Respiratory System الفريق الطبي االكاديمي Pathology sheet 5 Tuberculosis Done by: Ahmad Al-Sahele
Introduction: as we know TB is caused by mycobacterium tubercolosis; now keep in your mind another microorganism cause TB which is called mycobacterium bovis There is another specie that cause infection in immunocompromised patients so that it is called atypical mycobacteria which is mycobacterium avium complex (MAC) Mycobacteria Slender bacillus Aerobic (also it is called facultative anaerobes it is originally extracellular but they can live intracellularly (this is an initial thing in pathogenesis that enable this bacteria to live inside macrophages)) In straight or branching chains Waxy cell wall composed of unusual glycolipids and lipids including mycolic acid Retain stains even on treatment with a mixture of acid and alcohol so called: acid-fast Sometimes considered weakly gram (+) it is initially not classified but don't confuse when you listen it is gram +ve Tuberculosis (TB) Chronic pulmonary and systemic disease Caused (mainly) by: Mycobacterium tuberculosis Source of transmission: humans with active tuberculosis who release mycobacteria present in sputum The chain of transmission : coughing of actively diseased person release droplets susceptible person so that this disease is air borne Susceptible person after receive microorganism it is not necessarily to be actively diseased (there is 3 ways) Oropharyngeal and intestinal TB can be caused by Mycobacterium bovis (from infected cows) in milk rare nowadays except in countries where milk pasteurization is not performed TB, epidemiology Decreasing Older adults and immigrants from high-burden areas Infection with HIV makes people susceptible to rapidly progressive tuberculosis Poverty, crowding, and chronic debilitating illnesses Diabetes mellitus, Hodgkin lymphoma, chronic lung disease (particularly silicosis), chronic renal failure, malnutrition, alcoholism, and immunosuppression
*2 *1 *3 *1 : to be contiguous TB should be pulmonary (TB of ileum not contiguous) *2 : most likely to occur Caseating granulomatus inflammation in lung and lymph nodes that eliminate the organism Scar detected by X-ray *3 : there is granuloma formation but there is no complete elimination Uncontrolled 2ry infection is called latent infection *4 : uncontrolled active infection (both 1ry & 2ry)may present as: -bacterial pneumonia either bronchial or lobar -progressive pulmonary TB increase caseation and granulomatus inflammation (increase damage without any control) when the inflammation reach bronchial wall and pierce it this present at the patient as hemoptysis and cavities may present at X-ray (at this point disease become infectious) with time manifestations like weight loss, night sweat, debilitating disease and cachexia may occur -dissemination hematolymphoid route to different parts of body and form nodules called milliary bodies in liver spleen marrow etc TB, pathogenesis in details Entry into macrophage: receptors for M.TB: CR3, mannose binding lectin etc. Progressive pulmonary or dissemina M.TB continues to replicate inside the phagosome and inhibits phagolysosome formation protected from microbicidal actions at this stage: bacteremia can occurs within the 1 st 3 weeks with only flu-like symptoms. Seeding in different organs may occur These infected macrophages will become APCs for T cells, especially presenting the peptide antigens of these phagocytosed extracellular microbes in the draining lymph nodes here TH1 and MHCII do their work as we know from immunity TLR-2 on APCs (macrophages and dendritic cells) binds glycolipids and lipoproteins on M.TB (PAMPs) *4
After the 3 weeks: APCs will present the antigens in the draining lymph nodes and Th1 response will occur (IL-12 induced Th1 differentiation) IL-12 can be secreted from APCs after their TLR-2 binds PAMPs As we know from immunity IL12 activate the differentiation of Th cell to Th1 Th1 response will occur mainly in the lymph nodes and in the lung itself and this includes secretion of interferon-gamma (classical macrophage activation) phagolysosome maturation, increased killing by the phagocyte and granuloma formation Ghon complex is formed Secretion of cytokines and reactive oxygen species occur with chemotaxis of lymphocytes around the granulomas and caseation With activity (1ry or 2ry), the granulomatous reaction which is supposed to protect will become a cause of collateral damage besides the intractable infection here granuloma is present in lung and hilarity lymph nodes In active TB, erosion of the cavities into bronchial wall will cause airborne spread by cough *3 *1 *2 *1 : Here is the start point in infection (Ghon focus or Ghon complex) caseation mainly in the upper part of the lower lobe or lower part of the upper lobe (also hilar lymph nodes) 3 ways for Ghon complex: 1) granulomatus inflammation that end infection If calcification occur to Ghon complex it is become ranke complex which then scar 2) granulomatous inflammation that doesn t fully destroy bacteria and bacteria remain in dormant form infection may reactivated after years to decades 3) inflammation doesn t destroy bacteria and bacteria continue to proliferate and inflammation continue to worse the problem
