Tuberculosis (TB)

Mycobacterium

• Aerobic rods that grow in straight or branching chains
• Have waxy cell walls composed of mycolic acid
• The cell wall retains dyes after acid treatment – hence called acid fast
• TB is caused by M.tuberculosis

 

Epidemiology

• After HIV it is the 2^nd leading cause of infectious death
• There is increased risk of TB with certain other illnesses;
  • HIV
  • Diabetes
  • Hodgkins lymphoma
  • Chronic lung disease
  • Chronic renal failure
  • Malnutrition
  • Alcoholism
  • Immunosuppression

 

• Infection differs from the disease
  • Infection is the presence of the organisms that may or may not cause clinically significant disease. Most infection is caused by person to person transmission of airborne droplets
• In most causes primary TB is asymptomatic or it may cause a fever and pleural effusion
• Generally the only evidence of infection is a small, fibrocalcific nodule at the site of infection which contains viable organisms which may remain dormant for decades, only becoming reactivated when the individuals immune defences are lowered resulting in communicable and life threatening disease

 

Clinical

• Infection results in a delayed hypersensitivity response to M. tuberculosis antigens which can be detected by a Mantoux test or tuberculin test
• A positive test indicates cell mediated hypersensitivity to tuberculin antigens but doesn’t distinguish between infection, immunity and disease

 

• Primary TB occurs in previously unexposed individuals;
  • 95% have asymptomatic infections with a persistent latent lung infection focus
  • 5% have symptomatic infections with lobar consolidation, hilar lymphadenopathy and pleural effusions
  • Rarely lymphohaematologenous spread can lead to tuberculosis meningitis and miliary TB
• Secondary TB occurs in a previously sensitised host;
  • Infection usually occurs from the reactivation of latent infection with then immune resistance is weakened
  • Typically infection causes cavitation in the apex of the upper lung lobes with associated low grade fever, night sweats and weight loss

 

 

• Diagnosis is by;
  • Identifying acid fast bacilli in sputum of tissue
  • Culture from sputum of tissue – which can take 10 weeks but allows for sensitivity testing
  • PCR

 

• Cytokines released by macrophages result in malaise, fever, weight loss
• With progressive pulmonary involvement increasing amounts of sputum occur, first mucoid and then becoming more purulent
• Half of all cases have some degree of haemoptysis
• Pleuritic chest pain may result from extension of infection to the pleural surfaces

 

Pathogenesis

• Outcome depends upon host immunity, immune responses can control infection as well as contribute to the pathological manifestations of disease
• TB enters macrophages by phagocytosis – via binding of the mannose receptor to lipoarabinomannan and well as via complement receptors binding to opsonised bacteria
• M. tuberculosis can block the fusion of the phagosome with the lysosome allowing it to replicate within the macrophage
• NRAMP1 is a transmembrane protein found in endosomes and lysosomes which pumps divalent cations IN which are required for the generation of reactive oxygen species. Patients with polymorphisms in this gene may fail to make an effective immune response
• About 3 weeks after infection, there is a Th1 response mounted, activates macrophages to become bactericidal. This is done via the production of IFN-γ. IFN-γ stimulates the formation of the macrophages phagolysosome and stimulates the expression of nitric oxide synthase. NO results in the generation of nitrogen intermediates and free radicals capable of oxidative destruction
• As well as activating macrophages, the Th1 response results in the formation of granulomas and caseous necrosis;
• Activated macrophages release TNF-α which recruits monocytes. These monocytes differentiate into epithelioid histiocytes which characterise the granulomatous response
• The importance of TNF in the response is highlighted by the fact that patients with RA undergoing treatment with a TNF antagonist are at increased risk of TB reactivation

 

Morphology

• Pathological appearance depends of the disease stage, infection site and immune status
• Primary TB;
  • Almost always begins in the lungs (in countries where bovine TB and contaminated milk have been eliminated)
  • Typically the bacteria implant in the distal airspaces of the lower part of the upper lobe or the upper part of the lower lobe, close to the pleura
  • As sensitisation develops a 1-2cm are of inflammatory consolidation appears known as the Ghon focus
  • The centre of which generally undergoes caseous necrosis
  • Bacilli, either free or within phagocytes drain to the lymph nodes which can also caseate
  • The combination of the lung lesion and nodal involvement is called the Ghon complex
  • In the 95% of cases where cell mediated immunity controls the infection, the Ghon complex undergoes progressive fibrosis and calcification
  • Histologically, lesions are charcterised by granulomatous inflammation, with multinucleate giant cells. These are generally surrounded by a ring of lymphocytes
• Secondary TB
  • The initial lesion is a circumscribed focus of caesation usually involving the apical pleura. These may heal by fibrosis or disease progress to rupture into blood vessels causing haematogenous spread or into airways releasing bacteria during coughing
  • Progressive pulmonary TB may occur in the elderly an immunosuppressed. The apical region enlarges with expansion of the areas of caseation. It can erode into the brochus resulting in evacuation of the caseous centre
  • Miliary pulmonary disease results when organisms drain through the lymphatics into the lymphatic ducts which empty into the venous return into the right side of the heart and then into the pulmonary arteries