Tuberculosis (TB) is a chronic granulomatous disease. In humans it is caused by bacteria of the Mycobacterium tuberculosis complex (which includes M. tuberculosis, M. bovis and M. africanum). It is most commonly spread by inhalation of infected droplets (accounts for almost all cases in the UK). Infectious patients cough up huge numbers of mycobacteria, which can survive in the environment for long periods of time.
When M. tuberculosis is first encountered (primary infection), host macrophages in the lung engulf the organisms and carry them to hilar lymph nodes in an attempt to control infection. Some organisms may disseminate via the lymphatics or bloodstream to distant sites. Small granulomas (tubercles) are formed around the body to contain the mycobacteria. These may heal spontaneously and the bacteria is eliminated (in 80% of cases) or bacteria are encapsulated in a defensive barrier but persist in an otherwise healthy individual where the disease is considered dormant. Only a small proportion of patients progress to overt (active) TB.
- Miliary TB occurs when primary infection is not adequately contained and invades the bloodstream, resulting in severe disease.
- Secondary TB is due to subsequent reactivation of semi-dormant M. tuberculosis and is usually precipitated by impaired immune function such as malnutrition, AIDS or immunosuppressive therapy. Reactivation usually occurs in the apex of the lungs and can spread locally or to distant sites.
In 2010 there were 8,587 cases of TB in the UK (13.9 per 100,000), a 6% reduction on the previous year. There are many areas in the UK with much higher incidence rates, and those areas with incidence greater than 40/100,000 have different immunisation policies to prevent spread. Pulmonary TB accounts for 60% of TB in the UK.
Migration within Europe, particularly from former Eastern Bloc countries, should not be forgotten, as many European countries are classed as having a high incidence of TB. The rates in different countries can be seen on the Health Protection Agency's website.
TB is still a leading cause of death, particularly in sub-Saharan Africa. In large parts of Africa, TB is epidemic because of the increased susceptibility conferred by HIV infection.
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- Close contact of TB patient: a patient with untreated, infectious pulmonary TB will infect a further 10-15 people each year. The risk of infection is related to the nature and duration of exposure, with household members of a TB index case having a 1 in 3 chance of contracting the infection. Risk also extends to healthcare workers and close contacts at school or work.
- Ethnic minority groups: 72% of TB patients are from ethnic minority backgrounds (predominantly from South Asia and sub-Saharan Africa). Those individuals born in, or who have arrived or returned from high-prevalence areas within the last 5 years, are particularly at risk. Most of these patients are diagnosed within 5 years of entering the UK but their lifetime risk of developing TB remains higher than average and extends to their children and close contacts born in the UK. Rates of infection are particularly high in people from the Indian subcontinent and sub-Saharan Africa.
- Homeless patients, alcoholics and other drug abusers: poverty, malnutrition, overcrowding and poor housing encourage the spread of TB. Accurate estimates of the rates of TB in homeless people are unknown but thought to be more than 150 times the UK average. Persons who have recently been in prison may also be at increased risk.
- HIV-positive and other immunocompromised patients: worldwide, up to 60% of AIDS patients develop TB and the disease accounts for a third of all AIDS-related deaths. Rates of such concurrent infections in the UK are proportionally low but at least 3% of people with TB are HIV-positive. Patients on immunosuppressant drugs are particularly at risk (eg infliximab and etanercept, azathioprine, ciclosporin, etc.).
- Elderly patients: latent TB may reactivate in elderly patients.
- Other conditions: debilitating disease (especially haematological and some solid cancers), long-term steroids, diabetes, end-stage renal disease, silicosis and gastrectomy/jejuno-ileal bypass all confer an increased risk.
- Children: young children are particularly susceptible to mycobacterial infection, due to their immature immune systems. Children themselves are rarely infectious, as cavitating disease is uncommon but they will often have a close infectious contact.
The onset of TB is insidious. Primary infection is usually asymptomatic. The presentation of secondary infection is variable and often nonspecific. A high index of suspicion in patients from particular risk groups is essential to make a diagnosis. TB can affect all organs and body systems. Extrapulmonary TB is more common in children or in the immunosuppressed.
- General symptoms: fatigue, malaise, fever, weight loss, anorexia, failure to thrive and pyrexia of unknown origin (PUO).
- Pulmonary: respiratory TB accounts for 60% of cases in the UK. Symptoms include chronic, productive cough with purulent ± bloodstained sputum. May result in lobar collapse, bronchiectasis, pleural effusion and pneumonia.
- Genitourinary: the most common site outside the lungs often presents with 'sterile' pyuria. There may be kidney lesions, salpingitis, abscesses and infertility in females and swelling of the epididymis in males.
- Musculoskeletal: pain, arthritis, osteomyelitis and abscess formation (eg loin mass or psoas abscess from spinal TB), nerve root compression, isolated bone or joint lesions (monoarthritis).