increase destruction increase pneumonia cavitation progressive primary TB *2 : Usually as an acute bacterial pneumonia (lobar consolidation) with hilar lymphadenopathy & pleural effusion then cavitation etc Pneumonia may be: 1) bronchial (bronchopneumonia) 2) lobar pneumonia (patchy pneumonia) Consolidation it is the solidity of lung parenchyma in X Ray in this case lung become tense and alveoli become filled with inflammatory exudate (it is unspecific condition may present in pulmonary edema or pulmonary hemorrhage) *3 : Usually apical disease with caseation Classically: the apex of the upper lobes of one or both lungs Now how granuloma occur as we know from immunity macrophages that activated by IFN-gamma progress to classical pathway then macrophages secrete cytokines that attracts lymphocytes so that granuloma usually surrounded by lymphocytes TB, clinical features Before becoming dormant or eliminated: may be only fever and pleural effusion If 1ry active in the lung: similar to acute bacterial pneumonia with pleural effusion and hilar lymphadenopathy may become progressive active pulmonary TB If 2ry active localized in the lung: asymptomatic then insidious onset of manifestations (low-grade fever, weight loss, anorexia, malaise), hemoptysis, sputum, night sweats, pleuretic pain due to pleural involvement etc. If active outside the lung: according to the organ involved sometimes activity occurs in only one organ seeded by the organism Miliary pulmonary disease Millet seeds-like lesions When organisms draining through lymphatics enter the venous blood and circulate back to the lung in another words spread is hematogenous Individual lesions are either microscopic or small, visible (2-mm) foci of yellow-white consolidation scattered through the lung parenchyma Miliary lesions may expand and coalesce, resulting in consolidation of large regions or even whole lobes of the lung Systemic military TB: Mainly liver, bone marrow, spleen or any other organ Pleural involvement With progressive pulmonary tuberculosis, the pleural cavity is invariably involved: -Serous pleural effusions
-Tuberculous empyema means pus in the pleural cavity -Obliterative fibrous pleuritis Isolated TB outside the lung Addison disease adrenal insufficiency due to autoimmune condition Cold abscess differ from typical one in that no hotness and little amount of neutrophils Scrofula = Cervical tuberculous lymphadenitis The most common extrapulmonary manifestation TB in GI tract Mainly due to M. bovis in certain countries (unpasteurized milk) In countries where milk is pasteurized: more often caused by the swallowing of coughed-up infective material in patients with advanced pulmonary disease seeding to mucosal lymphoid aggregates with resultant granulomatous reaction then ulceration of overlying mucosa and strictures may occur Stricture is adhesion of mucosa lead to narrowing of cavity Ileum is the most common site inflammation occur in payer s patches TB, diagnosis 1- History, physical examination and radiographic findings: Cavitation and consolidation in lung apices Ghon complex with calcification become ranke complex 2-Smears of sputum (Ziehl-Neelsen special stain to demonstrate the acid-fast bacilli) less sensitive than culture
Examination of sputum is cytology not histology 3-Culture of sputum the most effective and sensitive but the result needs 6 weeks We can benefit from the culture by doing susceptibility tests After doing the culture we put antibiotic tablets in the Petri dish to discover to which antibiotics the bacteria is sensitive bacteria is sensitive when inhibition zone is formed this is an important procedure especially for multi drug resistant TB shows drug sensitivities PCR is more rapid with good sensitivity and detects rifampin-resistant M.TB but also: less sensitive than culture *** Tuberculin (PPD, or Mantoux) skin test Go back to the topic of delayed type hypersensitivity reaction (type 4) in immunology About 2 to 4 weeks after infection, intracutaneous injection of purified protein derivative of M. tuberculosis induces a visible and palpable induration that peaks in 48 to 72 hours so that it is called delayed A positive tuberculin test signifies T-cell mediated immunity to mycobacterial antigens but does not differentiate between infection and active disease (It only detects sensitized patients) The +ve result presents in any of 3 types of infection and we called them sensitized (there is memory cells) False-negative reactions (called: anergy to skin test): the disease is low sensitive -Certain viral infections immunity is weak -Sarcoidosis (abnormalities in CD4+ T cells) -Malnutrition -Hodgkin lymphoma -Immunosuppression, e.g., AIDS granulomas may be less and PPD may be negative in this case the test may give +ve and after some years become -ve The inflammation in those patients is mainly by sheaths of histiocytes instead of granuloma formation -Overwhelming active tuberculous disease False-positive reactions may result from: low specificity -Infection by atypical mycobacteria Mycobacterium Avium complex (MAC) -Prior vaccination with BCG (Bacillus Calmette-Guerin), an attenuated strain of M. bovis that is used as a vaccine in some countries Because of low specificity and low sensitivity the test is no more used in many countries Treatment
Multidrug resistant M. tuberculosis is an increasing problem Nowadays, in USA, at least 4 drugs are used to treat TB (except if the case is with known susceptibility)