Pathology of Tuberculosis PDF

PATHOLOGY OF TUBERCULOSIS Dr Marie Kokolski LEARNING OBJECTIVES Describe the aetiology, risk factors and diagnosis of TB Describe the signs and symptoms of TB Describe granulomatous inflammation as a specific type of chronic inflammation Describe the pathogenesis and sequelae of primary and secon...

PATHOLOGY OF TUBERCULOSIS Dr Marie Kokolski LEARNING OBJECTIVES Describe the aetiology, risk factors and diagnosis of TB Describe the signs and symptoms of TB Describe granulomatous inflammation as a specific type of chronic inflammation Describe the pathogenesis and sequelae of primary and secondary TB HISTORY • TB is an ancient disease - Neolithic, pre-Colombian, and early Egyptian remains. • A major public health problem during the Industrial Revolution, when crowded living conditions favoured its airborne spread. • In the eighteenth century, TB killed 1/4 of all adults in Europe. • Major improvements began in the 1940s with effective anti-tuberculous drugs • Currently, TB has its greatest impact in resource-limited countries where HIV rates are often high. • The situation is worst in Africa, where half of all HIV-infected adults also are infected with M. tuberculosis and 30-40% of all deaths due to AIDS are from TB. WORLDWIDE TB INCIDENT RATES WHO END TB STRATEGY TUBERCULOSIS IN ENGLAND – 2020 REPORT • In 2019, the number of people with TB reported to PHE increased by 2.4% compared to 2018. This is the first increase in cases since 2011 • Overall, 10.8% (308/2,862) of people had resistance to at least one first line drug, and 1.3% (36/2,862) had MDR-TB Tuberculosis in England Annual Report TUBERCULOSIS IN ENGLAND – 2021 REPORT • In 2020, the number of people with TB reported to PHE decreased by 12.6% compared to 2019 • Overall, 11.6% (253/2,190) of people had resistance to at least one first line drug, and 1.7% (41/2,450) had MDR-TB – an increase compared to 2019 • It was noted in the report that due to Covid-19, data currently available in England is limited and must be interpreted with caution GLOBAL IMPACT OF COVID-19 ON TB • In March 2021, WHO estimated that 1.4 million fewer people received TB care in 2020 compared to 2019 – a reduction of 21% across all countries examined • WHO concluded this could lead to an additional 500,000 TB deaths globally • WHO maintains a TB elimination target of 2035 WHY HAS TB NOT BEEN ERADICATED? Eradication has been difficult because: • Much of the initial improvement in TB rates in more developed countries was related to improvements in housing, nutrition and access to treatment, but these issues are still present in many countries that are less developed • Several strains of TB bacteria have developed resistance to 1 or more antiTB medications, making them much harder to treat • The BCG vaccination is effective against severe forms of the disease, such as TB meningitis in children, but it's not as effective against all forms of TB • The global epidemic of HIV that began in the 1980s has led to a corresponding epidemic of TB cases because HIV weakens a person's immune system, making them more likely to develop a TB infection • The rapid growth of international travel has helped the infection to spread LEARNING OBJECTIVES Describe the aetiology, risk factors and diagnosis of TB Describe the signs and symptoms of TB Describe granulomatous inflammation as a specific type of chronic inflammation Describe the pathogenesis and sequelae of primary and secondary TB AETIOLOGY • Tuberculosis is caused by an infection with Mycobacterium tuberculosis • Obligate aerobe, rod shaped bacteria spread mostly through airborn droplets and dust micro particles • Acid fast • Slow rate of growth • Sensitive to heat and UV radiation • Non-motile • Likes highly oxygenated tissue MYCOBATERIUM TUBERCULOSIS Identified in 1882 The genus Mycobacterium includes closely related species of obligate aerobes Many mycobacteria are harmless, and some live on the human body without causing disease while others are found in soil and other niches in the environment. Less frequent causes = M.bovis and M. africanum TB was endemic in the UK until the middle of the 20th century – introduction of BCG (Bacillus Calmette-Guérin) vaccination and effective drug regimes Attenuated M.bovis used for BCG vaccine RISK FACTORS This agent infects one-third of the world's population, but only 10% of those infected develop clinical disease. Generally, persons at high risk for developing TB disease fall into two categories: § Persons who have been recently infected with TB bacteria § Persons with medical conditions that weaken the immune system Persons who have been recently infected with TB bacteria Persons with medical conditions that weaken the immune system Babies and young children often have weak immune systems. Other people can have • Persons who have migrated from areas weak immune systems, too, especially people with any of these conditions: of the world with high rates of TB • Children less than 5 years of age who • Substance abuse, • Silicosis have a positive TB test • Diabetes mellitus, • Groups with high rates of TB transmission, such