Tuberculosis natural history, complications and prognosis

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: João André Alves Silva, M.D. [2]

Overview

Tuberculosis can have pulmonary and extra-pulmonary manifestations as well as severe parenchymal, vascular, pleural and chest wall complications. Pulmonary complications include pleural effusions, cavitations, lymphadenopathy, airway obstruction, pneumonia and bronchiectasis. The hematogenous dissemination of infection can lead to miliary tuberculosis. The post-primary infection can be due to either a recent infection or reactivation of an old infection. Without treatment, 1/3 of patients with active tuberculosis die within 1 year of diagnosis, and more than 50% die during the first 5 years. With early diagnosis and optimal medical therapy, M. tuberculosis infections have a good prognosis.

Natural History

Without treatment, 1/3 of patients with active tuberculosis die within 1 year of the diagnosis, and more than 50% during the first 5 years. Patients who have a positive sputum smear test for M. tuberculosis have a 5-year mortality rate of 65%. Those who survive past 5 years have a 60% probability of spontaneous remission.

Primary Pulmonary Tuberculosis

Primary tuberculosis develops soon after infection with M. tuberculosis and differs from clinical illness. In endemic regions, this form of TB is frequently seen at younger ages. Primary TB may be asymptomatic, or include mild symptoms, such as cough, fever and chest pain, related to pleurisy. Some patients may develop concomitant symptoms, such as erythema nodosum in the lower limbs and phlyctenulosis. The initial lesion (Ghon focus) often resolves spontaneously, becoming a calcified nodule that may be identified on the chest X-Ray. Pleuritic chest pain often results from the pleural reaction to the underlying Ghon focus.

Primary tuberculosis progresses more rapidly in patients with impaired immune system and in children, who commonly have immature cellular immunity. Progression of the disease leads to the enlargement of the Ghon focus. The disease may have the following manifestations:

• Pleural effusion - results from invasion of the pleural space by M. tuberculosis. This occurs more frequently when the focus of infection is subpleural.
• Cavitation - results from rapid enlargement of the Ghon focus, with ensuing necrosis of its nucleus.
• Lymphadenopathy - the spread of M. tuberculosis from the lungs to lymph leads to the enlargement of lymph nodes, especially of the paratracheal and perihilar regions.
• Airway obstruction - with symptoms of shortness of breath and wheezing. Commonly occurs in cases of severe enlargement of the lymph nodes, that compress the airways and possibly lead to distal collapse, partial obstruction with wheezing, or hyperinflation.
• Pneumonia - may occur when there is rupture and leakage of lymph node content into the airways.
• Bronchiectasis - progressive pneumonia may damage a specific segment of the lung, or an entire lobe, leading to bronchiectasis.

Primary infection leads to dissemination of M. tuberculosis through the blood. Hematogenous dissemination is often contained by an healthy immune system, however, in cases of compromised immune response, miliary tuberculosis may occur. Dissemination of the mycobacteria may lead to the formation of granulomatous lesions in other organs, which may develop different forms of the disease.

Chest X-Ray of patient with Miliary TuberculosisImage from Wikimedia Commons

Secondary Pulmonary Tuberculosis

Also known as "adult-type" or "post primary tuberculosis". May result from recent infection with M. tuberculosis, or from the reactivation of an endogenous focus that contained the latent form of the disease. Without treatment, about 1/3 of patients dies within months of disease onset. Of the remaining 2/3, some may experience remission, while others develop a chronic condition with debilitating symptoms. The surviving patients may show fibrotic and calcified lesions, as well as cavitations in some areas of the lungs, which may be later appreciated on a chest X-Ray.

Disease onset is insidious and unspecific, presenting with symptoms that may include:

• Fever
• Night sweats
• Weakness
• Malaise
• Anorexia
• Weight loss
• Cough (90% cases) - nonproductive at the outset, more frequent during the morning, that gradually progresses to productive cough, with purulent sputum, with occasional streaks of blood
• Hemoptysis (20-30% cases) may occur in the following cases:

• Rupture of a blood vessel on a cavity wall (severe hemoptysis)
• Rupture of a pulmonary artery aneurysm adjacent or within a tuberculous cavity (Rasmussen's aneurysm)
• Formation of an aspergilloma in a lung cavity

• Pleuritic chest pain
• Dyspnea (in severe disease)
• ARDS

Complications

Tuberculosis may be localized to the lungs, or involve other organs and regions of the body. Pulmonary TB may lead to permanent damage of the lungs and affected structures. Depending on the pulmonary, or extrapulmonary nature of the lesions, potential complications that may arise include:

