Pulmonary Tuberculosis

01Definition and overview

Tuberculosis is an infection by bacteria of the Mycobacterium tuberculosis complex (mainly M. tuberculosis; M. bovis from unpasteurised milk). The lung is the commonest site, which makes pulmonary TB the form that spreads. Three states are distinguished:

M. tuberculosis is a slow-growing, aerobic, non-motile bacillus (it divides about once in 15 to 20 hours) with a thick, waxy wall of mycolic acids, which makes it resistant to drying, to many antibiotics and to simple stains, and gives it the name acid-fast bacillus (AFB).

02Etiology and pathophysiology

Transmission

TB is an airborne infection. A person with lung or laryngeal disease coughs, sneezes or sings, and releases droplet nuclei (1 to 5 µm) that stay in the air for hours and that carry only a few bacilli. Only a small number needs to be inhaled for infection to take hold, but not all those infected become ill. The risk of infection depends on the infectiousness of the case (smear-positive, cavitary disease, cough), the closeness and length of contact, and ventilation. TB is not spread by touch or by objects. M. bovis comes from unpasteurised milk or from infected cattle.

Primary infection and latency

1. 1

   Entry

   The bacilli reach the alveoli and are ingested by alveolar macrophages, but the mycobacteria block the fusion of the phagosome with the lysosome and multiply inside the cell.
2. 2

   Ghon focus

   They spread to the hilar lymph nodes, where the bacilli meet T cells. The lung focus (Ghon focus), with the affected nodes, is the Ghon complex, which later calcifies.
3. 3

   Cell-mediated immunity

   After 3 to 8 weeks, T helper 1 cells release interferon-γ and tumour necrosis factor, which activate macrophages. The macrophages form a granuloma: a centre of caseous necrosis surrounded by epithelioid cells, Langhans' giant cells and lymphocytes. The tuberculin skin test and interferon-γ release assays become positive.
4. 4

   Containment

   In most people the granuloma contains the infection, and the bacilli can lie dormant for decades (latent TB). The central caseation, hypoxia and acidity hold the bacilli dormant.

On first contact, only a few develop primary progressive disease, mostly young children, and the immunocompromised. Over a lifetime, about 5 to 10 per cent of infected people develop active TB, about half of them in the first two years. The risk is far higher when immunity falls, as in HIV infection.

Post-primary disease

Most active adult TB is reactivation of a latent focus, often decades after infection. Reactivation happens when cell-mediated immunity weakens: HIV infection (the risk rises as the CD4 count falls), treatment with corticosteroids, anti-TNF drugs, chemotherapy or transplant drugs, diabetes, chronic kidney disease, malnutrition, alcohol and drug misuse, silicosis and ageing. The lesion is typically in the apical and posterior segments of the upper lobes and the superior segments of the lower lobes, where oxygen tension is highest and the aerobic bacilli do best. A strong immune response causes tissue damage: caseation, liquefaction and a cavity that communicates with a bronchus, where bacilli multiply in great numbers and are coughed out. From the lung, bacilli can spread through the blood (miliary TB), the lymphatics and the bronchi.

Risk factors include contact with infectious cases, origin from or travel to a high-incidence country, HIV and other immune defects, diabetes, chronic kidney disease, malnutrition, homelessness, prison, drug and alcohol misuse.

03Clinical features

Primary TB is usually silent. In children and the immunocompromised it may cause fever, cough, hilar or paratracheal lymph node enlargement (which can compress a bronchus), lobar consolidation or collapse, a pleural effusion, and erythema nodosum.

Pulmonary post-primary TB begins slowly. The cardinal symptoms are a cough that lasts for weeks, at first dry and then productive, haemoptysis and the systemic symptoms of fever, night sweats and weight loss, with malaise and loss of appetite. Pleuritic pain suggests pleural involvement, and a hoarse voice and severe cough suggest laryngeal TB, which is highly infectious. Signs may be few: crackles over the apex, signs of an effusion, cachexia, and, rarely, clubbing.

The complications are massive haemoptysis (from erosion of a vessel in a cavity, a Rasmussen aneurysm), pneumothorax, empyema, bronchiectasis, a fungal ball (aspergilloma) in a cavity, fibrosis and respiratory failure, and cor pulmonale. Extrapulmonary disease affects about one in six of notified cases worldwide (more in the immunocompromised) and includes:

• lymph node TB (cervical nodes, the commonest, firm and painless, with a "cold abscess");
• pleural TB (a lymphocytic exudate, see pleural effusions);
• miliary TB, with fever, weight loss, hepatosplenomegaly and millet-seed nodules on the film;
• meningitis (the most serious), bone and spine disease (Pott's disease), pericarditis, abdominal TB, genitourinary TB and skin disease.