- Central nervous system: tuberculous meningitis and tuberculomas - initially nonspecific symptoms (headache, vomiting, altered behaviour) followed by diminished consciousness ± focal neurological signs.
- Gastrointestinal: mainly ileocaecal lesions (abdominal pain, bloating, obstruction and simulating appendicitis) but occasional peritoneal spread causes ascites.
- Lymph nodes: hilar, paratracheal or superficial node involvement. Palpable nodes may be initially tender, firm and discrete but later matted and suppurative with discharging sinuses.
- Skin: erythema nodosum (represents an early immunological response to infection), skin sinus formation ("scrofuloderma"), erythema induratum.
- Pericardial: initially nonspecific; may be signs of pericardial effusion (pulsus paradoxus, elevated JVP) or constrictive pericarditis.
TB must not be forgotten and must be suspected amongst the differential diagnosis for carcinoma, lymphoma, pneumonia, PUO, fibrotic lung disease (eg sarcoidosis, extrinsic allergic alveolitis, pneumoconiosis and silicosis), chronic diseases such as anorexia nervosa and diabetes.
- CXR is essential even in non-pulmonary disease, as there may have been pulmonary infection.
- Primary TB usually appears as a central apical portion with a left lower-lobe infiltrate or pleural effusion.
- Reactivated TB - there is no pleural effusion and lesions are apical in position.
- Severe disease with poor immune response can produce a picture like millet seeds over the CXR. Hence the name miliary tuberculosis.
- Pulmonary TB is unlikely with a normal CXR.
Typical TB appearances include:
- Patchy or nodular shadows in the upper zones, loss of volume, fibrosis ± cavitation.
- Uniform 1-10 mm shadows throughout the lung in miliary TB.
- Microbiological samples: firm diagnosis rests on isolating the infecting organism, and subsequent sensitivity testing can be used to guide antibiotic therapy. Isolation of the organism can be difficult.
- Respiratory TB:
- Send at least 3 spontaneous sputum samples for culture and microscopy (including one early morning sample).
- If spontaneous sputum samples are not possible then consider bronchoscopy and lavage or, in children, gastric washings.
- Take samples before starting treatment or within 7 days of starting.
- Start treatment without culture results if there are clinical signs and symptoms of TB and complete treatment even if the culture results are negative.
- Send autopsy samples for culture if respiratory TB is suspected.
- If sputum cannot be expectorated or repeated specimens are negative, bronchoscopy and bronchial washings should be considered.
- Non-respiratory TB:
- Discuss the advantages and disadvantages of biopsy and needle aspiration with the patient.
- Send samples in a dry pot for TB culture. These may be lymph node biopsies, aspirated pus, early morning urine or any other samples.
- Start drug treatment, if the histology and clinical picture are consistent with TB, before culture results are available.
- Continue treatment even if culture results are negative.
- CXR should be done for co-existing respiratory TB in all patients with non-respiratory TB. Other investigations should also be considered.
- Staining with Ziehl-Neelsen (ZN) stain and rapid direct microscopy for acid/alcohol-fast bacilli.
- Culture on a Löwenstein-Jensen slope which takes 4-8 weeks due to slow bacterial growth.
- Respiratory TB:
- Laboratory tests:
- Risk factors - check HIV, hepatitis B and hepatitis C status.
- Only perform rapid diagnostic tests (molecular probes) on primary specimens:
- When rapid confirmation of TB would alter care of the patient.
- Before conducting large contact-tracing initiatives.
- If clinical signs and test results suggest TB meningitis, start treatment even when rapid test results are negative (false negatives may well occur).
- If risk assessment suggests multidrug-resistant (MDR) TB then:
- Do rapid diagnostic tests for rifampicin resistance.
- Start infection control measures and treat the MDR TB whilst awaiting test results.
See separate article Tuberculosis Prevention and Screening.
- Offer Mantoux testing to diagnose latent TB in people who are either household contacts or close work or school contacts (aged 5 years and older) of all patients diagnosed with active TB.
- As the Mantoux test may be positive in patients who have had the bacillus Calmette-Guérin (BCG) vaccine, interferon-gamma testing is recommended as a second-line test for people whose Mantoux testing shows positive results, or instead of Mantoux test in people for whom Mantoux testing may be less reliable - for example, BCG vaccinated people.
- If Mantoux testing is inconclusive, refer the person to a TB specialist.
Management of active tuberculosis
- Notification: all cases of tuberculosis (TB) must be notified under under the Public Health (Infectious Diseases) Regulations 1988, to provide surveillance data and to initiate contact tracing and nursing input. The doctor suspecting the diagnosis is legally responsible for notification of the consultant in communicable disease control (CCDC).
