PULMONARY TUBERCULOSIS

Definition

Chronic inflammatory response of prolonged duration (weeks,months,years) provoked by the persistence of the causative organism Mycobacterium tuberculosis accompanied by tissue destruction and repair of lung tissue.

Pulmonary TuberculosisTuberculosis (abbreviated as TB for tubercle bacillus or Tuberculosis) is a common and often deadly infectious disease caused by mycobacteria, mainly Mycobacterium tuberculosis. Tuberculosis usually attacks the lungs (as pulmonary TB).

TB TransmissionWhat is TB?TB is a disease caused by infection with a bacteria called Mycobacterium tuberculosis.

Causative organism: Mycobacterium tuberculosis Morphology :SlenderAerobicWeakly Gram + RodGrows in straight or branching chainsUnique waxy cell wallAcid Fast due to MYCOLIC ACID in the cell wall

AFB smearMycobacterium tuberculosis (stained red) in sputum

Pulmonary TuberculosisScanning electron micrograph of Mycobacterium tuberculosis

Characteristics of Mycobacterial infectionInfiltration of mononuclear cells

Tissue destruction

Healing with scar formation and fibrosis

Other Characteristics:Mode of transmission Person to person by air born organismsReservoir Humans with active disease of the lungPrimary infection Usually asymptomaticSecondary infection - Reactivation of primary focusTissue destruction by inflammatory cellsAttempts at repair with granuloma formation and fibrosis

TB TransmissionHow can you catch TB?TB is spread through tiny drops sprayed into the air when an infected person coughs, sneezes, or speaks, or another person breathes the air into their lungs containing the TB bacteria.

Epidemiology of TuberculosisAffect 1.7 billion people worldwide8-10 million new cases every year1.6 million deaths every yearOver 10 million people infected with both HIV and M. tuberculosis14000 new cases in USA every year

Predisposing factorsPovertyOvercrowdingAny chronic debilitating illnessCertain disease states: - Diabetes mellitus - Hodgkins lymphoma - Chronic lung disease (esp. silicosis) - Chronic renal failure

Other predisposing conditions:MalnutritionAlcoholismImmunosupression

TB - Infection & DiseaseCategories of TB - Latent & Active TB disease varies with age and the ability of your body to fight off bacteria.HIV is the strongest risk factor for the progression of Latent TB to Active TB infection.

ImmunologyDelayed hypersensitivity reactionMantoux Test : - Intradermal inj. of PPD - Visible/palpable induration >10 mm after 72 hrs - Signifies T-cell mediated immunity to mycobacterial antigen

DiagnosticsInject intradermally 0.1 ml of 5TU PPD tuberculinProduce wheal 6 mm to 10 mm in diameterRepresent DTH (delayed type hypersensitivity)

Reading of Mantoux testRead reaction 48-72 hours after injectionMeasure only indurationRecord reaction in mm

Even if a Skin Test is Negative..ChicllsFFeverTHINK TB!ChillsFatigueDifficultyin BreathingAnorexiaLossof AppetiteNight sweatsCoughingup Blood

False negative; certain viral inf., sarcoidosis, malnutrition, hodgkins lymphoma, immunosupression, miliary tuberculosis.

False positive; atypical mycobacterial inf., BCG vaccination

Pathogenesis :The Players (mononuclear phagocyte system)MacrophagesScattered all over (microglia, Kupffer cells, sinus histiocytes, alveolar macrophages, etc.)Circulate as monocytes and reach site of injury within 24 48 hrs and transformBecome activated by T cell-derived cytokines, endotoxins, and other products of inflammation

Macrophages serve to eliminate injurious agents and initiate repair- however, they are as well responsible for much of the tissue injury that occursIFN-gActivated T cell or NK cellTissue macrophageActivated macrophageNon Immune activation:Endotoxins, fibronectin, chemical mediatorsTissue injuryToxic oxygen metabolitesMetallo-proteasesCoagulation factorsAA metabolites and NOFibrosis (Scaring)Growth factors involved in fibroblast proliferation(PDGF,TGFb,FGF)Angiogenesis factors(FGF,VEGF)Collagen deposition (IL-13 and TGFb)

The Players.T and B lymphocytesAntigen-activated (via macrophages and dendritic cells)Release macrophage-activating cytokines (in turn, macrophages release lymphocyte-activating cytokines until inflammatory stimulus is removed)Plasma cellsTerminally differentiated B cellsProduce antibodies