as homeless persons, • Severe kidney disease, injection drug users, and persons with • Low body weight, HIV infection • Medical treatments such as corticosteroids • Persons who work or reside with or organ transplant people who are at high risk for TB in facilities or institutions such as hospitals, • Infection with HIV homeless shelters, correctional facilities, • Head or neck cancer, leukaemia, or Hodgkin's disease nursing homes, and residential homes for those with HIV • Close contacts of a person with infectious TB disease TB INFECTION • Not everyone infected with TB bacteria develops the clinical disease • As a result, two TB-related conditions exist: latent TB infection and TB disease. Latent infection: TB disease - No signs or symptoms - Host defences prevent growth of bacteria - Not infectious, cannot pass infection on - Skin or blood test positive - Normal chest X-ray - Primary infection or activation of latent TB - Signs and symptoms, patient feels sick - Can spread infection - Skin or blood test positive - May have abnormal chest Xray or sputum sample - Needs treatment DIAGNOSIS v Skin Test v Microbiological sampling v Blood Test v Molecular Testing v Imaging SKIN TEST • TST – tuberculin skin test • Also called Mantoux test • 0.1ml of tuberculin derived protein injected into skin of forearm • Positive test = 5mm or larger • Measure diameter of palpable, raised, hardened area or swelling (NOT erythema) at 48-72 hours MICROBIOLOGICAL SAMPLING Sputum analysis (x3) ­ Slender rods; aerobes ­ High content of complex lipid- ID by acid fast stains ­ Growth is slowed by acidic pH, presence of long chain fatty acids, anaerobic conditions ­ Cultures to check for drug susceptibility Acid fast – Ziehl Neelsen stain Fluorescence labelling ZIEHL NEELSEN Mycobacteria have the unusual property of retaining basic dyes when treated with acidic solutions. This property is a consequence of the mycobacterial envelope, which contains waxes composed of long-chain branched hydrocarbons. The most abundant wax, mycolic acid, is an α-alkyl-hydroxy fatty acid covalently linked to the cell wall. The name Mycobacteria reflects the presence of mycolic acid in the organisms. The waxy barrier greatly reduces permeability to many molecules, including Gram stain, and mycobacteria are neither Grampositive nor Gram-negative BLOOD TESTS - INTERFERON-GAMMA RELEASE ASSAYS (IGRAS) QuantiFERON®-TB Gold In-Tube test (QFT-GIT) or T-SPOT®.TB test (TSpot) White blood cells from infected persons release IFN-g upon exposure to antigens derived from M. tuberculosis ­ Rapid testing (approx. 24 hours) and BCG vaccination does not affect results ­ Blood samples must be stored and processed correctly ­ Limited data on progression to TB disease ­ Limited data on use in children under 5, immunocompromised, persons recently exposed to M. tuberculosis ­ Expense MOLECULAR TESTING - NAAT Rapid diagnostic nucleic acid amplification test (NAAT) • Many types available • Can diagnose the specific Mycobacterium (tuberculosis, bovis, africanum) and resistance to front line drugs • Very expensive NICE guidelines – Request if there is clinical suspicion of pulmonary TB disease, and: the person has HIV or rapid information about mycobacterial species would alter the person's care or the need for a large contact-tracing initiative is being explored. IMAGING • Type of imaging depends on site-specific investigations • Pulmonary TB – X-ray / CT thorax (Radiopaedia) Other examples • Pleural TB – X-ray / Bronchoscopy • Lymph node TB – Ultrasound / CT / MRI • CNS TB – CT / MRI LEARNING OBJECTIVES Describe the aetiology, risk factors and diagnosis of TB Describe the signs and symptoms of TB Describe granulomatous inflammation as a specific type of chronic inflammation Describe the pathogenesis and sequelae of primary and secondary TB SYMPTOMS Active TB infection will present with any or all of the following symptoms: • A persistent cough • Constant fatigue • Weight loss • Loss of appetite • Fever • Coughing up blood • Night sweats A person with latent TB has no symptoms Similar to symptoms for a range of other diseases so important to ensure diagnosis SYMPTOMS • Primary stage is asymptomatic/mild flu symptoms • Reactivated: (may take months to appear) gradual onset of anorexia, weight loss, fever (low grade, remitting), night sweats • Lung: Persistent cough lasting longer than 3 weeks. Sputum (mucoid then purulent); containing bacilli if cavitation occurs, haemoptysis • Systemic: many-local to infection e.g. headache and neurological deficit in brain metastasis, swelling in neck if lymph involvement LEARNING OBJECTIVES Describe the aetiology, risk factors and diagnosis of TB Describe the signs and symptoms of TB Describe granulomatous inflammation as a specific type of chronic inflammation Describe the pathogenesis and sequelae of primary and secondary TB GRANULOMATOUS INFLAMMATION • A form of chronic inflammation characterised by groups of activated macrophages, T lymphocytes and sometimes necrosis • It is the body’s attempt to section off an offending agent that is difficult to eradicate – the attempt