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Shocking Facts
Captain of all the men of death
Causes more deaths than any other single microbial agent
One-third of the worlds population infected Each year 1.7 million people die and 9 million new case occur 500,000 people infected with a MDR strain
Mycobacterium tuberculosis
Characteristics
AFB
Retain carbolfuchsin stain despite subsequent treatment with ethanol-hydrochloric acid mixture AAFB High lipid (mycolic acids and wax D) content of cell wall prevents Gram stain from staining
Obligate Aerobe
Disease in highly oxygenated tissues
Mycobacterium tuberculosis
Characteristics
Grows very slowly
Cultures 6 to 8 weeks
LJ medium complex nutrients and dyes Dyes inhibit unwanted normal flora present in sputum samples
Drugs 6 to 9 months
Mycobacterium tuberculosis
Characteristics
Cord factor - virulence PPD tuberculin skin test Resistant to
Acids Alkalis
NaOH concentrate clinical specimens
Dehydration
Survives in dried expectorated sputum transmission by aerosol
Mycobacterium tuberculosis
Characteristics
MDR and XDR strains
Chromosomal mutations Gene for mycolic acid synthesis Gene for catalase-peroxidase activate isoniazid to active drug
Mycobacterium tuberculosis
Habitat and Transmission
Humans natural reservoir Transmission - respiratory aerosol generated by coughing M. bovis gastrointestinal tuberculosis
Drinking unpasteurized cows milk
Mycobacterium tuberculosis
Habitat and Transmission
Disease TB occurs only in a small number of infected individuals
Highest risk - socioeconomically disadvantaged people, who have poor housing and poor nutrition Barometer of social welfare
Mycobacterium tuberculosis
Pathogenesis
NO exotoxin or endotoxin Infects, survives and multiplies within macrophages and other reticuloendothelial cells!!!
ERP (exported repetitive protein)
Mycobacterium tuberculosis
Pathogenesis
Exudative lesions acute inflammatory response Granulomas and caseation CMI Immunosuppression reactivation and dissemination Spread
Erosion into bronchus, swallowing, expectoration Bloodstream
Mycobacterium tuberculosis
Immunity & Hypersensitivity
Resistance
CD4+ T cells (Th-1 helper T cells) and macrophages Nramp gene NRAMP protein
Mycobacterium tuberculosis
Immunity & Hypersensitivity
Latent infection
PPD skin test + induration 10 mm or more 48 hours (delayed hypersensitivity response) Infected but not necessarily diseased
Mycobacterium tuberculosis
Immunity & Hypersensitivity
Latent infection
QuantiFERON-TB (QFT) test Interferon-gamma release assay (IGRA) ELISA test
Mycobacterium tuberculosis
Laboratory Diagnosis
ZN or Kinyoun stain - AFB LJ medium - slow-growing (3-6 weeks) colony Niacin and catalase + Serologic tests for Ab NOT useful
Mycobacterium tuberculosis
Treatment
Long-term (6-9 months) 3 drugs INH,rifampin,pyrazinamide 4th drug ethambutol Noninfectious 2 weeks Latent (asymptomatic infections) INH (6-9 months) MDR/XDR strains other drug combinations Noncompliance - DOT
Mycobacterium tuberculosis
Prevention
BCG vaccine Live,attenuated M.bovis Prevents or limits extent of disease but does not prevent infection
Atypical Mycobacteria
Differ from M.tb in various ways Environment MOTTS Colonies - > or < 7 days
Slow growers (pigment production) Rapid growers
M.marinum
Swimming pool or fish tank granuloma
Pulmonary Tuberculosis
Natural History & Morphology
It is important that infection with M. TB be differentiated from disease. Infection is the presence of organisms, which may or may not cause clinically significant disease.
The immunity to a tubercular infection is primarily mediated by T cells & is characterized by the two-prolonged development of hypersensitivity & the appearance of resistance to the organism.
Hypersensitivity is accompanied by a destructive tissue response, such that reactivation or re-exposure to the bacilli in previously sensitized host (secondary TB) results in rapid mobilization of defensive reaction but increased tissue necrosis.
Granulomatous Inflammation:
It is a distinctive (specific) pattern of chronic inflammation characterized by aggregates of activated macrophages that assume a squamous cell like (epitheloid) appearance.
Granuloma is a nodular collection of epitheloid macrophages surrounded by a rim of mononuclear cells (lymphocytes & plasma cells) mainly lymphocytes.
Types of granulomas:
Foreign body granulomas (non-immune): They are formed when the material is inert, too large and cannot be easily degraded by single macrophages (resistslysosomal degradation), e.g. talc, suture material, cement for fixing prosthesis. Immune granulomas: When the insoluble material is capable of eliciting a cell mediated immune response (T-cell hypersensitivity), e.g. TB and Lepra bacilli, Fungi, Parasites, Mineral dust.
Events that give rise to the formation of granuloma (type IV hypersensitivity reaction).
The aggregates of epitheloid macrophages are surrounded by a collar of lymphocytes secreting cytokines responsible for ongoing macrophage activation.
