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Tuberculosis

Background

Tuberculosis (TB) is an extremely common and serious infectious disease which has affected humans for millennia. Mainly caused by the Mycobacterium tuberculosis pathogen, approximately one third of the global population is latently infected with it. Although it most commonly affects the lungs, TB can cause infection in virtually any part of the body, and is second only to HIV in terms of deaths caused by infectious diseases.

Epidemiology

Approximately 8.8 million people became unwell with active TB in 2010, and 1.4 million were killed. Current trends are showing a decline in the number of people infected and killed by TB each year, with the mortality rate dropping by 40% from 1990 to 2010. Countries with the highest prevalence of TB are concentrated in Asia and sub-Saharan Africa.

In the United Kingdom, TB is a notifiable disease, meaning that public health authorities must be alerted when the diagnosis is made.

 

Risk factors

Some risk factors for developing TB include:

- Immunosuppression (for any reason, e.g. HIV, drugs (corticosteroids, anti-TNFα agents, disease modifying anti-rheumatic drugs), transplants, chronic illnesses),

- Close contact with TB patients, poverty, living in a TB-endemic country

- Drug abuse (smoking/alcohol)

- Poor sanitation (e.g. refugee camps)

- Being very young or elderly.

- Diabetes

TB Incidence 2010. All credits to the World Health Organization

Pathogenesis and Transmission

TB is transmitted through droplets which are produced when an infected person coughs or spits. These droplets remain airborne and are inhaled by other people, which spreads the illness. Following the primary infection (the originating site of which is called the Ghon focus), the disease can take one of two courses.

In the majority of people, they develop a latent disease where the immune system keeps the TB under control. These people are not infectious and asymptomatic, and the majority stay well. Later on in life, when the immune system is weakened for whatever reason (e.g. age, HIV, malignancy, drugs), the TB can reactivate, leading to active infection.

During the primary infection, the bacteria can spread through the lymphatic and blood systems to cause infection in other parts of the body. The immune system reacts by containing the bacteria inside granulomas, balls of immune cells with the bacteria inside. This whole initial episode happens over 2-8 weeks.

When the immune system fails, be it during the primary infection or decades afterwards, the patient develops active TB and becomes symptomatic and infectious. At this stage, the infected areas become damaged by effects of the TB and the immune system as it tries to stop the infection. This leads to fibrosis and scarring at the infective foci. Miliary or disseminated TB is when the bacteria enter the bloodstream and cause the formation of large numbers of tiny granulomas. These are visible on chest x-rays (see the investigations section for an example) and the condition is always lethal if not treated.



Pulmonary TB is the most contagious form because patients tend to cough large numbers of bacteria up. Extra-pulmonary TB is usually far less of a risk to other people as the bacteria are kept contained in one part of the body, but the public health authorities need to be informed regardless.

Multi-drug resistant TB (MDR-TB) is defined as TB which is resistant to rifampicin and isoniazid (i.e. the main first line drugs), and extensively-drug resistant TB (XDR-TB) is TB which is resistant to rifampicin, isoniazid, a fluoroquinlone, and any injectable second line drug. While they are not any more contagious or lethal than fully sensitive TB, the difficulty in treating them comes with an increased mortality for affected patients. Drug resistance develops when patients are only partially treated with drugs for whatever reason, e.g. poor compliance, insufficient duration of therapy, or not enough effective agents being used.

Other Mycobacteria

The mycobacterium tuberculosis complex is a group of bacteria which can all cause TB. M. tuberculosis is the most important of the group, but others which often cause illness include M. bovis, which usually causes TB in cattle but can affect humans, and M. africanum, which is mostly limited to West Africa. Other pathogens in the group cause TB, but are much rarer. The management of tuberculosis caused by these other bacteria is no different to that of M. tuberculosis.

There are dozens of ungrouped sub-species in the Mycobacteria family, most of which only affect the immunosuppressed. The mycobacterium avium complex, including M. avium and M. intracellulare, are particularly notable here,however they do not cause TB. M. leprae, the cause of leprosy, can lead to a form of leprosy called "tuberculoid leprosy", but this has nothing to do with tuberculosis.