In HIV with a low CD4 count, the picture is atypical: more lower-lobe disease, less cavitation, more extrapulmonary and disseminated disease, and a smear that may be negative.

04Diagnosis and management

Diagnosis

Suspect TB in anyone with a cough for more than 3 weeks, haemoptysis, weight loss and fever, or an abnormal chest film, especially with a risk factor. Tests:

• Chest X-ray: upper-zone consolidation, cavities with thick walls, fibrosis with volume loss, calcified nodules, an effusion, enlarged hilar nodes, or the miliary pattern. A normal film makes pulmonary TB unlikely (but does not exclude it in HIV).
• Sputum for AFB: at least two or three specimens, ideally early morning (the more samples, the higher the yield). If the patient cannot produce sputum, an induced sputum or bronchoscopy with lavage is used.
• Smear microscopy: Ziehl–Neelsen or the more sensitive fluorescent auramine–rhodamine staining. A smear-positive patient is infectious.
• Culture: liquid media in 1 to 3 weeks (longer on solid Löwenstein–Jensen or Middlebrook media, 3 to 8 weeks). It is the gold standard and gives the drug sensitivities.
• Nucleic acid amplification tests (PCR), such as Xpert MTB/RIF (now the Ultra cartridge): results in under 2 hours, detect M. tuberculosis DNA in smear-negative samples too, and detect the rpoB mutations that cause rifampicin resistance, a marker of MDR-TB. A rapid molecular test is now recommended as the first test. Whole-genome sequencing is replacing phenotypic testing in some countries.
• Other: biopsy for granulomas with caseation (nodes, pleura), pleural fluid with adenosine deaminase, CSF for meningitis, imaging for extrapulmonary sites, and a urine lipoarabinomannan (LAM) test in advanced HIV.
• Latent TB is detected by the tuberculin skin test (Mantoux) or an interferon-γ release assay (IGRA). Neither tells latent from active infection, and false-negative results are common in HIV, and in the very old and very young. BCG and most non-tuberculous mycobacteria cause false-positive skin tests but not IGRAs, which are specific (they use ESAT-6 and CFP-10; M. kansasii, M. szulgai and M. marinum are rare exceptions).
• Before treatment: an HIV test, a hepatitis B and C screen, liver and kidney function, a full count, baseline visual acuity and colour vision.

Treatment of drug-sensitive TB

The aim is to cure, to prevent resistance and to stop spread. A single drug breeds resistance, and the bacilli differ in their metabolic state, so several drugs are used together and for a long time.

The standard regimen is 2HRZE/4HR: isoniazid, rifampicin, pyrazinamide and ethambutol for 2 months (the intensive phase), then isoniazid and rifampicin for 4 months (the continuation phase), a total of 6 months. Meningitis is treated for 12 months, with HRZE for 2 months and then HR for 10, and dexamethasone tapered over several weeks (4 to 8 in UK guidance, up to 12 in some textbooks); a corticosteroid is also used for pericarditis. A 4-month regimen of rifapentine, moxifloxacin, isoniazid and pyrazinamide is an alternative for people aged 12 and over who weigh at least 40 kg, with pulmonary or non-severe disease. It is not used in severe extrapulmonary TB, in HIV with a CD4 count below 100, or in pregnancy and breastfeeding.

Management supports the drugs:

• Adherence: education and directly observed therapy for those likely to default (the homeless, substance misusers, people with mental illness or past non-adherence, those with drug-resistant TB).
• Monitoring: liver tests and weight at the start and when symptoms appear; the symptoms of hepatitis (nausea, jaundice) are reported at once. Stop the drugs for jaundice, or when the transaminases exceed three times the upper limit with symptoms or five times without, then reintroduce them one at a time, with a specialist.
• Isolation: in hospital a smear-positive patient is looked after in a single room, or in a negative-pressure room if the risk of multidrug resistance is high or immunocompromised patients are on the ward. For drug-sensitive disease, isolation can be relaxed after two weeks of effective treatment, if the patient is tolerating it, the cough has settled and there is no fever, among other criteria.
• Contact tracing of household and close contacts, with screening and treatment of latent TB.
• HIV: antiretroviral therapy is started within 2 to 8 weeks, depending on the CD4 count (in TB meningitis it may be delayed for 4 to 8 weeks), with attention to rifampicin interactions and immune reconstitution inflammatory syndrome.
• Pregnancy: HRZE is safe (pyridoxine given); streptomycin is avoided.

