Pulmonary tuberculosis (TB) is an infection of the lung and occasionally surrounding structures, caused by the bacterium Mycobacterium tuberculosis (Mtb). Two states of M. tuberculosis infection are recognized: Latent tuberculosis infection (LTBI) and acute tuberculosis disease, although infection and immunologic control exist across a spectrum. LTBI is a state of persistent immune response to stimulation by M. tuberculosis antigens without evidence of clinically manifested active TB and with bacillary replication absent or below some undefined threshold as a result of immunologic control. Most persons with LTBI never become sick with TB; however, 5% to 15% have progression to tuberculosis disease.¹ Multidrug-resistant (MDR) TB is defined as disease caused by strains of Mtb that are at least resistant to treatment with isoniazid (INH) and rifampin (RIF) (two of the most effective first-line drugs); extensively drug-resistant (XDR) TB refers to disease caused by MDR strains that are also resistant to treatment with any fluoroquinolone and bedaquiline or linezolid.

• TB

• •See "Etiology."
• •Primary pulmonary TB infection generally asymptomatic
• •Reactivation pulmonary TB:
  1. 1.Fever
  2. 2.Night sweats
  3. 3.Cough
  4. 4.Hemoptysis
  5. 5.Scanty nonpurulent sputum
  6. 6.Weight loss
  7. 7.Chest pain
• •Progressive primary pulmonary TB disease: Same as reactivation pulmonary TB
• •TB pleurisy:
  1. 1.Pleuritic chest pain
  2. 2.Fever
  3. 3.Shortness of breath
• •Rare massive, suffocating, fatal hemoptysis secondary to erosion of pulmonary artery within a cavity (Rasmussen aneurysm)
• •Chest examination:
  1. 1.Not specific
  2. 2.Usually underestimates extent of disease
  3. 3.Rales accentuated after a cough (posttussive rales)

