All you wanted to know about Tuberculosis

or

Plan to read and absorb this before attending the Tuberculosis Clinic

Tuberculosis is caused by one of the organisms in the Mycobacterium tuberculosis complex, most commonly M.tuberculosis and, much less frequently, M. bovis or M.africanum. We will call them all M.tuberculosis for convenience.

M. tuberculosis cannot survive outside of its host for any length of time – it is sensitive to light and to drying. The organism needs a human host (although it can also do quite well in some animals such as domestic pets and elephants!) and has survived for thousands of years by being transmitted from person to person by someone with tuberculosis in their lungs or respiratory tract excreting the organism in their exhaled air which then gets inhaled by a susceptible subject.

If we are exposed to someone who has tuberculosis in their lung we may become infected with M. tuberculosis. Infection is likely to occur if the person with tuberculosis has a large bacillary load in their exhaled air (smear positive sputum, often cavitary lung disease), if the duration of contact is long and if the environment is poorly ventilated. This would be the situation with most household contacts of a case of smear-positive pulmonary tuberculosis. Of course infection can occur with lesser degrees of exposure and even when the sputum is smear-negative but culture positive. Infection in that situation is most likely if the contact is susceptible as in the case of a young child, an immunocompromised or elderly person.

In most cases, exposure is not associated with infection.

Those who become infected will usually have no symptoms but infection can be recognised by doing a Mantoux (or, if you are quick, by finding the typical changes of primary TB on x-ray – a usually mid-or lower lung zone fluffy opacity associated with ipsilateral hilar lymph node enlargement). The purpose of a Mantoux test is to diagnose TB infection – the test is not useful for diagnosing tuberculosis (disease) because of a high false negative rate associated with active tuberculosis.

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Once infected, the majority of people (traditionally 90% but new data suggests up to 98%) will have no further issues with tuberculosis. The infection will proceed to disease in between 2 to 10% and in most this will occur within the first 1 – 2 years after the infection. In the remainder, if disease develops, it is usually because of the acquisition of risk factors which cause the infection to reactivate. Common factors which may trigger this include (with the risk for reactivation versus someone with no risk factors):

Immunocompromise Risk relative to someone with no risk factors - relative risk = 1

HIV 50-110 relative risk

Immunosuppresive medication

Anti TNFα therapy 4 - 8 relative risk

Post organ transplant medications 20–74 relative risk

Glucocorticoid therapy 4.9 relative risk

Chronic renal failure 10-25 relative risk

Silicosis 30 relative risk

Diabetes 2 – 3.6 relative risk

Untreated inactive post-primary pulmonary lesions (usually apical)

6 – 19 relative risk

In summary, tuberculosis exposure may lead to infection. Infection may lead to disease if the infection is recent, if the subject is immunocompromised or if there is inactive, untreated post-primary disease.

Why do a Mantoux?

In general, there is little point in diagnosing TB infection (by doing a Mantoux) unless one of these risks for progression to disease (recent infection or immunocompromise) is present and you are contemplating treating the latent TB infection.

The only other reason for doing a Mantoux would be as a baseline in someone who is entering a high- risk situation such as entry into health care or a plan to visit and work in a high prevalence TB environment. A repeat Mantoux after the exposure would then determine whether the person has become infected.

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Tuberculosis (disease)

TB infection may progress by the distribution of M.tuberculosis from the thoracic lymph nodes via the blood stream to parts of the body where the environment is favourable; lung apices, cervical lymph nodes, vertebral bodies, long bone metaphyses, kidneys, brain or just about anywhere else in the body. Direct spread may also occur from the primary lung lesion to the pleura. In these new sites, the organisms may multiply and establish disease or may remain dormant and be reactivated later if circumstances favouring their growth develop (HIV etc.). Pulmonary disease is the most common and is the most favourable for M.tuberculosis as it facilitates the survival of the organism through its spread to other people. Extra-pulmonary tuberculosis is becoming more common for reasons that are not clear. It does not lead to transmission of infection but it can be more difficult to diagnose and may also affect critical areas such as the meninges or brain. Children are particularly likely to develop disseminated TB and TB meningitis which may develop quite rapidly after the initial infection, especially in those under 5 years of age. In high prevalence TB environments, BCG vaccination is used for the express purpose of preventing this type of disease in children.