Drug-resistant TB

Resistance is acquired through incomplete treatment and spreads from person to person. Isoniazid resistance is found in about one in ten isolates in the UK. Multidrug-resistant TB (MDR-TB) is resistant to both isoniazid and rifampicin, and rifampicin-resistant (RR) and MDR-TB are now grouped together. Extensively drug-resistant (XDR) TB was once defined by resistance to injectable agents; the definition changed in 2021 to MDR/RR-TB with resistance to a fluoroquinolone plus bedaquiline or linezolid (pre-XDR is resistance to a fluoroquinolone only), and older textbooks still give the first. The preferred regimen for MDR/RR-TB is the 6-month all-oral BPaLM (bedaquiline, pretomanid, linezolid and moxifloxacin), replacing the 18 to 24 month regimens, which included injections until 2018. A second 6-month regimen (bedaquiline, delamanid, linezolid, levofloxacin and clofazimine) and 9-month all-oral regimens, when fluoroquinolone resistance is excluded, are also recommended; the 6-month regimens are not advised for meningitis, bone or disseminated disease. Isoniazid resistance with rifampicin susceptibility is treated for 6 months with rifampicin, ethambutol, pyrazinamide and levofloxacin. Treatment is by specialists.

Latent TB and prevention

Latent TB is treated in people at high risk of progression: close contacts of cases, health workers, new entrants from high-incidence countries, people with HIV, those about to start anti-TNF or other biologic drugs, and recipients of transplants. The regimens are isoniazid and rifampicin for 3 months or isoniazid alone for 6 months, and weekly isoniazid with rifapentine for 3 months or rifampicin for 4 months are also used. BCG vaccine (a live attenuated M. bovis strain) has variable efficacy in adults but protects young children from severe forms such as meningitis and miliary TB; it is given to infants in high-risk areas in the UK and to all in many high-burden countries. Other measures include screening, treating the disease, infection control and tackling poverty, malnutrition and HIV.

Non-tuberculous mycobacteria

Non-tuberculous mycobacteria (NTM) are environmental, found in soil and water. They are not usually spread between people (M. abscessus has spread between patients with cystic fibrosis). They cause lung disease in patients with structural disease (COPD, bronchiectasis, cystic fibrosis) or immunosuppression. M. avium complex is the commonest cause of lung disease; others include M. kansasii, M. xenopi, M. malmoense and M. abscessus. Treatment is suggested for a compatible illness with repeated positive cultures, and uses several drugs, such as a macrolide with ethambutol and rifampicin, for a year or more after the cultures turn negative.

05Epidemiology

TB is one of the world's major infectious killers. About 10.7 million people fell ill with TB in 2024 and about 1.2 million died, which makes TB the leading cause of death from a single infectious agent; COVID-19 held that place in 2020 to 2022. TB and HIV are linked: TB causes about a quarter of AIDS-related deaths. Most cases occur in a few dozen countries, mostly in South-East Asia, Africa and the Western Pacific. Drug resistance is a threat: about 390 000 people a year develop MDR/RR-TB, and fewer than half of them are diagnosed and treated.

In Europe the incidence is low and falling in most countries, with a higher rate in cities, among migrants from high-incidence countries and among the homeless, prisoners and the immunocompromised. Eastern Europe and Central Asia, though, have some of the highest proportions of MDR-TB among new cases in the world. TB is a disease of poverty, and the main drivers are poverty, malnutrition, HIV, diabetes, smoking, alcohol and overcrowding.

06Prognosis

Untreated pulmonary TB is often fatal: in HIV-negative patients with smear-positive disease, about 70 per cent died within 10 years without treatment, against about 20 per cent for smear-negative, culture-positive disease. With full treatment, drug-sensitive TB is cured in nearly all patients who complete treatment, with a global treatment success rate of about 88 per cent, and a relapse rate of a few per cent. Success is lower for MDR/RR-TB (about 70 per cent globally), and lower again, about 65 per cent, for XDR disease. Deaths on treatment are mostly in those who present late, with HIV, or malnourished.

The lung may be left with scarring, bronchiectasis, a cavity with a fungal ball, or chronic airflow obstruction, which is called post-TB lung disease and may need long-term follow-up. TB meningitis carries high mortality and disability even when treated. Relapse and reinfection are possible, so patients are told to come back if symptoms return.