Tuberculosis, Pulmonary

Essentials of Diagnosis

• Fatigue, weight loss, fever, night sweats, and productive cough

• Risk factors for acquisition of infection: household exposure, incarceration, drug use, travel to an endemic area

• Chest radiograph: pulmonary opacities, most often apical

• Sputum smear positive for acid-fast bacilli or sputum culture positive for Mycobacterium tuberculosis

General Considerations

• Primary infection

  • Occurs with inhalation of airborne droplets containing viable tubercle bacilli and subsequent lymphangitic and hematogenous spread before immunity develops

  • Up to one-third of new urban cases are from primary infection acquired by person-to-person transmission

• Latent tuberculosis infection (LTBI)

  • Occurs when bacilli are contained within granulomata

  • Nontransmissible while latent, but may become active disease if the infected person's immune function becomes impaired

• Drug-resistant strains of M tuberculosis are increasingly common worldwide, though rates in the US have fallen to less than 1.3%

• Risk factors for drug resistance include

  • Immigration from countries with a high prevalence of drug-resistant tuberculosis

  • Close and prolonged contact with individuals with drug-resistant tuberculosis

  • Unsuccessful previous antituberculosis therapy

  • Patient nonadherence to such therapy

• Resistance may be to single or multiple drugs

  • Drug-resistant tuberculosis is resistant to one first-line antituberculous drug, either isoniazid (INH) or rifampin (RIF)

  • Multidrug-resistant tuberculosis (MDR-TB) is resistant to INH and RIF, and possibly additional agents

  • Extensively drug-resistant tuberculosis (XDR-TB) is resistant to INH, RIF, fluoroquinolones and either aminoglycosides or capreomycin or both

• Nonadherence is a major cause of treatment failure, disease transmission, and development of drug resistance

Demographics

• Infects one-third of the world's population

• In 2014, there were 9.6 million new cases of tuberculosis worldwide with 1.5 million people dying of the disease

• In the United States, an estimated that 11 million people are infected with M tuberculosis and in 2014 there were 9421 active cases

• Occurs disproportionately among malnourished, homeless, and marginally housed individuals

• Risk factors for reactivation

  • Gastrectomy

  • Silicosis

  • Diabetes mellitus

  • HIV

  • Immunosuppressive drugs

• Risk factors for drug resistance

  • Immigration from regions with drug-resistant tuberculosis

  • Close contact with patients infected with drug-resistant tuberculosis

  • Unsuccessful prior antituberculosis therapy

  • Patient noncompliance with such treatment

Symptoms and Signs

• Cough is the most common symptom

• Blood-streaked sputum is common, frank hemoptysis is rare

• Slowly progressive constitutional symptoms include malaise, anorexia, weight loss, fever, and night sweats

• Patients appear chronically ill

• Chest examination is nonspecific; post-tussive apical rales are classic

• Atypical presentations are becoming more common, usually among the elderly and HIV-positive patients

Differential Diagnosis

• Pneumonia

• Lung abscess

• Lung cancer or lymphoma

• Mycobacterium avium complex (or other nontuberculous mycobacterial infection)

• Sarcoidosis

• Fungal infection, eg, histoplasmosis

• Endocarditis

• Silicosis or asbestosis

• Nocardiosis

Laboratory Tests

• Tuberculin skin test (TST) for LTBI

  • The Mantoux test is the preferred method: 0.1 mL of purified protein derivative (PPD) containing 5 tuberculin units is injected intradermally on the volar surface of the forearm using a 27-gauge needle on a tuberculin syringe. After 48–72 hours, the transverse width in millimeters of induration at the skin test site is measured

  • Table 9–13 summarizes the criteria established by the Centers for Disease Control and Prevention (CDC) for interpretation of the Mantoux TST

• Interferon gamma release assays (IGRAs) (including the QuantiFERON and T-SPOT tests) are in vitro assays of CD4+ T-cell-mediated interferon gamma release in response to stimulation by specific M tuberculosis antigens

  • In endemic areas, IGRAs are no more sensitive than the TST in active tuberculosis (20–40% false-negative rate) and cannot distinguish active from latent disease

  • IGRAs should not be used to exclude active tuberculosis

Imaging Studies

Chest radiograph

• Primary disease

  • Small unilateral infiltrates

  • Hilar and paratracheal lymph node enlargement

  • Segmental atelectasis

  • Pleural effusion is present in 30–40%, sometimes as the sole radiographic abnormality

• Reactivation tuberculosis

  • Associated with fibrocavitary apical disease, discrete nodules, and pneumonic infiltrates, usually in the apical or posterior segments of the upper lobes or in the superior segments of the lower lobes

  • Lower lung tuberculosis may masquerade as pneumonia or lung cancer

• A "miliary" pattern (diffuse small nodular densities) can be seen with hematologic or lymphatic dissemination of the organism

• Resolution of active tuberculosis leaves characteristic radiographic findings

  • Dense nodules in the pulmonary hila, with or without obvious calcification

  • Upper lobe fibronodular scarring

  • Bronchiectasis with volume loss

  • Ghon (calcified primary focus) complexes and Ranke (calcified primary focus and calcified hilar lymph node) complexes are seen in a minority of patients

Diagnostic Procedures

• Sputum induction is required for patients unable to voluntarily produce a sample