 

Presentation

TB manifests with several classical symptoms, in exam questions and in real life. A persistent cough, fever, night sweats, weight loss and haemoptysis are the commonest features.

A patient presenting with symptoms of a chest infection who fails to respond to multiple courses of antibiotics should also lead to the consideration of TB as a differential diagnosis.

Symptoms of extra-pulmonary TB vary depending on which organ site is affected. This is summarised in the accompanying diagram. Extra-pulmonary TB is more often seen in HIV-positive patients and children. Spinal TB is also known as Pott's disease.

TB symptoms by organ system

Investigations

The definitive method for diagnosing TB is through culture, but this takes considerably longer than most other bacteria - up to two months on Lowenstein-Jensen medium, slightly less using liquid Bactec culture, and checking for antibiotic sensitivities will take another few weeks.

Therefore, several samples are taken, and one set is stained with Ziehl-Neelsen stain to look for acid and alcohol fast bacilli (AAFB). All Mycobacteria species will show up as acid-fast, but if the clinical picture resembles tuberculosis and sputum samples are showing AAFB, this is sufficient grounds for starting treatment while the cultures grow. Ideally, at least three sputum samples should be obtained, and one needs to be an early morning sample (respiratory secretions pool overnightb  and this increases the likelihood of finding something significant). If the patient is not producing enough sputum for testing, get help from a physiotherapist, or take washings from a broncho-alveolar lavage.

In resource-high settings, the diagnosis can be made much faster using PCR to search for M. tuberculosis DNA. When drug resistance is a possibility, molecular probes can be used to rapidly detect rifampicin resistance.

Chest x-rays need to be ordered for all patients with suspected TB. Patchy infiltrates, focal consolidation (particularly in the apices), pleural effusions, cavitating lesions and a miliary appearance (see picture) are all signs to look for.

CT scans +/- biopsy are helpful if the chest x-rays are equivocal or an extra-pulmonary site of infection is suspected. Check all samples for AAFB. Histologically, the standard finding is a caseating granuloma.

Necessary blood tests include FBC, renal and liver function tests and inflammatory markers. While these may show non-specific findings, the liver function tests are important because of the risk of hepatotoxicity from TB treatment. Blood cultures can be done, but require a special media and prolonged incubation. Blood-borne virus screening (i.e. HIV, hepatitis B and hepatitis C) must be done in all patients with TB. HIV is particularly important because both infections need to be controlled and there are significant drug interactions between HIV and TB therapy.



The Mantoux or tuberculin skin test is used to screen people who are at risk of TB. This involves giving a subcutaneous injection of purified protein derivative of TB, usually into the forearm, and measuring the size of the induration (the raised lesion) 48-72 hours later. Interpreting the results depends on the patient's risk factors.

- > 5mm is positive in the significantly immunosuppressed (e.g. transplant recipients), recent TB contacts and HIV-positive people.

- > 10mm is positive in the moderately immunosuppressed (e.g. elderly), IV drug users and prisoners

- > 15mm is positive in healthy individuals with no risk factors.

Consider further investigation/treatment in patients who test positive and are symptomatic. The BCG vaccine is a huge contributor towards false positives, and Mantoux test does not have high specificity/sensitivity - false negatives can occur if the infection is severe enough to depress the immune system. The Heaf test was a similar procedure used for screening which has fallen out of favour in the UK. An alternative method for screening is the interferon gamma release assay (IGRA), a blood test which only requires one consultation. Current evidence suggests it is superior to the Mantoux test for detecting active infection, and it is generally used if Mantoux testing is inconclusive. However, neither of these tests should be used to rule out TB.

Management of TB

Active TB is always treated with a combination of drugs - any less than three and there is a serious risk of resistance occurring. Assuming full compliance with effective treatment, patients should no longer be infectious after two weeks of therapy, but until then, the patient should be isolated. The importance of adhering to treatment need to be emphasised to the patient, and they should be informed of the side effects of treatment.