The dominant cellular player in pulmonary tuberculosis is the tissue macrophage

It is joined by lymphocytes and plasma cells, however mast cells and eosinophils are as well involved in chronic allergic diseasesBlood monocyteTissue macrophage (RES)migrate into tissue within 48 hours after injuryand differentiateKupffer cell (liver)Microglia (CNS)Histiocytes (spleen)Alveolar macs (lung)LymphocytePlasma cell

Pathogenesis

PathogenesisA-Primary Pulmonary Tuberculosis (0-3 weeks): inhalation of Mycobacteria---enter alveolar macrophages---replication in phagosome---bacteremia---seeding of multiple sites

Pathogenesis B -Primary pulmonary tuberculosis (>3 weeks): Alveolar macrophages---IL-2---T Cells--- T-helper cells---Activated macrophages (i)--- TNF,ChemokinesHypersensitivity (epith. granulomas) and (ii)---Nitric oxide,reactive O2 sp.---Immunity (bactericidal activity)

Primary TuberculosisDevelops in unexposed, unsensitized personsMostly(95%) asymptomatic; Infection containedIn 5 % symptomatic; Primary progressive tuberculosisSource of organism; ExogenousDifficult to diagnose

Primary Tuberculosis Presentation :Lung consolidation; Lower and middle lobesHilar lymphadenopathyPleural effusionIn majority organism remain dormantIn severe immunosupression - TB Meningitis - Miliary Tuberculosis

Secondary TuberculosisArises in previously sensitized hostMany years after primary infectionReactivation of latent infection or overwhelming exogenous infectionInvolves apex of upper lobesCavitation more prominant

Secondary TuberculosisIn majority symptomatic; insidious onset of malaise, anorexia, weightloss, fever, productive cough (mucoid, purulent, hemoptysis) , pleuritic pain.

Extrapulmonary manifestations

May be asymptomatic when localised

TB Infection & DiseaseThere are 2 Categories of TB: Latent & ActiveTB infection of the lungs can fall into 2 categories of disease: Latent TB or Active TB.Latent TB means a person is infected by TB bacteria, but cannot infect others, and is not coughing or appearing sick. Latent TB means the bodys immune system has contained the infection.

TB - Infection & Disease Categories of TB - LatentPersons with latent TB are identified by a positive skin test (PPD).

Persons who are not infected with Mycobacterium tuberculosis have a negative skin test (PPD).

In Pulmonary Tuberculosis macrophage accumulation persists by different mechanisms:

Continued recruitment of monocytes from the circulation

Local proliferation

Prolonged survival and immobilization

Outcome of Tuberculous infectionUlcers

Fistulas

Granulomatous diseases

Fibrotic diseases

and combinations of the above

DiagnosisHistoryPhysical examinationX-Rays ;Consolidation/ cavitation in lung apicesSputum for AFB : - Z.N Stain - > 10000 organisms in clinical specimen

DiagnosisSputum Culture : - conventional ---upto 10 weeks - liquid --- within 2 weeks

P.C.R : - 10 org. in clinical specimen

Chest radiographyNo chest X-ray pattern is absolutely typical of TB10-15% of culture-positive TB patients not diagnosed by X-ray40% of patients diagnosed as having TB on the basis of x-ray alone do not have active TB

Number of sputum samples requiredoverall diagnostic yield for sputum examination related to the quantity of sputum (at least 5 mL) the quality of sputummultiple samples obtained at different times to the laboratory for processing3 samples obtained at least eight hours apart with at least one sample obtained in the early morning

Cultures

Morphology A-Primary Tuberculosis :Ghon complex - subpleural parenchymal lesion (lower part of upper lobe) - hilar lymphadenopathyProgressive fibrosisCalcification

Histology : Epithelioid cell granulomas epithelioid cells lymphocytes plasma cells multinucleated langhans type giant cells with or without central caseation

Granulomatous InflammationClusters of T cell-activated macrophages, which engulf and surround indigestible foreign bodies (mycobacteria, H. capsulatum, silica, suture material)Resemble squamous cells, therefore called epithelioid granulomas

Morphology B Secondary Tuberculosis : Focus of consolidation, < 2 cm Within 1-2 cm of apical pleura

Histology : Caseating granulomas

Morphology C Progressive Pulmonary Tuberculosis:Elderly/ immunosupressed

Apical lesion---Spreads to adjacent lung tissue---Involves : a) Bronchi b) Blood vessels

Irregular cavity , poorly walled off by fibrosis

Morphology D Miliary Pulmonary Tuberculosis :Organisms draining through lymphatics enter venous blood and circulate back into the lung and involving most of the parenchymal tissue.