• •Mtb, a slow-growing, aerobic, non-spore-forming, nonmotile bacillus, with a lipid-rich cell wall:
  1. 1.Lacks pigment
  2. 2.Produces niacin
  3. 3.Reduces nitrate
  4. 4.Produces heat-labile catalase
• •Mtb staining: Acid-fast and acid-alcohol fast by Ziehl-Neelsen method, appearing as red, slightly bent, beaded rods 2 to 4 microns long (acid-fast bacilli [AFB]), against a blue background
• •Polymerase chain reaction (PCR) to detect <10 organisms/ml in sputum (compared with the requisite 10,000 organisms/ml for AFB smear detection)
• •Culture:
  1. 1.Growth on solid media (Löwenstein-Jensen; Middlebrook 7H11) in 2 to 6 wk
  2. 2.Growth in liquid media (BACTEC, using a radioactive carbon source for early growth detection) often in 9 to 16 days
  3. 3.Enhanced in a 5% to 10% carbon dioxide atmosphere
• •Genome sequencing:
  1. 1.Facilitates immediate identification of Mtb strains and resistance in early growing cultures
  2. 2.False negatives possible if growth suboptimal
• •Humans are the only reservoir for Mtb
• •Transmission:
  1. 1.Aerosolized droplets containing AFB generated through cough, speaking, singing, bronchoscopy, or autopsy are inhaled directly into alveoli
  2. 2.Facilitated by close exposure to high-velocity cough (unprotected by proper mask or respirators) from patients with AFB-positive sputum and cavitary lesions
  3. 3.Locations of increased TB transmission risk include hospitals, homeless shelters, correctional facilities, nursing homes, and residential homes for those with HIV
• •Pathogenesis:
  1. 1.Mtb are ingested by macrophages in alveoli, then transported to regional lymph nodes, where spread is contained
  2. 2.Some Mtb may reach bloodstream and disseminate widely
  3. 3.Primary TB (often asymptomatic, minimal pneumonitis in lower or midlung fields, with hilar lymphadenopathy) is essentially an intracellular infection, with multiplication of organisms continuing 2 to 12 wk after primary exposure, until cell-mediated hypersensitivity (detected by positive skin test reaction to tuberculin PPD) matures, and results in subsequent containment of infection
  4. 4.Local and disseminated Mtb are thus contained by the following T-cell-mediated immune responses:
     1. a.Recruitment of monocytes
     2. b.Transformation of lymphocytes with secretion of lymphokines
     3. c.Activation of macrophages and histiocytes
     4. d.Organization into granulomas, where Mtb may survive within macrophages (Langhans giant cells), but within which multiplication essentially ceases (95%) and from which spread is prohibited
  5. 5.Progressive primary pulmonary disease:
     1. a.May immediately follow the asymptomatic phase
     2. b.Necrotizing pulmonary infiltrates
     3. c.Tuberculous bronchopneumonia
     4. d.Endobronchial TB
     5. e.Interstitial TB
     6. f.Widespread miliary lung lesions
  6. 6.Postprimary TB pleurisy with pleural effusion:
     1. a.Develops after early primary infection, although often before conversion to positive PPD
     2. b.Results from pleural seeding from a peripheral lung lesion or rupture of lymph node into pleural space
     3. c.May produce a large (sometimes hemorrhagic) exudative effusion (with polymorphonuclear cells early, rapidly replaced by lymphocytes), frequently without pulmonary infiltrates
     4. d.Generally resolves without treatment
     5. e.Portends a high risk of subsequent clinical disease and therefore must be diagnosed and treated early (pleural biopsy and culture) to prevent future catastrophic TB illness
     6. f.May result in disseminated extrapulmonary infection
  7. 7.Reactivation pulmonary TB:
     1. a.Occurs months to decades after primary TB
     2. b.Preferentially involves the apical posterior segments of the upper lobes and superior segments of the lower lobes
     3. c.Associated with necrosis and cavitation of involved lung, hemoptysis, chronic fever, night sweats, weight loss
     4. d.Spread within lung occurs via cough and inhalation
  8. 8.Reinfection TB:
     1. a.May mimic reactivation TB
     2. b.Ruptured caseous foci and cavities, which may produce endobronchial spread
  9. 9.Mtb in both progressive primary and reactivation pulmonary TB:
     1. a.Intracellular (macrophage) lesions (undergoing slow multiplication)
     2. b.Closed caseous lesions (undergoing slow multiplication)
     3. c.Extracellular, open cavities (undergoing rapid multiplication)
     4. d.INH and RIF are bactericidal in all three sites
     5. e.Pyrazinamide (PZA) especially active within acidic macrophage environment
     6. f.Extrapulmonary reactivation disease also possible
  10. 10.Rapid local progression and dissemination in infants with devastating illness before PPD conversion occurs
  11. 11.Most symptoms (fever, weight loss, anorexia) and tissue destruction (caseous necrosis) from cytokines and cell-mediated immune responses
  12. 12.Mtb has no important endotoxins or exotoxins
  13. 13.Granuloma formation related to tumor necrosis factor (TNF) secreted by activated macrophages

• •Necrotizing pneumonia (anaerobic, gram-negative)
• •Histoplasmosis
• •Coccidioidomycosis
• •Melioidosis
• •Interstitial lung diseases (rarely)
• •Cancer
• •Sarcoidosis
• •Silicosis
• •Rare pneumonias:
  1. 1.Rhodococcus equi (cavitation)
  2. 2.Bacillus cereus (50% hemoptysis)
  3. 3.Eikenella corrodens (cavitation)