to eradicate is often damaging to healthy tissue • Activated macrophages can begin to resemble epithelial cells – epithelioid cells • Some macrophages fuse together to form Langhans giant cells GRANULOMATOUS INFLAMMATION • Older granulomas have fibroblasts and collagen • Hypoxia causes necrotic core • In TB ONLY: caseous necrosis; yellow-white cheese-like (gross) amorphous granular lysed cells with no cell outlines/architecture. • Seen in few diseases: TB, leprosy, cat scratch disease, syphilis, sarcoidosis, Crohn's disease LEARNING OBJECTIVES Describe the aetiology, risk factors and diagnosis of TB Describe the signs and symptoms of TB Describe granulomatous inflammation as a specific type of chronic inflammation Describe the pathogenesis and sequelae of primary and secondary TB TRANSMISSION Exposure to persons with active TB disease Infected persons can project high numbers of bacteria in cough Small droplets or aerosols containing the bacteria from coughs= inhaled and reach alveoli Waxy outer coating makes organism resistant to desiccation PATHOGENESIS First 3 weeks: • Inhaled mycobacteria engulfed by macrophages • Manipulate endosomes (pH and maturation) • Defective phagolysosome formation • Mycobacterial proliferation in macrophages • Mild flu symptoms/ asymptomatic • Resistance of organism • Hypersensitivity of host • 95% will heal • Cell mediated immune response • Macrophages drain to lymph nodes • Antigens presented to T cells • T cells converted to Th1 cells • Th1 cells activate macrophages (gamma IFN) • Monocytes recruited free radicals and ROS • Epithelioid macrophages GHON FOCUS AND GHON COMPLEX Ghon focus - Primary lesion of granulomatous inflammation - Usually subpleural Ghon Complex (primary complex) - A Ghon focus & infection of adjacent lymphatics and hilar lymph nodes - When a Ghon's complex undergoes fibrosis and calcification it is called a Ranke complex The primary complex usually resolves within weeks or months, leaving signs of fibrosis and calcification detectable on chest X-ray. In general the risk of disease progression following primary infection is low, but young children and immunocompromised patients are at increased risk. GHON FOCUS AND GHON COMPLEX TB WITH CAVITATION If the immune system of the person with a TB granuloma deteriorates, these bacteria can be reactivated and TB may break out again Once the TB bacilli become reactivated, they rapidly destroy the lung tissue around the granuloma. This causes major damage to the tissue, which gets destroyed SPREAD OF TB • Caseating tubercle erodes into lung vasculature • Systemic dissemination to any organ via pulmonary vein (commonly liver, kidney, spleen) • If pulmonary artery involved (ie lymph drainage to right heart): miliary TB of lung Isolated organ (metastatic) TB: If few organisms invade the blood stream they are dealt with or can remain latent in an organ for years (eg brain, kidney, adrenals) MILIARY TB OF LUNG & SPLEEN • John Jacob Manget 1700 - based on how appearance in autopsy findings • The bodies would have a lot of very small spots similar to hundreds of tiny seeds about 2mm long, in various tissues. • Since a millet seed is about that size, the condition became known as miliary TB - a very serious, lifethreatening illness • Seeds expand, coalesce and destroy large areas of organ TB SUMMARY Secondary TB Primary TB (exogenous) Immunocompetent Immunocompromised Primary lesion is subpleural caseous granuloma: Ghon focus Caseating hilar lymph node involvement: Ghon complex Heals by fibrous encapsulation. Latent TB in tubercle Resistance of organism and hypersensitivity of host. Few symptoms Primary progressive TB Enlargement of caseation of lymph nodes: erodes into bronchial wall or vessel Bronchus: Tuberculous bronchopneumonia (lower lobes; galloping consumption) Vessel: miliary or isolated organ TB (reactivated/endogenous) Immunocompetent Immunocompromised Apical lesion of caseating granuloma. Immune response activated and healing by fibrosis Not lymph nodes Apical lesion enlarges: large mass with little collagen Increased risk of erosion into vasculature/bronchi Bronchus: Tuberculous bronchopneumonia. Live bacilli in sputum: open TB Vessel: miliary or isolated organ TB KEY POINTS - MYCOBACTERIUM TUBERCULOSIS This agent infects one-third of the world's population, but only 10% of those infected develop clinical disease. The bacterium is usually acquired by inhaling aerosolized droplet nuclei. ØM. tuberculosis can cause illness that begins soon after initial infection (primary disease) or can remain latent for years before reactivating and causing illness (endogenous reactivation). ØInfection may elicit a cellular immune response that controls infection, with the only sequelae being a positive tuberculin skin test. Or, ØInfection may elicit a host immune response responsible for the pathologic features of the disease. Active tuberculosis (TB) most often causes pulmonary disease associated with fever, weight loss, and drenching night sweats. ØTB is usually diagnosed by microscopy and culture of sputum. ØTB is more risky for those who are immuno-compromised (HIV