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 UK). Infectious patients cough up huge numbers of mycobacteria, which can survive in the environment for long periods of time.^3,4

When Mycobacterium 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. The tubercles may heal spontaneously or calcify and persist in an otherwise healthy individual.

Only a small proportion of patients develop overt TB or further disease. 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 Mycobacterium 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 1993 the World Health Organization (WHO) declared tuberculosis to be a global emergency. There is a worsening epidemic with a variety of contributory factors and challenges to healthcare:²

• There is increased susceptibility to TB conferred by HIV infection.
• The effectiveness of the bacillus Calmette-Guérin (BCG) vaccine is only partial.
• The effectiveness of treatment of latent tuberculosis is unclear in high-incidence setting.
• The diagnostic methods used in many parts of the world are still very similar to those used 100 years ago.
• The long duration of treatment needed reduces its effectiveness.
• Multidrug-resistant (MDR) and extensively drug-resistant (XDR) disease is increasing.
• There are new diagnostic, treatment and preventative measures but the challenge is to apply these advances to the populations most at risk.
• Massive effort, political will and resources are needed for the development of a comprehensive worldwide plan co-ordinating the work of health agencies.

Worldwide

• The figures are worse now than when described as a global emergency in 1993.
• Worldwide, approximately one third of the population is infected with TB and, from this pool, about 9 million cases of active TB emerge every year.⁶
• These active cases resulted in approximately 1.7 million deaths in 2004.⁵ TB now causes nearly 2 million deaths each year.²
• It is the 2nd leading cause of death from an infectious disease (after HIV) and the leading cause of death among curable infectious diseases.⁷
• The disease is responsible for more than a quarter of all avoidable adult deaths in the developing world.
• Most new cases appear in the most populated nations - India and China, but the highest rates are seen in sub-Saharan Africa, Indonesia, the Philippines, Afghanistan, Bolivia and Peru.⁶ Rates in these regions exceed 300 cases per 100,000 per year.
• In 2004, TB incidence was stable or falling in 5 out of 6 WHO regions, but growing at 0.6% globally because of a rising TB incidence in Africa. This incidence is slowing, probably as the HIV incidence is also slowing.⁵
• Incidence in eastern Europe (mostly countries of the former Soviet Union) increased in the 1990s but has fallen since peaking in 2001.⁵

The United Kingdom

• A decline in incidence throughout the latter half of the 20th century occurred in the UK as in North America and western Europe.
• However, over the last 10 years the number of reported cases of TB is rising again in the UK:
  • There were approximately 7,000 cases in the UK in 2004 after falling to a low of 5,086 in 1987.⁴
  • There were 8,497 TB cases in the UK in 2006 with a rate of 14 per 100,000 population and 8417 cases in 2007 with a rate of 13.8 per 100,000 population. The numbers and rates have remained stable since 2005.²
  • This has been ascribed to immigration, HIV/AIDS and the neglect of TB control programmes.⁶
• 92% of cases were reported in England. London accounted for the largest proportion (39% of UK cases) and the highest regional rate (43.2 per 100,000 population).⁷
• Initially, successes were due to better nutrition and housing, effective drug treatment, improved public health measures, milk pasteurisation and the BCG vaccination.
• Infection occurs predominately in urban areas, due to immigration from developing countries with higher TB prevalence, high population densities or larger numbers of patients in the high-risk groups (see below).
• 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 HPA website.⁸

Risk factors^4,9

• 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.¹⁰
• Ethnic minority groups: 72% of TB patients are from ethnic minority backgrounds (predominantly from South Asia and sub-Saharan Africa). 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.¹⁰
• 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.¹⁰
• 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.⁵
• Elderly patients: latent TB may reactivate in elderly patients.
• Other conditions: debilitating disease, long-term steroids, diabetes, end-stage renal disease, silicosis and gastrectomy/jejuno-ileal bypass all confer an increased risk.¹¹
• 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.⁹

The onset of TB is insidious. Primary infection is usually asymptomatic. The presentation of secondary infection is variable and often non-specific. A high index of suspicion in patients from particular risk groups is essential to make a diagnosis.¹¹ TB can affect all organs and body systems. Extra-pulmonary TB is more common in children or in the immunosuppressed.
See separate articles on Non-pulmonary Tuberculosis and Childhood Tuberculosis.

