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588 • RESPIRATORY MEDICINE (p. 594). If these reparative processes fail, primary progressive disease ensues (Fig. 17.36). The estimated lifetime risk of developing disease after primary infection is 10%, with roughly half of this risk occurring in the first 2 years after infection. Factors predisposing to TB are summarised in Box 17.45 and the natural history of infection with TB is summarised in Box 17.46. Clinical features: pulmonary disease Primary pulmonary TB Primary TB refers to the infection of a previously uninfected (tuberculin-negative) individual. A few patients develop a self- limiting febrile illness but clinical disease occurs only if there is a hypersensitivity reaction or progressive infection (Box 17.47). Progressive primary disease may appear during the course of the initial illness or after a latent period of weeks or months. Miliary TB Blood-borne dissemination gives rise to miliary TB, which may present acutely but more frequently is characterised by 2–3 weeks of fever, night sweats, anorexia, weight loss and a Fig. 17.34 Worldwide incidence of tuberculosis (2014). Estimated new cases (all forms) per 100 000 population. From World Health Organisation. Global tuberculosis report, 20th edn. Geneva: WHO; 2015. 0–9.9 10–19 20–49 50–124 125–299 300–499 ≥500 No data Not applicable Fig. 17.35 Tuberculous granuloma. Normal lung tissue is lost and replaced by a mass of fibrous tissue with granulomatous inflammation characterised by large numbers of macrophages and multinucleate giant cells (white arrow). The central area of this focus shows caseous degeneration (black arrow). Courtesy of Dr William Wallace, Department of Pathology, Royal Infirmary of Edinburgh. Tuberculosis Epidemiology Tuberculosis (TB) is caused by infection with Mycobacterium tuberculosis (MTB), which is part of a complex of organisms including M. bovis (reservoir cattle) and M. africanum (reservoir humans). The resurgence in TB in the UK observed over the latter part of the last century has finally halted and notification of TB has fallen by around 1.5% per year since 2000. None the less, its impact on world health remains significant. An estimated 9.6 million new cases were recorded in 2014, with the majority presenting in the world’s poorest nations, which struggle to cover the costs associated with management and control programmes (Fig. 17.34). In the same year, 1.5 million men, women and children died of TB, and TB continues to rank alongside HIV as a leading cause of death worldwide. Pathology and pathogenesis M. bovis infection arises mainly drinking non-sterilised milk from infected cows. M. tuberculosis is spread by the inhalation of aerosolised droplet nuclei from other infected patients. Once inhaled, the organisms lodge in the alveoli and initiate the recruitment of macrophages and lymphocytes. Macrophages undergo transformation into epithelioid and Langhans cells, which aggregate with the lymphocytes to form the classical tuberculous granuloma (Fig. 17.35). Numerous granulomas aggregate to form a primary lesion or ‘Ghon focus’ (a pale yellow, caseous nodule, usually a few millimetres to 1–2 cm in diameter), which is characteristically situated in the periphery of the lung. Spread of organisms to the hilar lymph nodes is followed by a similar pathological reaction, and the combination of the primary lesion and regional lymph nodes is referred to as the ‘primary complex of Ranke’. Reparative processes encase the primary complex in a fibrous capsule, limiting the spread of bacilli. If no further complications ensue, this lesion eventually calcifies and is clearly seen on a chest X-ray. Lymphatic or haematogenous spread may occur before immunity is established, however, seeding secondary foci in other organs, including lymph nodes, serous membranes, meninges, bones, liver, kidneys and lungs, which may lie dormant for years. The only clue that infection has occurred may be the appearance of a cell-mediated, delayed-type hypersensitivity reaction to tuberculin, demonstrated by tuberculin skin testing or an interferon gamma release assay (IGRA): so-called latent TB
