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Related Subjects: |Assessing Breathlessness |Fever - Pyrexia of unknown origin |TB Meningitis |Lady Windermere syndrome

About

• Mycobacterium tuberculosis is the typical and most common form affecting humans.
• Human disease in developing countries from infected milk products where there is no pasteurisation from Mycobacterium bovis
• Mycobacterium kansasii or avium intracellulare do not normally cause human disease
• Increasing due to HIV/AIDS and patients may not be open about a prior HIV diagnosis. May be seen when CD4 < 200

Epidemiology

• Worldwide 2 Billion infected 95% in developing world 3 million deaths per year
• IN UK - Sub-Saharan Africans, Bangladeshi, Indian, Pakistan
• Homeless, alcohol-dependent, immunocompromised - HIV
• Drug and Multidrug resistant (Rifampicin) TB is a problem

Types

• Mycobacterium tuberculosis (causes TB in human)
• Mycobacterium bovis (endemic in cattle, rarely infects human).
• Atypical mycobacteria.

Microbiology

• Mycobacterium tuberculosis bacilli are gram-positive (no cell membrane but have a cell wall with a high lipid content ) rods and are obligate aerobes growing most successfully in tissues with a high oxygen content, such as the lung apices.
• They are facultative intracellular pathogens usually infecting mononuclear phagocytes (e.g. macrophages) and slow-growing with a generation time of 12 to 18 hours (c.f. 20-30 minutes for Escherichia coli).
• They are impermeable to the usual stains, e.g. Gram's stain and are known as "acid-fast bacilli" because of their lipid-rich cell walls, which are relatively impermeable to various basic dyes unless the dyes are combined with phenol. Once stained, the cells resist decolourisation with acidified organic solvents and are therefore called "acid-fast".

Pathology

• Classed as one of the granulomatous inflammatory conditions.
• The granulomata contain areas which to the naked eye have the texture of soft white cheese and is so termed Caseous necrosis with later calcification
• Ghon focus - initial infection affects subpleural of mid-zone with a transient acute inflammatory reaction followed by a Th1 reaction ith epithelioid macrophages, Langhans giant cells, lymphocytes and central Caseous necrosis. The Ghon focus + local hilar lymphadenopathy is called a Ghon complex.

Aetiology

• The initial infection occurs as the Mycobacterium reach the alveoli and are taken up into macrophages.
• They then pass to the hilar lymph nodes to form a Ghon complex usually in the upper zone just below the pleural.
• Initial response is with neutrophils followed by recruitment of monocytes to the site of granuloma formation with central caseation and Langan's giant cells.
• There is localised mediastinal and hilar lymphadenopathy. In most cases, the inflammatory response keeps the bacteria in check and the Ghon lesion with localised nodes is called a Ghon complex. Often it calcifies. Tubercle bacilli remain present which can reactivate later.
• In some cases inflammatory response is insufficient and there is dissemination by the bloodstream with seeding of many organs including lungs - miliary TB

Miliary TB

Disease mechanism

• Response to infection is increased production of interferon-gamma by T helper cells
• M. tuberculosis enters Macrophages by endocytosis by several mechanisms e.g. mannose-binding receptors bind surface glycolipid on the bacterium
• Macrophages act as antigen-presenting cells stimulating CD4+ T helper cells via Class II MHC receptors.
• The Th1 subset of T cells produces the cytokine interferon-gamma which activates macrophages and intracellular killing. Bactericidal and a strong Th1 response lead to granuloma formation and protective immunity.
• DNA studies show that many supposed reactivations are new infections.
• Macrophages stimulated by cytokines enlarge to form epithelioid macrophages.
• The granuloma formed creates an inhospitable acidic and anoxic environment for the bacteria which are then held in check if not destroyed.
• The immune response may be genetically determined in part by the possession of polymorphisms of the NRAMP1 gene which is involved in generating the content of lysosomes
• Activated Macrophages release TNF alpha in response to Interferon-gamma
• The important concept is that the Th1 mediated immunity comes at the cost of tissue damage

Th1 response in TB is important for

• Bactericidal killing
• Granuloma formation
• Caseous necrosis
• Protective immunity
• Requires IL-12 and IFN - &gamma
• These are required to become immunocompetent to deal with the infection

Clinical

• Bacillus must get directly to the distal acinus to avoid the mucociliary escalator
• Spread is by usually by aerosol droplets 0.5-3 um
• Infected humans are the only reservoir and host
• Transmission can only occur from people with active "smear-positive" TB