• 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: arthritis, osteomyelitis and abscess formation, particularly in the spine (Pott's disease).
• Central nervous system: tuberculous meningitis and tuberculomas.
• Gastrointestinal: mainly ileocaecal lesions 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), erythema induratum.¹²

1. 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.
   Even patients with non-pulmonary disease may have CXR findings due to initial lung infection. Remember that other infections may mimic CXR appearance.
   Typical 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
2. 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.

• Sputum
• Early morning urine
• Biopsy material

• Microscopy using concentrated sputum smears is much more sensitive than with unconcentrated sputum⁶.
• If sputum cannot be expectorated or repeated specimens are negative, bronchoscopy and bronchial washings should be considered.
• Biopsy specimens should never be sent to the laboratory in formalin.

Samples are analysed by:³

• Staining with Ziehl-Nielson (ZN) stain and rapid direct microscopy for acid/alcohol-fast bacilli
• Culture on a Lowenstein-Jensen slope which takes 4-8 weeks due to slow bacterial growth.

Antibiotic sensitivity cultures take a further 3-4 weeks. Rapid detection of rifampicin resistance from cultured M. tuberculosis is now possible using molecular techniques. Results are fairly accurate and allow appropriate treatment to begin more promptly; however, results must still be confirmed with conventional techniques.¹¹

Tuberculin skin tests are rarely used in the diagnosis of tuberculous disease but can detect previous exposure to the organism (or BCG vaccination) by provocation of a well-established, cell-mediated immune reaction (see Prevention and screening below).

Serological tests have good negative predictive value except in HIV. They are used more in research. Polymerase chain reaction (PCR) is being developed but there are problems with sensitivity.

National Institute for Clinical Excellence guidance¹³

The following advice when diagnosing active TB is set out in recent National Institute for Clinical Excellent (NICE) guidance:

• Respiratory TB:
  • CXR and, if this suggests TB, arrange further tests.
  • 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 suspected.
• 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 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.
• Laboratory tests:
  • Only perform rapid diagnostic tests 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.
  • If risk assessment suggests MDR TB then:
    • Do rapid diagnostic tests for rifampicin resistance.
    • Start infection control measures and treat the MDR TB whilst awaiting test results.

Tuberculosis must not be forgotten and must be suspected amongst the differential diagnosis for carcinoma, lymphoma, pneumonia, PUO, fibrotic lung disease (e.g. sarcoidosis, extrinsic allergic alveolitis, pneumoconiosis and silicosis), chronic diseases such as anorexia nervosa and diabetes.

See separate article Tuberculosis (TB) Management.

Screening and testing of high-risk and contact groups may identify new cases (e.g. healthcare workers, new immigrants and HIV patients). In 2005 the routine BCG immunisation of schoolchildren in the UK was stopped. It has been replaced by a screening programme targeting neonates and children at greatest risk.
See separate article BCG Vaccination, and immunisation guidelines⁴ and NICE guidance.¹³ Preventing transmission of TB, contact tracing, screening and BCG vaccination are key targets in the NICE guidance.

Tuberculin skin testing^10,16

Skin testing can detect previous exposure to the organism (or BCG vaccination) by provocation of a well established, cell-mediated immune reaction. A purified protein derivative (PPD) of M. tuberculosis is injected intradermally into the flexor surface of the forearm and the local response is measured. The interpretation of tuberculin tests depends on BCG vaccination history, immune status and concurrent viral infection. For example, in HIV-positive patients, a negative tuberculin test does not exclude TB as it may be due to general anergy.
The standard skin test for TB in the UK is the Mantoux test. The Mantoux test is used (2 different strengths) both:

• As a screening test for TB infection or disease (2TU/0.1ml).
• As an aid to the clinical diagnosis of TB infection (10TU/0.1ml).

