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Tuberculosis

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Jamie is a 4-year-old with ongoing pyrexia for a couple of weeks.  He has a mild cough but nothing else.  The family mentioned in passing that Grandad recently had TB.

Tuberculosis is the second greatest killer worldwide due to a single infectious agent and is a massive public health concern.

Bottom Line

Tuberculosis is a global burden, although rare in developed countries

Children don’t always have the typical presentations of TB and are at greater risk of extrapulmonary disease

A small number have the classic triad for TB diagnosis.

Tuberculin skin test >15 mm is diagnostic of TB but new tests (IGRA) more specific and sensitive

TB is treatable and curable

Treatment needs good, directly observed therapy to reduce multi-drug-resistant TB

What causes tuberculosis?

It is caused by 5 closely related Mycobacteria

  • Mycobacterium Tuberculosis
  • M. Bovis
  • M.Aficanum
  • M.Microti¡
  • M. Canetti

Tubercile Bacilli are a non-spore-forming, non-motile, weak gram-positive curved rod.  Its hallmark is its acid-fast capacity.

Each mycobacteria has its own unique fingerprint of mycolic acids.

It is slow growing.

Isn’t tuberculosis only found in developing countries?

It is much more common in developing countries.  The reasons for this are HIV epidemics, population migration, overcrowding/more populated countries, increased poverty; inadequate health coverage and poor access, and inefficient TB control programs.

How is TB transmitted?

TB is transmitted from person to person – usually by airborne mucous droplets.

Adult patients have copious production of sputum and a severe forceful cough, and environmental conditions such as poor air circulation exaggerate the risk.

However, in children with TB, the cough is often absent, and they lack the tussive force required to suspend infectious particles of the correct size.

What do all the TB terms mean?

Primary Pulmonary Disease

There are parenchymal/pulmonary foci in 70% of cases.  Initially, the inflammation is not seen on CXR, but there is tissue hypersensitivity, which leads to large regional lymph nodes.  This leads to lobar pneumonia and progressive primary pulmonary disease (rare).

Extrapulmonary Disease

There is where there is clinical TB outside the lungs – e.g. lymph nodes, pleura, brain, kidneys, or bones.

Disseminated TB

This is where there is spread to other organs due to primary TB.

Reactivation TB

Healed TB remains in the lung with no extrapulmonary spread.  Reactivation is rare in childhood – those <2 years of age rarely acquire reactivation.  It is more common >7 years of age or in adolescents.

Miliary TB

This is where tubercles form in different organs due to the dissemination of bacilli through the body by the bloodstream/lymphatics.  It varies in severity.

What are the symptoms of tuberculosis?

This depends on the age and type of TB, and there is a wide spectrum of clinical presentations.

The majority of children with TB develop no signs or symptoms.  They can occasionally have low-grade fever/mild cough, and there is rarely the ‘classic’ of high fever, cough, night sweats, weight loss, or lethargy.

Younger infants <2 years are more likely to have extrapulmonary TB

The mild symptoms can go on for many months, resulting in delays in seeking care and increased transmission rates.  TB can infect up to 10-15 other people through close contact over the course of a year, and this emphasises the importance of contact tracing.

So, what are the most useful clinical indicators of TB?

A Melbourne review for ICHRC (2008) recommended considering TB with

  • Unexplained weight loss/failure to grow normally
  • Unexplained and prolonged fever >2 weeks
  • Chronic cough >30 days
  • Exposure to an adult with probable/definite TB

Where does transient microscopic haematuria come in?

Transient microscopic haematuria is a common sign of TB infection

Haematuria has been noted to be a presenting symptom of urinary tuberculosis.  Renal TB is rare and manifests in adulthood but can present in children.

There is thought to be an association between haematuria and mycobacterial infection (Dworkin et al.).

Other than the lungs, where else does TB affect?

TB can affect pretty much anywhere in the body: middle ear, tonsils, pericardium, CNS, bones, muscle, intestine, epididymis, liver, adrenal glands, and kidneys.

How is TB diagnosed?

  • CXR
  • Tuberculin skin test
  • History of exposure
  • Cultures should be obtained
  • Confirmation with: induced sputum – difficult in infants; gastric aspirates – 50% yield
  • Look for disseminated/extrapulmonary disease (these can predict/change the length of treatment)

Check out how to perform the tuberculin skin test.  And how to read the results.