Infections of the respiratory system • 589 17 Fig. 17.36 Primary pulmonary tuberculosis. (1) Spread from the primary focus to hilar and mediastinal lymph glands to form the ‘primary complex’, which heals spontaneously in most cases. (2) Direct extension of the primary focus – progressive pulmonary tuberculosis. (3) Spread to the pleura – tuberculous pleurisy and pleural effusion. (4) Blood-borne spread: few bacilli – pulmonary, skeletal, renal, genitourinary infection, often months or years later; massive spread – miliary pulmonary tuberculosis and meningitis. 1 2 4 3 dry cough. Hepatosplenomegaly may develop and the presence of a headache may indicate coexistent tuberculous meningitis. Auscultation of the chest is frequently normal but in more advanced disease widespread crackles are evident. Fundoscopy may show choroidal tubercles. The classical appearances on chest X-ray are of fine 1–2 mm lesions (‘millet seed’) distributed throughout the lung fields, although occasionally the appearances are coarser. Anaemia and leucopenia reflect bone marrow involvement. ‘Cryptic’ miliary TB is an unusual presentation sometimes seen in old age (Box 17.48). Post-primary pulmonary TB Post-primary disease refers to exogenous (‘new’ infection) or endogenous (reactivation of a dormant primary lesion) infection in a person who has been sensitised by earlier exposure. It is most frequently pulmonary and characteristically occurs in the apex of an upper lobe, where the oxygen tension favours survival of the strictly aerobic organism. The onset is usually insidious, developing slowly over several weeks. Systemic symptoms include fever, night sweats, malaise and loss of appetite and weight, and are accompanied by progressive pulmonary symptoms (Box 17.49). Very occasionally, this form of TB may present with one of the complications listed in Box 17.50. Radiological changes include ill-defined opacification in one or both of the upper lobes, and as progression occurs, consolidation, collapse and cavitation develop to varying degrees (Fig. 17.37). It is often difficult to distinguish active from quiescent disease on radiological criteria alone but the presence of a miliary pattern or cavitation favours active disease. In extensive disease, collapse may be marked and results in significant displacement of the trachea and mediastinum. Occasionally, a caseous lymph node may drain into an adjoining bronchus, leading to tuberculous pneumonia. 17.46 Natural history of untreated primary tuberculosis Time from infection Manifestations 3–8 weeks Primary complex, positive tuberculin skin test 3–6 months Meningeal, miliary and pleural disease Up to 3 years Gastrointestinal, bone and joint, and lymph node disease Around 8 years Renal tract disease From 3 years onwards Post-primary disease due to reactivation or re-infection Adapted from Davies PDO, ed. Clinical tuberculosis. London: Hodder Arnold; 1998. 17.45 Factors increasing the risk of tuberculosis Patient-related • Age (children > young adults < elderly) • First-generation immigrants from high-prevalence countries • Close contacts of patients with smear-positive pulmonary TB • Overcrowding (prisons, collective dormitories); homelessness (doss houses and hostels) • Chest X-ray evidence of self-healed TB • Primary infection < 1 year previously • Smoking: cigarettes, bidis (Indian cigarettes made of tobacco wrapped in temburini leaves) and cannabis Associated diseases • Immunosuppression: HIV, anti-tumour necrosis factor (TNF) and other biologic therapies, high-dose glucocorticoids, cytotoxic agents • Malignancy (especially lymphoma and leukaemia) • Diabetes mellitus • Chronic kidney disease • Silicosis • Gastrointestinal disease associated with malnutrition (gastrectomy, jejuno-ileal bypass, cancer of the pancreas, malabsorption) • Deficiency of vitamin D or A • Recent measles in children 17.47 Features of primary tuberculosis Infection (4–8 weeks) • Influenza-like illness • Skin test conversion • Primary complex Disease • Lymphadenopathy: hilar (often unilateral), paratracheal or mediastinal • Collapse (especially right middle lobe) • Consolidation (especially right middle lobe) • Obstructive emphysema • Cavitation (rare) • Pleural effusion • Miliary • Meningitis • Pericarditis Hypersensitivity • Erythema nodosum • Phlyctenular conjunctivitis • Dactylitis 17.48 Cryptic tuberculosis • Age over 60 years • Intermittent low-grade pyrexia of unknown origin • Unexplained weight loss, general debility (hepatosplenomegaly in 25–50%) • Normal chest X-ray • Blood dyscrasias; leukaemoid reaction, pancytopenia • Negative tuberculin skin test • Confirmation by biopsy with granulomas and/or acid-fast bacilli in liver or bone marrow