Fully sensitive pulmonary TB is treated in two phases: for the first two months four drugs are used:

- Rifampicin

- Isoniazid

- Pyrazinamide

- Ethambutol

After these two months, rifampicin and isoniazid are used alone for a further four months. The second phase can be lengthened depending on the site of TB infection, e.g. TB meningitis is treated for 12 months in total. Combination tablets of several of these medications are available to reduce the patient's pill burden. Patients do not need to be hospital to start treatment unless severely unwell or treatment is likely to be complex (e.g. some forms of extrapulmonary TB or drug-resistant cases)

 

Side effects of TB medication:

Rifampicin - harmless discoloration of bodily fluids, particularly urine and tears, hepatotoxicity, multiple interactions with many drugs.

Isoniazid - peripheral neuropathy. Patients are often given pyridoxine (vitamin B6) to prevent this.

Pyrazinamide - hepatotoxicity (less common than with rifampicin) and gout.

Ethambutol - optic neuritis, starting with loss of colour vision.

Rifater - a combination pill of three anti-TB medicines.

Directly observed therapy - short course ("DOTS") is used when compliance with medication is likely to be a problem - this, as the name implies, involves healthcare personnel physically watching people take their medications.

In addition to treating the patient, close contacts (i.e. people living in the same household) need to be screened for TB as well. As it is a notifiable disease, newly diagnosed cases of TB must be reported to the public health authorities. People with latent TB are treated with six months of rifampicin or isoniazid, or three months of both.

Second line anti-TB agents for drug resistant cases include:

- fluoroquinolones, e.g. moxifloxacin and levofloxacin

- aminoglycosides, e.g. amikacin, kanamycin,

- para-aminosalicylic acid

- prothionamide

- cycloserine

- capreomycin

These agents usually are variously not used straight away because of cost, lower efficacy, increased toxicity and difficult routes of administration.

MDR-TB management involves finding as many effective drugs as possible to use (at least four active drugs) from different classes and continuing treatment under strict supervision at least 20 months in total (8 month intensive phase, 12 month continuation). In some cases where antibiotics have failed and the disease is confined to one localised area, surgery may be considered to remove the infection altogether.

 

The Bacillus Calmette-Guérin (BCG) vaccine was developed at the beginning of the twentieth century and is derived from Mycobacterium bovis. Its efficacy in preventing TB varies considerably depending on the country where it is used - in general, countries closer to the equator derive less benefit from it. In India, it has no effect at all, while in the UK, it is up to 80% effective in preventing TB. Why this variation occurs is currently not known.

It also provides some protection against other illnesses caused by mycobacteria, e.g. leprosy, and is used as treatment for bladder cancer. In the UK, the BCG vaccine is usually only given to people coming from TB-endemic countries (particularly infants), close contacts of confirmed cases and healthcare workers. Schoolchildren are no longer routinely vaccinated. As it is a live vaccine, it should not be used in HIV-positive people.

Prognosis

If effective treatment is available and the patient complies with it, the prognosis is generally good, and this applies to MDR and XDR forms as well. Recurrence rates with DOT range from 0-14% - having active TB does not confer immunity and patients can be re-infected. Miliary TB is 100% fatal if untreated, but this improves considerably to a mortality of 10% if treatment is started early. Currently, mortality from TB in the UK is less than 1 per 100,000 people.

References

- Kumar and Clark Clinical Medicine 6th Edition Kumar, P and Clark, M

- Guidelines for the programmatic management of  drug-resistant tuberculosis 2011 update World Health Organization

Available from: http://whqlibdoc.who.int/publications/2011/9789241501583_eng.pdf [Accessed 5/3/2012]

- Miliary Tuberculosis Sasasivam, S http://www.radrounds.com/photo/1791588:Photo:2622 [Accessed 17/3/12]

- Tuberculosis Thomas, H http://www.patient.co.uk/doctor/Tuberculosis.htm [Accessed 11/3/12]

- Tuberculosis Herchline, T E http://emedicine.medscape.com/article/230802-overview [Accessed 11/3/12]

- Tuberculosis NICE Guidelines http://www.nice.org.uk/nicemedia/live/13422/53638/53638.pdf

 

 

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