Primary infection

• Usually pulmonary from a patient with active lung disease. Gastrointestinal disease may be seen affects terminal ileum and tonsils. Mainly seen in children and adolescents. Manifests as fever and fatigue and arthralgias, chest pain and pleuritic chest pain - enlarged nodes, erythema nodosum, phlyctenular conjunctivitis, pleural effusion, formation of a Ghon complex, dactylitis. CXR - Hilar adenopathy and/or pleural effusion. Right middle lobe collapse may complicate the adenopathy. It takes 2-12 weeks for tuberculin testing to become positive
• Simon focus - fibronodular disease in lung apices may be seen

Miliary disease

• Blood spread - Occurs in the elderly or malnourished patients
• Yellow Caseous tubercles found in other organs.
• May involve bone and kidney which may take years to become apparent.
• Night sweats and weight loss, Hepatosplenomegaly
• Millet seed-like opacities on chest film < 5 mm
• Choroidal tubercles, Meningitis
• False negative tuberculin testings

Post primary TB

• There is now a degree of immunity developed with the primary infection
• There is reinfection or reactivation of the disease in someone with preexisting immunity.
• There are fever and night sweats. Malaise, weight loss and breathlessness, cough and sputum.
• Reactivation is seen with - HIV, alcohol, Age, malignancy, alcohol, immunodeficiency, malnutrition, use of immunosuppression, Anti TNF alpha drugs

Pulmonary disease

• Cavitatory disease with Parenchymal lung destruction with areas of necrosis leading to cavity formation. May be haemoptysis. Predominately apical disease with significant tissue destruction and fibrotic reaction. This is clinically detected as areas of consolidation and collapse and fibrosis.
• Right middle lobe collapse and Bronchiectasis "Brock's syndrome" due to localised lymphadenopathyPleural disease usually seen as part of the primary disease or post-primary with an effusion. Is less common in later disease.
• Pneumothorax is uncommon but can happen

Extrapulmonary disease

• Lymph nodes - nodes can suppurate and forms sinuses and even fistulas. Most notable cervical nodes can be involved causing scrofula. Mediastinal nodes also commonly affected.
• CNS - meningitis and tuberculoma. Can present with headache, confusion, seizures and personality changes and the CSF shows a raised lymphocyte count and protein levels but smears rarely positive. Tuberculomas cause symptoms of raised pressure and localising signs and symptoms of a space-occupying lesion. Steroid therapy may be considered for CNS disease.
• Skin - lupus vulgaris and erythema induratum
• Heart - tuberculous pericardial effusion and constrictive pericarditis. Steroids may be indicated.
• GI - terminal ileal disease and subacute obstruction. Weight loss, peritonitis, ascites
• Genitourinary - can affect the kidney and lead to renal failure. Send early morning urines. Image with CT or IVU. Epididymitis, endometrial or tubal involvement and infertility.
• Adrenal - adrenal insufficiency
• Bone/Joints - Osteomyelitis, arthritis, paravertebral abscesses, vertebral collapse. Spinal cord compression. Classically Pott's disease of the spine due to TB infection of the vertebrae cn cause cord compression and paraplegia or form a cold abscess which can track down to the psoas muscle.

Investigations

• FBC, U&E LFT's CRP and ESR - may suggest anaemia or ongoing inflammatory process
• CXR - upper zone shadowing and cavitation seen with active infectious disease. There may be an older disease with fibrosis and calcification. The trachea may be displaced. There may be hilar lymphadenopathy. In (non-HIV) - patients - pulmonary TB cavitation is synonymous with infectivity. Those with HIV may be infectious without cavitation.
• CT scan becoming used more to the image associated lung disease
• Direct staining and microscopy of a smear from recently expectorated sputum. If bacilli seen is "Smear positive" and infectious. Inducing sputum is said to be as effective as Bronchoalveolar lavage.
• Auramine O is an alternative to ZN especially as the dye fluoresces under UV light and so the bacilli are easier to see
• Cultures are the gold standard but take 3-6 weeks to grow and then identify species. Other techniques have been developed.
• Sputum analysis - DNA analysis using PCR of MTB can be made identifying serotype and drug sensitivity
• Tuberculin testing - Uses purified protein derivative (PPD) to elicit a delayed-type hypersensitivity response which is mediated by T lymphocytes. The reaction is maximal at 2-3 days after inoculation. Positive tuberculin testing does not always suggest active disease/ It suggests a prior immune response - previous infection or BCG. So only a grade 3/4 (10 mm induration) or a negative test are useful in those with a history of BCG.
• It is important to elicit a wheal to demonstrate that it is intradermal and not subcutaneous. Most with active TB will have a positive skin test (=10 mm). Must measure the induration, not erythema. Tuberculin skin tests are not contraindicated in BCG-vaccinated persons and skin test reactivity should be interpreted and treated as for unvaccinated persons. False negatives occur in Immunosuppressed, Steroids, Malnourished, HIV, Severe TB (eg, miliary disease), Early primary disease - Becomes positive 2-12 weeks post-primary infection
• Bronchoscopy and BAL may be useful to get samples in difficult cases when there is an unproductive cough and high clinical suspicion. It may help to exclude other causes such as tumours with a potential for biopsy of abnormal tissue
• Microbiological culture from - Sputum analysis, Gastric aspirate - used in children, Urine for renal TB, Bone marrow biopsy, CSF, Liver biopsy, Bronchoalveolar lavage
• A high level of interferon-gamma production is presumed to be indicative of TB infection. There is current work on the use of such assays in the management of TB. There are two methods for detecting the IFN-gamma released by the T cell, an enzyme-linked immunosorbent assay (ELISA, eg, QuantiFERON assay [QFT-TB]) and an enzyme-linked immunospot assay (ELISPOT, eg, T SPOT-TB assay)
• Consider HIV test in all patients with TB
• ECG:pericardial disease shows low voltage and ST-T changes
• Elevated Adenosine deaminase levels have high sensitivity and specificity for tuberculous pericardial disease