Parenchymal Lesions

Complication	Description
Tuberculoma	Single or multiple lesions of > 0.5 cm May occur in primary or secundary TB Main finding on the chest X-ray in 5% of the cases of secondary TB Caused by inflammatory or connective tissue surrounding M. tuberculosis The center of the tuberculoma is often necrotic Satellite lesions in 80% of the cases Nodular or diffused calcifications in 20-30% of the cases
Cicatrization	Common in secondary TB Marked fibrosis in ≤40% of secondary TB cases, which may present as: Upper lobe atelectasis Compensatory hyperinflation of the lower lobe Hilar retraction Mediastinal shift Unspecific X-Ray findings may include: Parenchymal bands Fibrotic cavities Fibrotic nodules Traction bronchiectasis
Thin-walled cavity	Present in active and inactive forms of the disease May regress with treatment Air-filled cysts may persist May be misidentified as an emphysematous bulla or pneumatocelle.
Aspergilloma	Mass of hyphae, cell debris and mucus, commonly located in a cavity or bronchus Previous history of chronic cavitary TB in 25-55% of cases presenting with aspergilloma Frequently concomitant with hemoptysis in 50-90% of the cases X-ray shows a mobile mass ringed by an air shadow CT shows a mobile mass, generally interspaced with air shadows May be calcified
Lung destruction	Common in later stages of TB Involvement of the airways and parenchyma May follow primary TB or secondary TB Spreads across the lung with cavitation and fibrosis Concomitant infection with bacteria or fungi may occur Complicates assessment of TB activity in the lung with the chest X-ray
Bronchogenic carcinoma	May be misinterpreted as TB progression Scar formation in TB may lead to carcinoma May cause reactivation of TB

Airway Lesions

Complication	Description
Bronchiectasis	Result from the bronchial wall involvement, with fibrosis, and secondary bronchial dilation, often called traction bronchiectasis Identified on CT in 30-60% of cases of secondary TB, and in 71-86% of cases of inactive TB Highly suggestive of TB when located at the apical-posterior segment of the lung
Tracheobronchial stenosis	Predominance on the left main bronchus Caused by: Granulomatous tracheobronchial wall changes Enlargement of peribronchial lymph nodes pressing on the tracheobronchial wall Endobronchial involvement in 2-4% of the cases Tracheobronchial narrowing from the formation of intraluminal granulation tissue CT scan findings may include: Uniform wall thickening Mediastinal lymph node enlargement Concentrical luminal narrowing
Broncholithiasis	Rare complication Calcified material within the tracheobronchial lumen, originated on a calcified lymph node Recurrent pneumonia and hemoptysis are frequent in broncholithiasis On the chest X-ray, common findings may include: Airway obstruction Atelectasis Air trapping on expiration Frequent change in position of the calcified material Mucoid impaction CT scan findings may include: Endo or peribronchial calcified lymph nodes Atelectasis Obstructive pneumonitis Bronchiectasis

Vascular Lesions

Complication	Description
Pulmonary or bronchial arteritis and thrombosis	Perform acid-fast staining whenever in presence of necrotizing granulomatous pulmonary vasculitis to rule out TB
Bronchial artery dilatation	Common in parenchymal TB or TB complicated by bronchiectasis CT is the imaging test of choice for diagnosis, allowing identification of dilated bronchial arteries. It avoids wrongful biopsy of an hypertrophied bronchial artery, instead of a lymph node.
Rasmussen's aneurysm	Results from the replacement of normal media and adventitia by granulation tissue that weakens the arterial wall Commonly presents with hemoptysis Life-threatening when massive hemoptysis occurs