The diagnosis of tuberculosis should be made by submitting material for mycobacterial culture.

Treatment

Treatment of tuberculosis (disease) requires a combination of drugs to stop the rapidly metabolizing and multiplying organism from growing out naturally drug resistant mutants.

In summary, we use four drugs:

rifampin is the most effective anti-tuberculosis agent isoniazid is the second most effective anti-tuberculosis agent pyrazinamide is used to shorten the treatment regimen from 9 to 6 months ethambutol is used to protect the susceptibility to rifampin or isoniazid in the event that the organism is already resistant to one of these agents.

Rifampin and isoniazid are continued for the full duration of treatment

Pyrazinamide is used for the first 2 months of treatment

Ethambutol is stopped once the organism has been shown to be susceptible to rifampin and isoniazid

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The duration of a standard treatment regimen for a rifampin- and isoniazid- susceptible organism is 6 months. However, the regimen is not sufficiently robust to remain effective if the appropriate medications are not taken as prescribed. If the regimen is incomplete this will increase the risk for relapse (recurrence after initial clearing of the organism) or for the development of resistance. For this reason, the standard of care for tuberculosis is with the provision of full treatment supervision by a designated supervisor (each dose of medication is given and seen to be swallowed). In the event that treatment is not provided by Direct Observation (DOT) the duration of treatment should be extended to 9 months. 9-Month regimens are also recommended when pyrazinamide is not taken for the initial 2 months and when the sputum culture remains positive after 2 months of treatment for cavitary pulmonary tuberculosis.

In the case of a resistant organism, treatment regimens need to be revised and prolonged. Multidrug resistant (MDR) tuberculosis refers to an organism which is resistant to rifampin and to isoniazid. Extensively drug resistant (XDR) tuberculosis is diagnosed when the organism is resistant to rifampin, isoniazid, a fluoroquinolone and one of the injectables (amikacin, kanamycin or capreomycin).

NOTE: fluoroquinolones are effective against M.tuberculosis and may cause a false negative culture if you are treating a suspected case of tuberculosis with one of these agents.

Treatment of latent TB infection (LTBI) or for previously untreated, inactive apical pulmonary tuberculosis should only be offered when there is certainty that there is no active disease and when the risks for developing disease outweigh the risks for drug side-effects.

The standard treatment for LTBI is with isoniazid for 9 months. A variety of short-course regimens have been evaluated and include rifampin and isoniazid or rifampin alone for 4 months.

TB Medication Side-effects

Pyrazinamide, isoniazid and rifampin, in descending order, may cause hepatic damage.

Rifampin is particularly troublesome for its drug interactions, especially with corticosteroids, warfarin and many of the antiretroviral agents through its induction of enzymes in the cytochrome P450 group. In practice this can be problematic in young women on the contraceptive pill, in patients with HIV on antiretroviral medication and in older patients being treated with warfarin, beta-blocking agents, hypoglycemic medications, digoxin etc. In most instances the efficacy of the other drug is reduced but for some drugs such as clopidogrel (Plavix) the activity may be increased.

Isoniazid may cause peripheral neuropathy which is, at least in part, related to its anti-pyridoxine effect. This side effect may be especially troublesome and frequent in patient with diseases such as renal failure and diabetes.

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Isoniazid may compete with phenytoin and some other anti-convulsants for metabolism and toxicity from elevated levels of these drugs and of isoniazid may arise.

Pyrazinamide is especially poorly tolerated in the elderly and may cause profound anorexia, fatigue and weight loss.

Pyrazinamide interferes with uric acid clearance and might precipitate gout in susceptible individuals.

Ethambutol may cause optic neuritis and blindness which is especially likely to develop in patients with poor renal function.

Resistant TB

In its wild/natural state M.tuberculosis is fully susceptible to the anti-tuberculosis drugs (an exception is M. bovis which is naturally resistant to pyrazinamide). Resistant M.tuberculosis is man-made and caused by poor treatment and poor treatment programs. With the lack of any new and effective antituberculosis medications, existing medications need to be protected and to ensure this it is widely believed that tuberculosis management should be provided by central specialized tuberculosis programs. Inappropriate prescriptions with regard to drug dosage and combinations are common outside of such specialized programs and in Alberta, tuberculosis drugs are available only in Tuberculosis Services clinics and in acute care facilities.

R. L. (Bob) Cowie

2011

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