590 • RESPIRATORY MEDICINE distortion of the bowel, with caecal involvement predominating. Diagnosis rests on obtaining histology by either colonoscopy or mini-laparotomy. The main differential diagnosis is Crohn’s disease (p. 813). Tuberculous peritonitis is characterised by abdominal distension, pain and constitutional symptoms. The ascitic fluid is exudative and cellular, with a predominance of lymphocytes. Laparoscopy reveals multiple white ‘tubercles’ over the peritoneal and omental surfaces. Low-grade hepatic dysfunction is common in miliary disease, in which biopsy reveals granulomas. Occasionally, patients may be frankly icteric, with a mixed hepatic/cholestatic picture. Pericardial disease Disease occurs in two forms (see Fig. 17.38 and p. 542): pericardial effusion and constrictive pericarditis. Fever and night sweats are rarely prominent and the presentation is usually insidious, with breathlessness and abdominal swelling. Coexistent pulmonary disease is very rare, with the exception of pleural effusion. Pulsus paradoxus, a raised JVP, hepatomegaly, prominent ascites and peripheral oedema are common to both types. Pericardial effusion is associated with increased pericardial dullness and a globular enlarged heart on chest X-ray, and pericardial calcification occurs in around 25% of cases. Constriction is associated with an early third heart sound and, occasionally, atrial fibrillation. Diagnosis is based on the clinical, radiological and echocardiographic findings (p. 542). The effusion is frequently blood-stained. Open pericardial biopsy can be performed where there is diagnostic uncertainty. The addition of glucocorticoids to antituberculosis treatment has been shown to help both forms of pericardial disease. Fig. 17.37 Chest X-ray: major manifestations and differential diagnosis of pulmonary tuberculosis. Less common manifestations include pneumothorax, acute respiratory distress syndrome (ARDS; p. 198), cor pulmonale and localised emphysema. ‘Miliary’ diffuse shadowing Differential diagnosis • Sarcoidosis • Malignancy • Pneumoconiosis • Infection (e.g. histoplasmosis) Pleural effusion/empyema Differential diagnosis • Bacterial pneumonia • Pulmonary infarction • Carcinoma • Connective tissue disorder Cavitation Differential diagnosis • Pneumonia/lung abscess • Lung cancer • Pulmonary infarct • Granulomatosis with polyangiitis (Wegener’s granulomatosis) • Progressive massive fibrosis Consolidation/collapse Differential diagnosis • Pneumonia • Bronchial carcinoma • Pulmonary infarct *From swallowed sputum. 17.50 Complications of chronic pulmonary tuberculosis Pulmonary • Massive haemoptysis • Cor pulmonale • Fibrosis/emphysema • Atypical mycobacterial infection • Lung/pleural calcification • Aspergilloma/chronic aspergillosis • Obstructive airways disease • Bronchiectasis • Bronchopleural fistula Non-pulmonary • Empyema necessitans • Laryngitis • Enteritis* • Anorectal disease* • Amyloidosis • Poncet’s polyarthritis 17.49 Clinical presentations of pulmonary tuberculosis • Chronic cough, often with haemoptysis • Pyrexia of unknown origin • Unresolved pneumonia • Exudative pleural effusion • Asymptomatic (diagnosis on chest X-ray) • Weight loss, general debility • Spontaneous pneumothorax Clinical features: extrapulmonary disease Extrapulmonary TB accounts for 20% of cases in those who are HIV-negative but is more common in HIV-positive patients. Lymphadenitis Lymph nodes are the most common extrapulmonary site of disease. Cervical and mediastinal glands are affected most frequently, followed by axillary and inguinal, and more than one region may be involved. Disease may represent primary infection, spread from contiguous sites or reactivation. Supraclavicular lymphadenopathy is often the result of spread from mediastinal disease. The nodes are usually painless and initially mobile but become matted together with time. When caseation and liquefaction occur, the swelling becomes fluctuant and may discharge through the skin with the formation of a ‘collar-stud’ abscess and sinus formation. Approximately half of cases fail to show any constitutional features, such as fevers or night sweats. The tuberculin test is usually strongly positive. During or after treatment, paradoxical enlargement, development of new nodes and suppuration may all occur but without evidence of continued infection; surgical excision is rarely necessary. In non-immigrant children