The local skin reaction to tuberculin purified protein derivative (PPD) injected into the skin is used to assess an individual's sensitivity to tuberculin protein. The greater the reaction, the more likely it is that an individual is infected or has active TB disease.¹⁶ Precise interpretation depends on whether it is being used for screening or clinical diagnostic purposes.

• Another classic test - no better test is so widely available
• When to use:¹⁰
  • Immediate: contacts, immigrants from high-risk countries, clinically or radiologically suspected
  • Annual: HIV-infected children or household, residential homes
  • Routinely (for example, at 4-6 years and 11-16 years): high prevalence areas, travel or family travel to high-risk countries/areas
• How to administer:
  • Mantoux test (0.1 ml, 27-gauge needle, raise 6-10 mm wheal)
  • Read at 48 to 72 hours
  • Tine and Heaf tests are no longer recommended (lack of sensitivity and specificity)
• Care and consultation needed in interpretation, especially when used in clinical diagnosis. For example:
  • Positive at >5 mm in contacts, immunosuppressed, abnormal CXR
  • Positive at >10 mm in at risk and under five years
  • Positive at 15 mm or more in over age five and without risk factors
  • Beware false positives and false negatives
  • Previous BCG may affect interpretation but not if TB is strongly suspected

The Heaf test uses a 6-pointed apparatus to deliver the solution, and the degree of induration at the puncture site is measured 3-10 days later. This test is no longer recommended in the UK where it was used for larger less targeted screening programmes. The grading criteria are shown below:

For primary and secondary prophylaxis see British Thoracic Society (BTS) guidelines⁹ and the NICE guidance.¹³

1. Maartens G, Wilkinson RJ; Tuberculosis. Lancet. 2007 Dec 15;370(9604):2030-43. [abstract]
2. Guidelines for tuberculosis prevention and control, Health Protection Agency (2008)
3. Mims C, Playfair J, Roitt I, Wakelin D, Williams R. Lower respiratory tract infections. In Medical Microbiology, Second Edition (1998), pp 199-219. London: Mosby.
4. Immunisation against infectious disease - 'The Green Book', Department of Health (various dates)
5. WHO; World Health Organization: Tuberculosis, Basic Facts
6. Chan ED, Iseman MD; Current medical treatment for tuberculosis. BMJ. 2002 Nov 30;325(7375):1282-6.
7. HPA - TB surveillance statistics. Health Protection Agency.
8. Health Protection Agency; Tuberculosis
9. 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. [abstract]
10. DH; Stopping Tuberculosis in England: An action plan from the Chief Medical Officer; 2004
11. Kumar P and Clark M. Respiratory Disease. In Clinical Medicine, Fourth Edition (1999), pp 745-827. London: WB Saunders.
12. Scheinfeld NS, Cho KH; Erythema induratum (nodular vasculitis). eMedicine, March 2008.
13. Tuberculosis, NICE Clinical Guideline (March 2006); Clinical diagnosis and management of tuberculosis and measures for its prevention and control
14. The American Thoracic Society; Diagnostic Standards and Classification of Tuberculosis in Adults and Children 1999
15. Meredith S, Watson JM, Citron KM, et al; Are healthcare workers in England and Wales at increased risk of tuberculosis? BMJ. 1996 Aug 31;313(7056):522-5. [abstract]
16. Tuberculosis; Department of Health; Tuberculosis in Immumisation against Infectious Disease.'The Green Book'.

• WHO; World Health Organization - Tuberculosis
• HPA - TB surveillance statistics. Health Protection Agency.
• Tuberculosis, NICE Clinical Guideline (March 2006); Clinical diagnosis and management of tuberculosis and measures for its prevention and control