Originally a pathologic and then a radiographic description Now – all forms of progressive, widely disseminated hematogenous TB

o Can arise as a result of progressive primary infection o Via reactivation of a latent focus with subsequent spread o Approximately 3% of incident cases in the United States o Disseminate via the lymphatics

Hematogenously to the most vascular organs • Liver • Spleen • Bone marrow • Brain

o Pulmonary disease

50% of patients with miliary TB Dyspnea or cough Rales or rhonchi Hypoxemia was common Pleuritic chest pain

Mycobacterium Tuberculosis What the Primary Care PA Needs to Know 13

• Miliary Tuberculosis – Cont. o Lymphatic disease

Node enlargement o Bone and joint disease

Spinal TB (Pott’s disease) bone or joint pain

o Gastrointestinal disease Hepatic disease Tuberculous enteritis Tuberculous peritonitis Pancreatitis Cholecystitis

o Central nervous system disease Meningitis or tuberculoma

o Genitourinary and adrenal disease Hematuria, proteinuria, and "sterile" pyuria Flank pain, hydronephrosis, and cystitis

o Cardiovascular disease (rare) Pericarditis

o Cutaneous disease Cutis miliaris disseminata

o Breast disease Mimics breast cancer Solitary, ill-defined, unilateral hard lump

o Other organ involvement Thyroid Otitis media Seeding in every organ of the body

• Summary

o Globally, tuberculosis continues to be a major cause of morbidity and mortality. Risk factor: immigration from high rate-infection countries

o United States: Shift in demographics – greater focus on foreign-born individuals from Africa,

Southeast Asia, India, Central/South America, etc. (high & intermediate rates of infection).

Rates of infection continue to drop. o Consider TB as a possibility:

Risk factors Clinical manifestations Prior history of TB infection

• IGRA/TST Known exposures/Travel/immigration status Radiographic features Labs – sputum

Mycobacterium Tuberculosis What the Primary Care PA Needs to Know 14

• Summary – Cont. o Start appropriate treatment for persons with TB disease o Ensure patients complete treatment

DOT o Drug resistance

Not common…but still possible Country of origin and exposure are important clues to this possibility

o LTBI TST vs. IRGA DOT

o Miliary tuberculosis Again, not particularly common Any organ…any place

• References used to prepare the lecture • CDC. Reported Tuberculosis in the United States, 2014. Atlanta, GA: U.S. Department of Health

and Human Services, CDC, October 2015. • World Health Organization 2015 Global Tuberculosis Report. (2015). Retrieved April 10, 2016,

from http://apps.who.int/iris/bitstream/10665/191102/1/9789241565059_eng.pdf?ua=1 • Papadakis, M. A., McPhee, S. J., & Rabow, M. W. (2014). Current Medical Diagnosis & Treatment

2015 (45th ed.). McGraw-Hill Education. • Pozniak, A. (2016, January 12). Clinical manifestations and complications of pulmonary

tuberculosis. Retrieved April 13, 2016, from http://www.uptodate.com/contents/clinical-manifestations-and-complications-of-pulmonary-tuberculosis/contributors, Wolters Kluwer

• Bernardo, J. (2015, September 11). Clinical manifestations, diagnosis, and treatment of extrapulmonary and miliary tuberculosis. Retrieved April 5, 2016, from http://www.uptodate.com/contents/clinical-manifestations-diagnosis-and-treatment-of-extrapulmonary-and-miliary-tuberculosis, Wolters Kluwer

• Pai, M., & Menzies, D. (2016, March 25). Diagnosis of latent tuberculosis infection (tuberculosis screening) in HIV-uninfected adults. Retrieved April 7, 2016, from http://www.uptodate.com/contents/diagnosis-of-latent-tuberculosis-infection-tuberculosis-screening-in-hiv-uninfected-adults , Wolters Kluwer

• Bernardo, J. (2015, November 04). Diagnosis of pulmonary tuberculosis in HIV-uninfected patients. Retrieved April 7, 2016, from http://www.uptodate.com/contents/diagnosis-of-pulmonary-tuberculosis-in-hiv-uninfected-patients , Wolters Kluwer

• Pozniak, A. (2016, January 12). Clinical manifestations and complications of pulmonary tuberculosis. Retrieved April 13, 2016, from http://www.uptodate.com/contents/clinical-manifestations-and-complications-of-pulmonary-tuberculosis/contributors

• Horsburgh, R., Jr. (2015, October 01). Epidemiology of tuberculosis. Retrieved April 05, 2016, from http://www.uptodate.com/contents/epidemiology-of-tuberculosis, Wolters Kluwer

• Pai, M., & Menzies, D. (2016, March 16). Interferon-gamma release assays for diagnosis of latent tuberculosis infection. Retrieved April 07, 2016, from http://www.uptodate.com/contents/interferon-gamma-release-assays-for-diagnosis-of-latent-tuberculosis-infection, Wolters Kluwer

Mycobacterium Tuberculosis What the Primary Care PA Needs to Know 15

• References used to prepare the lecture – Cont. • Riley, L. (2015, March 10). Natural history, microbiology, and pathogenesis of tuberculosis.

Retrieved April 13, 2016, from http://www.uptodate.com/contents/natural-history-microbiology-and-pathogenesis-of-tuberculosis, Wolters Kluwer

• Horsburgh, R., Jr. (2016, March 09). Treatment of latent tuberculosis infection in HIV-uninfected adults. Retrieved April 05, 2016, from http://www.uptodate.com/contents/treatment-of-latent-tuberculosis-infection-in-hiv-uninfected-adults, Wolters Kluwer

• Sterling, T. (2016, January 21). Treatment of pulmonary tuberculosis in HIV-uninfected adults. Retrieved April 05, 2016, from http://www.uptodate.com/contents/treatment-of-pulmonary-tuberculosis-in-hiv-uninfected-adults, Wolters Kluwer