in the UK, most mycobacterial lymphadenitis is caused by opportunistic mycobacteria, especially of the M. avium complex. Gastrointestinal tuberculosis TB can affect any part of the bowel and patients may present with a wide range of symptoms and signs (Fig. 17.38). Upper gastrointestinal tract involvement is rare and is usually an unexpected histological finding in an endoscopic or laparotomy specimen. Ileocaecal disease accounts for approximately half of abdominal TB cases. Fever, night sweats, anorexia and weight loss are usually prominent and a right iliac fossa mass may be palpable. Up to 30% of cases present with an acute abdomen. Ultrasound or CT may reveal thickened bowel wall, abdominal lymphadenopathy, mesenteric thickening or ascites. Barium enema and small bowel enema reveal narrowing, shortening and
Infections of the respiratory system • 591 17 immunologically mediated polyarthritis that usually resolves within 2 months of starting treatment. Genitourinary disease Fever and night sweats are rare with renal tract TB and patients are often only mildly symptomatic for many years. Haematuria, frequency and dysuria are often present, with sterile pyuria found on urine microscopy and culture. In women, infertility from endometritis, or pelvic pain and swelling from salpingitis or a tubo-ovarian abscess occurs occasionally. In men, genitourinary TB may present as epididymitis or prostatitis. Investigations The presence of an otherwise unexplained cough for more than 2–3 weeks, particularly in regions where TB is prevalent, or typical chest X-ray or CT changes (Fig. 17.39) should prompt further investigation (Box 17.51). Direct microscopy of a sputum smear remains the most important first step. At least two sputum samples (including at least one obtained in the early morning) from a spontaneously produced deep cough should be obtained. Induced sputum may be used in those unable to expectorate. In selected cases, bronchoscopy and lavage or aspiration of a lymph node by EBUS may be used. Light-emitting diode fluorescent microscopy with auramine staining is increasingly replacing the more traditional standard light microscopy and Ziehl–Neelsen stain (Fig. 17.40) or the use of mercury-vapour fluorescent microscopy. A positive smear is sufficient for the presumptive diagnosis of TB but definitive Central nervous system disease Meningeal disease represents the most important form of central nervous system TB. Unrecognised and untreated, it is rapidly fatal. Even when appropriate treatment is prescribed, mortality rates of 30% have been reported, while survivors may be left with neurological sequelae. Clinical features, investigations and management are described on page 1120. Bone and joint disease The spine is the most common site for bony TB (Pott’s disease), which usually presents with chronic back pain and typically involves the lower thoracic and lumbar spine (see Fig. 17.38). The infection starts as a discitis and then spreads along the spinal ligaments to involve the adjacent anterior vertebral bodies, causing angulation of the vertebrae with subsequent kyphosis. Paravertebral and psoas abscess formation is common and the disease may present with a large (cold) abscess in the inguinal region. CT or MRI is valuable in gauging the extent of disease, the amount of cord compression, and the site for needle biopsy or open exploration, if required. The major differential diagnosis is malignancy, which tends to affect the vertebral body and leave the disc intact. Important complications include spinal instability or cord compression. TB can affect any joint but most frequently involves the hip or knee. Presentation is usually insidious, with pain and swelling; fever and night sweats are uncommon. Radiological changes are often non-specific but, as disease progresses, reduction in joint space and erosions appear. Poncet’s arthropathy is an Fig. 17.38 Systemic presentations of extrapulmonary tuberculosis. Exudative ascites Mesenteric adenitis Intestinal obstruction Cranial nerve palsy Lymph node enlargement Pericardial effusion Constrictive pericarditis Monoarthritis Haematuria/dysuria Infertility in women Epididymitis Anorectal ulceration Headache, vomiting, seizures, delirium Lymphocytic meningitis Hydrocephalus Space-occupying lesion (tuberculoma) Kyphosis Cord compression Abdominal mass Psoas abscess General observation Weight loss Fever Night sweats Chronic back pain