Microscopic or small visible yellowish white foci resembling millet seeds

Coalesce to form larger cavity

Pleural cavity :Involvement of Pleural cavity in Progressive pulmonary tuberculosis;

Serous pleural effusionTuberculous empyemaObliterative fibrous pleuritis

E Endobroncheal,Endotracheal or Laryngeal Tuberculosis :

Spread via lymphatics orExpectoration of infected materialHistology : - Mucosal lining studded with tiny granulomas

TB Infection and DiseaseThe lungs are the most common place for TB. This is known as pulmonary TB.TB of the voice box is the second most common and is usually called laryngeal TB.

F Systemic Miliary Tuberculosis :Bacteremia--- Involvement of Systemic Arterial System--- Any organ : - Liver - Bone marrow - Spleen - Adrenals - Meninges - Kidneys - Fallopian tubes - Epididymus

G Isolated Tuberculosis :Any organ or tissue can be involved in isolation ; hematogenous spread ; - Meninges - Kidneys - Adrenals (Addisons Disease) - Bone - Fallopian tubes - Vertebra (Potts Disease) . Paraspinal Cold Abscess track along tissue planes ( Abdominal or pelvic mass)

H Intestinal Tuberculosis :Drinking contaminated unpasteurised milk or Swallowing of coughed - up infected material in patients with advanced pulmonary tuberculosisOrganism invade lymphoid aggregates--- Granulomatous inflammation--- Mucosal ulceration (usually illeum)

I- Lymphadenopathy :

Most common presentation of Extrapulmonary TuberculosisUsually in Cervical region (Scrofula)Unifocal or localisedMultifocal in HIV patients

Lymph Nodes and LymphaticsLymphatics drain tissuesFlow increased in inflammationAntigen to the lymph nodeToxins, infectious agents also to the nodeLymphadenitis, lymphangitisUsually contained there, otherwise bacteremia ensuesTissue-resident macrophages must then prevent overwhelming infection

Systemic effectsFeverOne of the easily recognized cytokine-mediated (esp. IL-1, IL-6, TNF) acute-phase reactions includingAnorexiaSkeletal muscle protein degradationHypotensionLeukocytosisElevated white blood cell count

Systemic effects (contd)Bacterial infection (neutrophilia)Parasitic infection (eosinophilia)Viral infection (lymphocytosis)

Granulomatous inflammationGranulomas are millimeter size nodules of chronic inflammatory cells that can be isolated or confluent.Granuloma formation is the result of dealing with indigestible substances or pathogens and walls them offThe essential component are modified macrophages named epithelioid cell (because of shape).Epithelioid cells can form multinucleated giant cells.Epithelioid cells are surrounded by a collar of lymphocytes and occasionally plasma cells.Fibrous connective tissue often surrounds granulomas (remodeling of tissue)Areas within the granuloma can undergo necrosis (prototype: caseous necrosis in tuberculosis). Necrosis can lead to calcification or liquefaction and formation of a cavern if drained.

Microscopic and macroscopic appearance of tuberculosisCavity formation due to liquefaction and drainage of TBC lesionMacroscopic lesion in TBCCharacteristic tubercle with caseating necrosis in center

Differential Diagnosis :LEPROSY -Mycobacterium Leprae Tuberculoid Form: Granulomas with acid fast bacilli in macrophages and epitheloid cells.

CAT SCRATCH DISEASE -Gram positive bacilli Rounded or stellate granulomas containing central granular debris with neutrophils.

SCHISTOSOMIASIS -S.Mansoni,S hematobium,S.japonicum Granulomas around eggs with numerous eosinophils .

FUNGAL Cryptococcus neoformans Organism yeast like, budding, 5-10 mm clear capsule. Coccidioides immitis Organism appears as 30 80 mm cyst containing spores of 3 5 mm each.

IN ORGANIC METALS , DUSTS

Silicosis : Beryliosis : Involvement of lungs ,fibrosis .

SARCOIDOSIS

Unknown Etiology : Noncaseating granulomas ,langhan and foreign body type giant cells.