Mediastinal Lesions

Complication	Description
Esophagobronchial fistula	Occurs when an infected lymph node erodes the bronchial wall
Esophagomediastinal fistula	Rare Complication of tuberculous lymphadenitis May lead to: Strictures Mediastinal or tracheobronchial fistulas Traction diverticulae Common symptoms include: Fever Cough Weight loss Dysphagia Chest discomfort Back pain Common envolvement of the subcarinal region
Constrictive pericarditis	Complicates 1% of TB cases Frequently caused by extension of tuberculous lymphadenitis May occur in miliary TB Common findings on CT may include: Lymphadenopathy Pericardial thickening Pericardial effusion may be present 10% of cases of tuberculous pericarditis complicate into constrictive pericarditis
Lymph node calcification	83-96% of pediatric cases occur with lymphadenopathy Commonly affected adults: Pubertal women Elderly Immunosuppressed patients Caseating granulomas, cause mediastinal lymphadenitis (predominantly on the right side) Affected lymph nodes show central attenuation (caseating material) and peripheral enhancement (hypervascularity and inflammatory reaction) on CT.
Fibrosing mediastinitis	Rare May present with mild symptoms, such as: Low-grade fever Cough Related to compression of neighboring structures (airways, esophagus and superior vena cava) Granulomas may lead to fibrosing mediastinitis Chest X-ray findings may include: Mediastinal widening Localized mass CT findings may include: Hilar or mediastinal mass Calcification Tracheobronchial narrowing Obstruction of the superior vena cava Pulmonary infiltrates May cause bronchial obstruction, and consequently: Obstructive pneumonia Atelectasis
Extranodal extension	Commonly affects the following structures: Bronchus Pericardium Esophagus

Pleural Lesions

Complication	Description
Bronchopleural fistula	May occur: Spontaneously After trauma After surgery Associated with high a mortality rate: Acute phase - due to toxicity, tension pneumothorax, or disease spread Chronic phase - multiple seedings of bacteria Diagnostic findings include: Increased sputum production Changes in the air-fluid level Air trapping in the pleural space Spread of pneumonic infiltration to the contralateral lung
Fibrothorax and chronic empyema	Pleural infection may occur following: Rupture of a subpleural focus of infection Lymph node infection caused by hematogenous dissemination Chronic empyema may follow tuberculous pleurisy CT findings in chronic tuberculous empyema may include: Pleural thickening Calcification Disease inactivity is marked by absence of effusion with persistence of pleural thickening Infected pleura may alter lipid and cholesterol transfer across the membrane, causing lipid accumulation in the pleural fluid
Pneumothorax	Occurs in about 5% of patients with secondary TB Rare in miliary TB Present in severe stages of tuberculous lung disease Commonly follows empyema and bronchopleural fistula Consider active TB if after reexpansion, apical changes are noted

Chest Wall Lesions

Complication	Description
Tuberculous spondylitis (Pott's disease)	Hematogenous spread of pulmonary TB Commonly affected areas include: Lower thoracic vertebrae Upper lumbar vertebrae X-ray findings in the early stage of the disease may include: Vertebral end plate irregularities Reduction of the intervertebral disk space Adjacent bone sclerosis In later stages of the disease, kyphosis, due to anterior compression of the vertebral bodies, and paravertebral abscesses may occur CT findings may include: Paravertebral abscess Peripheral rim enhancement Area of low-attenuation at the center of the abscess, after enhancement
Rib tuberculosis	In the chest wall, TB may involve: Rib Sternum Sternoclavicular joint Characterized by: Abscesses Bone destruction Masses of the soft tissues, possibly calcified, which may, or may not show lung or pleural involvement on the CT scan Chest wall bones and cartilages may be normal Hematogenous or direct dissemination from the infectious foci to the chest wall bone Empyema necessitatis - subcutaneous abscess resulting from the discharge of an empyema through the parietal pleura
Malignancy	Rarely associated with tuberculous empyema (average of 25 years of chronic empyema until the diagnosis of malignancy) Malignancy frequency according to the histopathologic diagnosis: Malignant lymphoma Squamous cell carcinoma Mesothelioma Malignant fibrous histiocytoma Liposarcoma Rhabdomyosarcoma Angiosarcoma Hemangioendothelioma Malignancy may occur due to: Prolonged inflammatory process in he case of malignant lymphoma Action of oncogenic substances in the pleura or prolonged stimulation of mesothelial cells in other types of malignancy Chest X-ray findings include: Bone destruction around the region of the empyema Increased thoracic cavity opacity Medial deviation of the affected pleura Swelling of the soft-tissue CT scan findings may include: Enhancement of a mass around the region of the empyema Attenuation of soft tissues surrounding the empyema Perform biopsy to differentiate between infection and malignancy

Prognosis

• If untreated, active TB is often fatal. According to studies performed in several countries, 1/3 of the untreated patients died within 1 year after the diagnosis, while > 50% died within the first 5 years. However, with early diagnosis and adequate treatment, these patients have a good prognosis.
• Symptoms of uncomplicated TB usually improve after 2-3 weeks of treatment initiation.
• Improvements in the chest X-ray require several weeks to months to be noted.