- Staff and services: all health authorities should have an integrated policy for prevention and control of TB. Most cases can be managed as outpatients but occasional admission may be needed. Patients with suspected TB should be admitted to a single side-room vented to the outside until they are proven to be non-infectious. Consideration should also be given to the likelihood of MDR and the immune status of the other patients on the ward. Only physicians with full training and expertise in management of TB with access to TB nurse specialists and health visitors should be responsible for patients with respiratory TB.
- Drug treatment:
- Standard regimen is a six-month, four-drug initial regimen (six months of isoniazid and rifampicin supplemented in the first two months with pyrazinamide and ethambutol) - used for respiratory TB.
- Patients with active meningeal TB have a 12-month regimen, initially 4 drugs (isoniazid, pyrazinamide, rifampicin and a fourth drug (for example, ethambutol)) for the first two months, followed by isoniazid and rifampicin for the rest of the treatment period plus a glucocorticoid (prednisolone 20-40 mg if on rifampicin, otherwise 10-20 mg for adults; 1-2 mg/kg for children (max 40 mg). Gradual steroid withdrawal can start after 2 weeks of treatment.
- Patients with HIV co-infection should follow the British HIV Association guideline.
- Compliance: this is a major determinant of the success of drug treatment, as it is essential to prevent treatment failure and acquisition of drug resistance. A patient should always be aware of their diagnosis and be prepared for a long course of treatment. Supervised therapy can improve compliance in some treatment groups. Directly observed therapy (DOT) is not usually necessary - but patients should be assessed for compliance at the initiation of therapy; it may be appropriate for homeless street dwellers, etc. All patients should have a key worker whom they can contact for more information.
- Isoniazid is the most potent bactericidal drug. It has good penetration of tuberculous lesions and is excreted by the kidneys.
- Rifampicin is a potent mycobacterial RNA polymerase inhibitor. It has good tissue penetration and gives an orange discoloration to body fluids. It is metabolised by the liver and excreted in urine and bile. Rifampicin is a cytochrome P450 enzyme inducer and therefore interacts with the effects of other drugs.
- Pyrazimamide is bacteriostatic against semi-dormant, intracellular mycobacteria and is excreted by the kidneys.
- Ethambutol gradually inhibits mycobacterial growth and is excreted in urine and faeces.
Treatment is divided into an initial phase and a continuation phase. Occasionally, extended regimens are used.
Second-line agents are used by specialists in certain situations (for example, resistance and intolerance) and include: amikacin, capreomycin, cycloserine, macrolides (azithromycin, clarithromycin) and quinolones (moxifloxacin, levofloxacin).
Streptomycin is unlicensed and now rarely used in the UK.
Treatment of latent infection
Treat contacts if active TB has been excluded (by CXR and clinical examination), but latent TB likely because they are interferon-gamma positive, or Mantoux positive (either 6 mm or greater without prior BCG vaccination or strongly positive (≥15 mm) with prior BCG vaccination), or TB nodules on CXR without history of adequate treatment.
- Treatment is either 6 months of isoniazid (6H) or three months of rifampicin and isoniazid (3RH).
- If HIV positive, 6 months of isoniazid (6H) is preferred.
- Contacts aged ≤35 years of people with isoniazid-resistant TB get 6 months of rifampicin (6R).
Further reading & references
- Tuberculosis, World Health Organization
- Tuberculosis, Health Protection Agency
- National Knowledge Service - TB
- Immunisation - The Green Book; Dept of Health
- Tuberculosis, NICE Clinical Guideline (March 2011)
- Tuberculosis Fact Sheet, World Health Organization
- Tuberculosis Update, Health Protection Agency (March 2011)
- World Health Organization (WHO) estimates of tuberculosis incidence by country, 2009 (sorted by country); Health Protection Agency
- Maartens G, Wilkinson RJ; Tuberculosis. Lancet. 2007 Dec 15;370(9604):2030-43.
- BTS; Chemotherapy and management of tuberculosis in the United Kingdom: recommendations 1998. Joint Tuberculosis Committee of the British Thoracic Society. Thorax. 1998 Jul;53(7):536-48.
- Stopping Tuberculosis in England: An action plan from the Chief Medical Officer, Dept of Health, 2004
- Kumar P and Clark M. Respiratory Disease. In Clinical Medicine, Fourth Edition (1999), pp 745-827. London: WB Saunders.
- Scheinfeld NS, Erythema induratum (Nodular Vasculitis), Medscape, Oct 2010
- Guidelines for the treatment of TB/ HIV co-infection, British HIV Association (2009)
|Original Author: Dr Richard Draper||Current Version: Dr Huw Thomas||Peer Reviewer: Dr Hayley Willacy|
|Last Checked: 28/09/2011||Document ID: 474 Version: 27||© EMIS|
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