Treatment

Treatment for Active TBThe CDC recommends that infections due to Mycobacterium tuberculosis be treated with several drugs in addition to INH: Rifampin, Ethambutol, Streptomycin, and Pyrazinamide.

Tuberculosis treatment

The standard "short" course treatment for tuberculosis (TB), is isoniazid, rifampicin, pyrazinamide, and ethambutol for two months, then isoniazid and rifampicin alone for a further four months. The patient is considered cured at six months (although there is still a relapse rate of 2 to 3%). For latent tuberculosis, the standard treatment is six to nine months of isoniazid alone.If the organism is known to be fully sensitive, then treatment is with isoniazid, rifampicin, and pyrazinamide for two months, followed by isoniazid and rifampicin for four months. Ethambutol need not be used.

DrugsAll first-line anti-tuberculous drug names have a standard three-letter and a single-letter abbreviation:ethambutol is EMB or E, isoniazid is INH or H, pyrazinamide is PZA or Z, rifampicin is RMP or R, Streptomycin is STM or S.

DrugsThere are six classes of second-line drugs (SLDs) used for the treatment of TB. A drug may be classed as second-line instead of first-line : it may be less effective than the first-line drugs.aminoglycosides: e.g., amikacin (AMK), kanamycin (KM); polypeptides: e.g., capreomycin, viomycin, enviomycin; fluoroquinolones: e.g., ciprofloxacin (CIP), levofloxacin, moxifloxacin (MXF); thioamides: e.g. ethionamide, prothionamide cycloserine (the only antibiotic in its class); p-aminosalicylic acid (PAS or P).

Drugs Third-line drugs" Not very effective or because their efficacy has not been proven . Rifabutin is effective, but is not included on the WHO list because for most developing countries, it is impractically expensive.

rifabutin macrolides: e.g., clarithromycin (CLR); linezolid (LZD); thioacetazone (T); thioridazinea; arginine; vitamin D; R207910.

DrugsMulti-drug resistant TB (MDR-TB) is defined as resistance to the two most effective first-line TB drugs: rifampicin and isoniazid. Extensively drug-resistant TB (XDR-TB) is also resistant to three or more of the six classes of second-line drugs.

Treatment for Active TBMultidrug-resistant TB (MDR)Multidrug-resistant TB is on the rise. MDR TB means that some TB bacteria have developed resistance, so that traditional antibiotics, like INH, no longer kill the bacteria. This is due to people not taking their medication properly; new strains of the bacteria evolve.

Monitoring and DOTSDOTS stands for "Directly Observed Therapy, Short-course" and is a major plan in the WHO global TB eradication programme. The DOTS strategy focuses on five main points of action. These include government commitment to control TB, diagnosis based on sputum-smear microscopy tests done on patients who actively report TB symptoms, direct observation short-course chemotherapy treatments, a definite supply of drugs, and standardized reporting and recording of cases and treatment outcomes.

Treatment for Active TB.TB is curable, IF it is diagnosed early and appropriate treatment is started promptly.Active TB can be spread to other people if the person is not taking medication to kill the bacteria!

Treatment for Active TBWhen a person with active TB is diagnosed, they should be isolated from other people until the medication begins to kill the bacteria-usually 2 weeks, but sometimes longer.

Prevention

TB prevention and control takes two parallel approaches :

In the first, people with TB and their contacts are identified and then treated. Identification of infections often involves testing high-risk groups for TB. In the second approach, children are vaccinated to protect them from TB.

Current Surgical Intervention

Patients with hemoptysis first received Bronchial Artery Embolization because of the recurrent hemoptysis. Current indication of Lung Resection for pulmonary tuberculosis includes MDR-TB with a poor response to medical therapy, hemoptysis due to bronchiectasis or Aspergillus superinfection, and destroyed lung as previously reported, which are consistent with our indications. Surgery remains a crucial adjunct to medical therapy for the treatment of MDR-TB and medical failure lesions.

Fundamentals of TBInfection Control PracticesIdentify persons with active TB early.

Initiate effective and appropriate isolation of known or suspected TB cases.

Initiate effective anti-TB treatment promptly. ..

As a healthcare worker, how can I protect myself from being exposed?Instruct your patients to cover their mouth when coughing and do not transport patients with TB throughout the hospital unless they are wearing a mask.