• •Sputum for AFB stains and Mtb culture.
• •The Xpert MTB/RIF: An automated molecular test for Mtb and resistance to RIF that provides sensitive detection of TB and RIF resistance directly from untreated sputum in less than 2 h with minimal hands-on time.
• •Chest x-ray (Fig. E1).
• •Target groups for LTBI screening are summarized in Table E2. PPD (tuberculin skin test), or interferon gamma release assays (IGRA) can be used for screening of LTBI (Fig. E2):
  1. 1.Recent conversion from negative to positive within 3 mo of exposure is highly suggestive of recent infection.
  2. 2.Negative PPD never rules out acute TB.
  3. 3.Prior positive PPD may become negative after several years and return to positive only after second repeated PPD; repeat second PPD within 1 wk, which thus may mimic skin test conversion.
  4. 4.Positive PPD reaction is determined as follows:
     1. a.Induration 48-72 h after intradermal injection of 0.1 ml of 5 tuberculin PPD.
     2. b.5-mm induration in persons living with HIV (or other severe immunosuppressed state affecting cellular immune function), close contact of active TB, fibrotic chest lesions.
     3. c.10-mm induration if in high-medical risk groups (renal failure, gastrectomy, silicosis, diabetes, <90% ideal body weight), foreign-born where TB rates are high (Southeast Asia, Latin America, Africa, India), living in a congregate setting, people who abuse drugs, TB lab workers, children <5 yrs, children exposed to adults of high-risk.
     4. d.15-mm induration if low risk.
  5. 5.PPD cannot distinguish between TB disease and TB infection.
• •IGRAs: Diagnostic test for LTBI, known as the QuantiFERON TB Gold test (QFT-G) and T-SPOT.TB Assay. These blood tests measure interferon response to specific Mtb antigens. The test may assist in distinguishing true positive reactions from individuals with latent TB from PPD reactions related to nontuberculous mycobacteria, prior bacillus Calmette-Guérin vaccination, or difficult-to-interpret skin-test results from people with dermatologic conditions or immediate allergic reactions to PPD. IGRAs have a specificity >95% for diagnosis of latent TB. The sensitivity of the T-SPOT assay (90%) appears to be higher than the QFT-G test (80%). It should be noted that IGRA sensitivity is diminished by HIV infection. As with PPD, negative tests do not rule out active TB disease, and positive tests cannot distinguish between TB infection and disease.

Figure E2 Latent tuberculosis infection screening algorithm.

Individuals at high likelihood of having LTBI, due to demographic or specific exposure history or an untreated previously positive TST or IGRA, and a high probability of a presently false-negative result, due to immunodeficiency or immunosuppression, should be considered for treatment. *IGRA preferred for individuals with prior bacillus Calmette-Guérin and individuals at high risk for becoming lost to follow-up. TST preferred for children younger than 5 yr. Dual testing (not shown) may be considered for certain situations. IGRA, Interferon gamma release assay; LTBI, latent tuberculosis infection; Mtb, Mycobacterium tuberculosis; TB, tuberculosis; TST, tuberculin skin test.

(From Broaddus VC et al: Murray & Nadel’s textbook of respiratory medicine, ed 7, Philadelphia, 2022, Elsevier.)

• •Sputum for TB PCR, AFB stains, and mycobacterial culture:
  1. 1.Induced sputum if patient not coughing productively
• •Sputum from bronchoscopy if high suspicion of TB in patients unable to produce expectorated induced sputum for AFB:
  1. 1.Postbronchoscopy cough specimen may improve yield
  2. 2.Consider lung biopsy if sputum negative, especially if infiltrates are predominantly interstitial
• •AFB stain-negative sputum may grow Mtb subsequently (especially in HIV).
• •Gastric aspirates may be helpful, especially in children.
• •CBC:
  1. 1.Variable values:
     1. a.White blood cells (WBCs): Low, normal, or elevated (including leukemoid reaction: >50,000)
     2. b.Normocytic, normochromic anemia often
• •Rarely helpful diagnostically.
• •Erythrocyte sedimentation rate usually elevated.
• •Thoracentesis:
  1. 1.Exudative effusion:
     1. a.Elevated protein and adenosine deaminase
     2. b.Decreased glucose
     3. c.Elevated WBCs (polymorphonuclear leukocytes early, replaced later by lymphocytes)
     4. d.May be hemorrhagic
  2. 2.Pleural fluid usually AFB-negative
  3. 3.Pleural biopsy often diagnostic-may need to be repeated for diagnosis
  4. 4.Culture pleural biopsy tissue for AFB
• •Bone marrow biopsy is often diagnostic in difficult-to-diagnose cases, especially miliary TB.