• Bronchoscopy may be considered in smear-negative patients in whom there is a high suspicion of disease

• Needle biopsy of the pleura reveals granulomatous inflammation in 60% of tuberculous pleural effusions

• Pleural fluid cultures are positive for M tuberculosis in 23–58% of cases

• Culture of three pleural biopsy specimens combined with microscopic examination increases the diagnostic yield to 90%

• Tests for pleural fluid adenosine deaminase and interferon-gamma can be extremely helpful diagnostic aids, particularly in making decisions to pursue invasive testing in complex cases

  • Adenosine deaminase at levels > 70 units/L is approximately 90% sensitive and specific for pleural tuberculosis

  • Interferon-gamma is 89% sensitive, 97% specific, according to a recent meta-analysis

Medications

• Medications: see characteristics of drugs and dosages in Tables 9–14 and 9–15

• Treatment involves using multiple drugs to which the organism is susceptible

  • When treatment failure is suspected, addition of at least two new antituberculosis drugs is recommended

  • When a twice- or thrice-weekly regimen is used, dosages are increased (Table 9–15)

• Coadminister pyridoxine, 10–50 mg/day, for patients at risk for INH-related neuropathy (those with diabetes mellitus, uremia, malnutrition, alcoholism, HIV infection, seizure disorder) or during pregnancy and lactation

HIV-infected patients

• 6-month rather than 9-month regimen

• Daily INH, RIF, and pyrazinamide (PZA) for 2 months

• Ethambutol (EMB) or streptomycin added where prevalence of INH resistance is 4% or higher

• If isolate is RIF- and INH-sensitive, continue these two drugs for 4 months

• Therapy is continued for at least 3 months beyond documentation of negative sputum cultures for MTB

• Directly observed therapy (DOT) regimens

  • INH/RIF/PZA plus EMB or streptomycin daily for 2 months, then INH/RIF 2–3 times/week for 4 months if susceptibility is demonstrated

  • INH/RIF/PZA plus EMB or streptomycin daily for 2 weeks, then 2 times/week for 6 weeks, then INH/RIF 2 times/week for 4 months if susceptibility is demonstrated

  • INH/RIF/PZA plus EMB or streptomycin 3 times/week for 6 months

Drug-resistant TB

• MTB resistant only to INH can be treated with 6 months of RIF/PZA plus EMB or streptomycin or 12 months of RIF/EMB

• Treatment requires individualized daily regimens with DOT under an experienced clinician

• Most resistant MTB strains have at least INH or RIF resistance and require three drugs to which susceptibility is proven

• The three-drug regimen is continued until negative cultures are documented; a two-drug regimen is then continued for another 12–24 months

Pregnant or lactating women

• INH, RIF, and EMB, with EMB excluded if INH resistance is unlikely

• Teratogenicity of PZA is unknown; streptomycin is contraindicated owing to a risk of congenital deafness

• Pyridoxine should be given with INH

• Breast-feeding is not contraindicated

Extrapulmonary disease

• In most cases, regimens effective for pulmonary disease are adequate

• Miliary, meningeal, bone, or joint involvement require 9 months of therapy

• Corticosteroids help prevent constrictive pericarditis from tuberculous pericarditis and neurologic complications from tuberculous meningitis

Surgery

• Early débridement and drainage are recommended for skeletal tuberculosis

Follow-Up

• Complete blood counts, pulmonary function tests, and kidney function should be checked at baseline

• Visual acuity and red-green color vision should be tested prior to EMB use and audiometry, prior to streptomycin use

• Routine monitoring of liver biochemical tests for evidence of drug toxicity is not recommended unless baseline results are abnormal or liver disease is suspected

• Monthly visits for monthly sputum AFB smears and TB cultures until documented negative

• If sputum smear is negative for AFB after 2 months of therapy, then repeat smear and culture at the end of therapy

• Patients with multidrug-resistant tuberculosis (MDRTB) should have monthly sputum AFB smears and TB cultures throughout therapy

• Chest radiograph is recommended at conclusion of successful therapy

• Patients whose cultures do not turn negative or who have persistent symptoms after 3 months of therapy should be evaluated for MDRTB

Complications

• Development of drug resistance

• Potential drug toxicities

  • Loss of visual acuity or development of red-green colorblindness with EMB

  • Hearing loss with streptomycin

Prevention

• Bacillus Calmette-Guérin (BCG) vaccination

• BCG vaccination is not recommended in the United States because of its variable effectiveness, the low prevalence of TB infection, and the interference of the vaccine with determination of LTBI

• All suspected and confirmed cases of MTB should be reported to local and state public health authorities

Prognosis

• Almost all properly treated patients with tuberculosis can be cured; relapse rates among those properly treated are less than 5% with current regimens

• The main cause of treatment failure is medication nonadherence

When to Refer

• All cases of drug-resistant TB

• DOT is recommended with MDRTB and those receiving twice- or thrice-weekly therapy

When to Admit

• Hospitalization is not necessary for initial therapy in most patients

• Admit patients who are incapable of self-care or who are likely to expose susceptible individuals (eg, infants) to tuberculosis

• Hospitalized patients require isolation in appropriately ventilated rooms until three sputums from different days are negative for MTB organisms