Management

• Smear positive must be isolated. It is a notifiable disease. Smear-negative patients are rarely infectious. Smear positive patients can be considered not infectious after 2 weeks of treatment
• Prevention through Vaccination with BCG. BCG vaccination in infants gives some protection against serious forms of tuberculosis - indeed - reduces disseminated and tuberculous meningitis

Management

• Treatment may well start on the basis of clinical suspicion as there may be a delay in getting the result of microbiological tests
• Patients should be treated with 4 drug regimen [RIPE] for 2 months and 2 drug regimen for 4 months. In those with a low chance of resistance then Isoniazid, Rifampicin and Pyrazinamide only many be used [RIP]
• RIPE 2 months ? RI 4 months
• RIP 2 months ? RI 4 months - low chance of resistance

Exceptions

• TB of CNS - Treatment is for 12 months
• Resistance to any of the drugs (isoniazid or rifampicin) means a 9-month course
• Drugs can all be taken once daily on empty stomach before breakfast. Combination tablets are available.
• First line treatment is safe in pregnancy and breastfeeding women
• Multidrug resistance TB is much commoner in HIV patients
• Compliance is the main barrier to successful treatment and Directly Observed treatment is one of the cornerstones of trying to ensure good drug compliance for the treatment of TB especially in homeless, alcohol, mental illness and MDR TB and those with a history of non-compliance. Rifampicin turns urine red.

Multidrug resistant tuberculosis

• Should be suspected in a representation of a previously treated case of Tuberculosis
• Contact with drug resistant TB
• Birth in a foreign country with more than 40 cases per 100,000
• HIV infection
• London residence
• Male
• Failed treatment - smear positive after 3 months treatment

TB AND HIV

• In patients with HIV the CXR changes may be less specific and the clinical picture less classical
• HIV infection with CD4+ T-cell counts 200-300 cells/mm3 tend to present as a secondary tuberculosis type picture with apical disease and cavitation as they are more immunocompetent
• HIV infection with CD4+ T-cell counts < 200 cells/mm3 tend to present as a progressive primary tuberculosis type picture with lower/mid lobe consolidation and lymphadenopathy.
• Mantoux tests can easily be normal in those with impaired delay type hypersensitivity and should not be relied upon
• There is atypical granuloma formation and pathological changes
• The length of anti-tuberculous treatment is the same as that used for non-HIV patients - treatment includes starting HAART and trying to minimise interactions between therapies. Rifampicin is the main drug with significant interactions.
• Chest X-Ray changes tend to be the lower zone with some occasional cavitation however there may be additional changes with consolidation, collapse, effusions and hilar lymphadenopathy
• Be aware of immune reconstitution inflammatory syndrome which can lead to a worsening in symptoms and signs several weeks after stating HAART
• Drug interactions between Anti TB therapy and HAART are significant and dual therapy should only be led by specialists

Drug Dose for 70 g man

• Rifampicin 600 mg/day
  • Bactericidal, Induces liver enzymes
  • Reduces Warfarin, COCP, Phenytoin, Steroids, Theophylline, Ciclosporin
  • Red urine and contact lenses
• Isoniazid 300 mg/day
  • Bactericidal, Enzyme inhibitor
  • Increases Phenytoin, Carbamazepine, Warfarin
  • Hepatitis -Avoid alcohol
  • Peripheral neuropathy
  • Give Pyridoxine 10 mg/day
• Pyrazinamide 2 g/day
  • Bactericidal, Increased urate, Liver toxicity
• Ethambutol 1.2 g/day
  • Bacteriostatic, Optic neuritis - Snellen chart assessment of acuity before starting
• Give all drugs together once daily with breakfast.
• 4 drugs for 2 months then RI for 4 months
• TB meningitis: treat for 12 months: RIPE 3 months, RI 9 months.
• Steroids in TB meningitis, pericarditis and spinal tuberculosis with neurological compression.