• •Chest x-ray examination:
  1. 1.Primary infection reflected by calcified peripheral lung nodule with calcified hilar lymph node
  2. 2.Reactivation pulmonary TB:
     1. a.Necrosis
     2. b.Cavitation (especially on apical lordotic views)
     3. c.Fibrosis and hilar retraction
     4. d.Bronchopneumonia
     5. e.Interstitial infiltrates
     6. f.Miliary pattern
     7. g.Many of the previous findings may also accompany progressive primary TB
  3. 3.TB pleurisy:
     1. a.Pleural effusion, often rapidly accumulating and massive
  4. 4.TB activity not established by single chest x-ray examination
  5. 5.Serial chest x-ray examinations are excellent indicators of progression or regression

• •High-calorie, high-protein diet to reverse malnutrition and enhance immune response to TB
• •Isolation in negative-pressure rooms with high-volume air replacement and circulation, with health care provider wearing proper protective 0.5- to 1-micron filter respirators, until three consecutive sputum AFB smears are negative during workup (taken in 8- to 24-h intervals, with at least one being an early morning specimen) or a diagnosed patient has been on standard multidrug treatment for at least 2 wk and is clinically improving

• •Generally, treatment of active TB consists of two phases: An intensive phase, followed by a continuation phase
• •Compliance (rigid adherence to treatment regimen) chief determinant of success:
  1. 1.Supervised directly observed therapy (DOT) recommended for all patients and mandatory for patients with high likelihood of loss to follow-up
• •Adult initial regimen:
  1. 1.INH 5 mg/kg (INH; max 300 mg) PO, RIF 10 mg/kg (RIF; max 600 mg) PO, ethambutol (EMB) by weight increments (EMB: 40 to 55 kg, 800 mg; 56 to 75 kg,1200 mg; 76 to 90 kg, 1600 mg) PO, and PZA by weight increments (PZA: 40 to 55 kg, 1000 mg; 56 to 75 kg, 1500 mg; 76 to 90 kg, 2000 mg) PO dosed daily
  2. 2.Pyridoxine (vitamin B₆, 25 mg/day) should be given with INH to prevent peripheral neuropathy
  3. 3.Usually decreased to INH and RIF after 8 wk depending on susceptibilities, with ultimate duration of therapy dependent on HIV treatment status, extent of disease, regimen used, and treatment response, but generally at least 6 mo
  4. 4.Alternative, more complicated DOT regimens
  5. 5.In patients with rifampin-susceptible TB, a strategy involving initial treatment with an 8-wk bedaquiline-linezolid regimen was shown to be noninferior to standard treatment for TB with respect to clinical outcomes. This strategy was associated with a shorter duration of treatment and with no evident safety concerns²
• •Monitor for clinical toxicity (especially hepatitis). Pharmacology and adverse effects of antituberculosis medications are summarized in Table E4
  1. 1.Patient and physician awareness that anorexia, nausea, right upper quadrant pain, and unexplained malaise require immediate cessation of treatment
  2. 2.Evaluation of liver function testing:
     1. a.Minimal aspartate aminotransferase/alanine transaminase elevations without symptoms generally transient and not clinically significant
• •Drug resistance (often multiple drug resistance TB [MDRTB]) increased by:
  1. 1.Prior treatment
  2. 2.Acquisition of TB in countries with high TB burden
  3. 3.Known contact with MDR TB
  4. 4.Other factors associated with increased risk: Homelessness, incarceration, AIDS, IV drug use
• •Other medications used in MDR or XDR TB include levofloxacin, moxifloxacin, cycloserine, aminoglycosides such as amikacin or kanamycin, PAS, clofazimine, bedaquiline, delamanid, pretomanid, linezolid, and ethionamide. A recent trial with the combination of bedaquiline, pretomanid, and linezolid revealed a favorable outcome at 6 mo after the end of therapy in a high percentage of patients with highly drug-resistant forms of TB. Other trials³ have shown that a 6-mo bedaquiline pretomanid-moxifloxacin regimen that included linezolid at a dose of 600 mg daily may be used in place of longer regimens in persons older than 14 yr of age who have multidrug-resistant or rifampin-resistant TB, regardless of their HIV status
• •Drug-resistant TB should be treated in consultation with a TB expert
• •Preventive treatment for PPD conversion only (infection without disease):
  1. 1.Must be certain that chest x-ray examination is negative and patient has no symptoms of TB
  2. 2.Most important groups:
     1. a.HIV-positive and other severely immunocompromised patients
     2. b.Close contact with active TB
     3. c.Recent converter
     4. d.Old TB on chest x-ray examination
     5. e.IV drug addict
     6. f.Medical risk factor
     7. g.High-risk foreign country
     8. h.Homeless
     9. i.Box E1 summarizes persons in whom preventive therapy should be initiated to prevent progression to TB
  3. 3.Treatment of latent M. tuberculosis (Tables E5 and E6)
• •Infants generally given prophylaxis immediately if recent contact with active TB (even if infant PPD negative), then retested with PPD in 3 mo (continuing INH if PPD becomes positive and stopping preventive treatment if PPD remains negative)