Causes of false positive tuberculin skin test (TST)

Cross sensitisation to antigen of non-TB mycobacteria

Previous vaccination with BCG (especially if 2 X BCGs)

Boosting effect of multiple TST (increased reaction to TST with serial testing)

Half of infants who receive BCG vaccine never develop a reactive TST

Older children and adults do get tuberculin reactivity.  This is normally <10 mm.  If >10 mm, then this warrants further investigation for TB.

Interferon-gamma release assays

Two tests

  • T.spot TB
  • Quantiferon TB Gold

Detect interferon gamma generation by patients’ T cells in response to specific M. tuberculin antigen:

Disadvantage: cost and specialised equipment.

Advantage: one-person encounter; lacks cross-reaction with BCG and other mycobacteria; an absence of boosting.

A meta-analysis in 2008 (Pai et al.) showed:

Specificity of 98% for the Quantiferon tests: 99% in patients not vaccinated with BCG and 96% in BCG-vaccinated patients.

T-SPOT TB test appears to be more sensitive for latent tuberculosis than the Quantiferon tests or tuberculin skin testing.

How do you treat tuberculosis?

TB is a treatable and curable disease.

Standard treatment for primary TB

  • Six-month course of three antimicrobial drugs to reduce secondary drug resistance
  • Izoniazid(H), rifampin(R), pyrazinamide(Z)
  • HRZ for two months; Then HR for the remainder of 4 months (so a total of six months)

If no CNS disease

DOTS and the Stop TB Strategy recommended by WHO

  • Supportive care
  • Notifying public health

N.B. isoniazid resistance can happen – add a fourth agent, either streptomycin/ethambutol/ethionamide.  The reason for the fourth is that pyrazinamide is not effective in preventing the emergence of rifampin resistance.

Multi-drug-resistant TB

Standard anti-TB drugs have been used for decades, and resistance to the medicines is growing.

Multidrug-resistant tuberculosis (MDR-TB) is a form of TB caused by resistance to, at least, isoniazid and rifampicin.

Inappropriate treatment, poor-quality medication and poor adherence are the main causes of MDR- TB

Use second-line drugs (although it is rare in children)

If suspected, use FOUR anti-TB agents till cultures – this requires longer treatment therapy 

What are the adverse effects of the medication?

Isoniazid

Antibacterial activity only against mycobacteria (first line)

Mild hepatic enzyme elevation, hepatitis, peripheral neuritis, hypersensitivity

Rifampin

Bactericidal activity – intracellular and against slow and intermittently growing bacteria

Orange discolouration of secretions or urine, staining of contact lenses, vomiting, hepatitis, influenza-like reaction, thrombocytopenia, pruritus

Pyrazinamide

Hepatotoxic effects, hyperuricemia, arthralgias, gastrointestinal tract upset

Pyridoxine

Vitamin B supplements are given to combat isoniazid side effects

How do we prevent the spread of TB?

TB is prevented through case finding and treating – 30-50% of household contacts to infectious cases are TST +ve, and 1% have overt disease; public health/chest clinics; BCG vaccination

BCG vaccination

  • Only vaccine available
  • Initially derived from M.bovis and given by intradermal injection
  • Dosing schedule varies (WHO – single dosing in infancy)
  • The optimal age is unknown, and some countries repeat the vaccine
  • Most reactions are mild and resolve
  • Immunocompromised patients have a higher risk of disseminated TB
  • BCG is 50% effective in preventing TB – higher in disseminated and meningeal TB<

References

Marais BJ, Gie RP, Schaaf HS, Hesseling AC, Obihara CC, Starke JJ, Enarson DA, Donald PR, Beyers N. The natural history of disease of childhood intra-thoracic tuberculosis: a critical review of the prechemotherapyiterature. Int J Tuberc Lung Dis 2004;8:392-402.

Azzopardi P, Graham S. What are the most useful clinical indicators of tuberculosis in childhood? International Child Health Review Collaboration  2008.

Dworkin G, Reisman L, Ben-Zvi Z, Lieberman KV. Association of hematuria and mycobacterial infection. Child Nephrol Urol. 1991;11(1):44-6.

Pai M, Zwerling A, Menzies D. Systematic review: T-cell-based assays for the diagnosis of latent tuberculosis infection: an update. Ann Intern Med 2008; 149:177–184.

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