Generally not indicated beyond treatment described previously

• •Monthly follow-up by physician experienced in TB treatment.
• •Confirm sensitivity testing and alter treatment appropriately.
• •Frequent sputum samples until culture is negative.
• •Confirm regression on chest x-ray examination at 2 to 3 mo.
• •Approximately 5% of patients with drug-susceptible TB have a relapse after 6 mo of first-line therapy. Higher minimum inhibitory concentration values of INH or RIF in predominant isolates of M. tuberculosis are associated with a greater risk of relapse.

• •To infectious disease expert for:
  1. 1.HIV-positive patient
  2. 2.Patient with suspected drug-resistant TB
  3. 3.Patients previously treated for TB
  4. 4.Patients whose fever has not decreased and sputum has not converted to negative in 2 to 4 wk
  5. 5.Patients with overwhelming pulmonary or extrapulmonary TB
• •To pulmonologist for bronchoscopy or pleural biopsy, if necessary for diagnosis

• •All contacts (especially close household contacts and infants) should be properly tested for PPD or IGRA conversions during 3 mo after exposure.
• •Those with positive PPD or IGRA should be evaluated for active TB and properly treated or given prophylaxis.
• •Previous treatment is a common risk factor for XDR and MDR TB.
• •In treatment of LTBIs, evidence exists for the efficacy and safety of INH monotherapy, rifampicin monotherapy, and combination therapies.
• •Left untreated, 5% to 10% of patients with latent TB develop active TB. Updated guidelines from the CDC and the National Tuberculosis Controllers Association for latent TB treatment include any of the following regimens:
  1. 1.Once-weekly INH plus rifapentine for 3 mo administered under direct observation. The guideline recommends this regimen for adults and children (age <2 yr), including patients who are HIV-positive.
  2. 2.Daily RIF for 4 mo is also strongly recommended, especially for HIV-negative people, and perhaps has the lowest toxicity.
  3. 3.Daily RIF plus INH for 3 mo is another alternative.
  4. 4.A recent 4 mo trial of rifapentine regimens with or without moxifloxacin for tuberculosis revealed that the efficacy of a 4-mo rifapentine-based regimen containing moxifloxacin was noninferior to the standard 6-mo regimen in the treatment of tuberculosis.¹