Older granulomas develop a surrounding rim of fibroblast & connective tissue (rim of scarring that usually contains the injurious agent).
Frequently, multinucleated giant cells 40 - 50m in diameter are also seen. They consist of a large mass of cytoplasm and multiple nuclei and they are derived from fusion of 20 or more macrophages.
In granuloma associated with certain infectious organisms (TB), a combination of hypoxia & free radical injury leads to a central zone of necrosis.
Grossly, this zone of necrosis has agranular cheesy appearance and is therefore called caseous necrosis.
Granuloma
Lymphocytic Rim Caseous Necrosis
Epithelioid Macrophage
Primary TB Morphology:
Typically, the inhaled bacilli implant in the distal airspaces of the lower part of the upper lobe or the upper part of the of the lower lobe, usually close to the pleura (1-1.5 cm area of gray-white inflammatory consolidation Ghon focus with a center of caseous necrosis).
Tubercle bacilli, either free or within phagocytes, drain to the regional nodes, which also often caseate (the combination of parenchymal lung lesion & nodal involvement is referred to as the Ghon complex. Ghon complex undergoes progressive fibrosis, followed by radiologically detectable calcification (Ranke complex).
Histologically, sites of active involvement are marked by granulomatous inflammation forming both caseating & non-caseating tubercles. The granulomas are enclosed within a fibroblastic rim punctuated by l ymphocytes.
During first few weeks, there is also a hematogenous & lymphatic seeding of other body parts but without any lesions develop.
Primary TB Morphology:
Low & high magnification of a characteristic tubercle illustrating a central caseation necrosis surrounded by epitheloid & multinucleated giant cells.
Secondary TB - Morphology:
Secondary pulmonary tuberculosis classically involves the apex of the upper lobes of one or both lungs. Because of the pre-existence of hypersensitivity, the bacilli elicit a prompt and marked tissue response that tends to wall off the focus of infection. The regional lymph nodes are less prominently involved early in secondary than they are in primary tuberculosis. But, cavitation occurs readily in the secondary form.
The initial lesion is usually a small focus of consolidation, less than 2 cm in diameter, within 1-2 cm of the apical pleura (sharply circumscribed, firm, gray-white yellow areas with central caseation & peripheral fibrosis).
Localized apical secondary TB may heal with fibrosis either spontaneously or by treatment, or the disease may progress and extend:
Progressive pulmonary TB: The apical lesion enlarges with expansion of the area of caseation. Erosion into a bronchus evacuates then caseous center creating irregular cavity. Hemoptysis results from erosion of blood vessels. Healing is by fibrosis distorting the pulmonary architecture.
Secondary TB - Morphology:
Miliary pulmonary disease occurs when organisms drain through lymphatics
into right side of the heart and thence into pulmonary arteries, individual lesions are either microscopic or small visible foci of yellow-white consolidation that will expand and coalesce.
With progressive pulmonary TB , the pleural cavity is invariably involved causing pleural effusion, tuberculous empyema, or obliterative fibrous pleuritis.
Endobronchial, endotracheal, and laryngeal TB may develop when infective material is spread either through lymphatics channels or from expectorated infectious material (the mucosal lining may be studded with minute granulomatous lesions).
Secondary TB - Morphology:
Systemic miliary TB occurs when infective foci in the lungs seed the pulmonary
venous return to the heart; the organisms subsequently disseminate through the systemic arterial system (almost every organ is seeded) lesions resemble those in the lung. Miliary TB is prominent in the liver, BM, spleen, adrenals, meninges, kidneys , fallopian tubes, and epididymis.
Isolated organ TB may appear in any one of the organs or tissues seeded hematogenously & may be the presenting manifestation of TB (e.g. TB meningitis, osteomylitis, renal TB).
Lymphadenitis is the most frequent form of extrapulmonary TB, usually occurring in the cervical region.
In years past, intestinal TB contracted by the drinking of contaminated milk as fairly common as a primary TB. In developed countries intestinal TB is more often a complication of advanced secondary TB.
Secondary pulmonary tuberculosis. The upper parts of both lungs are riddled with gray-white areas of caseation and multiple areas of softening and cavitation.
Secondary TB Morphology:
Miliary TB of the spleen. The cut surfce shows numerous gray-white granulomas.
Etiology
M- tuberculosis most common M- bovis from un pasturized milk M- africum M- Microti M- tuberculosis:
Rod shaped , non- spore forming Aerobic Acid fast
Clinical Features
Pulmonary Extra pulmonary Pulmonary Tuberculosis:
Primary Post primary
Primary Tuberculosis
Clinical illness after infection Common in children up to 4 years of age and in immuncompromised persons May be severe or disseminated Low level of transmission
Primary
Primary:
occurs soon after initial infection Seen in children Middle and lower zones Hilar or para tracheal LAP Healed lesions with calcified nodule (gohn lesion) May progress rapidly to clinical illness Pleural effusion in 1/3 Progressive primary tuberculosis with cavitation haematogenons dissemination Miliary tuberculosis or tuberculous meningitis
Post primary
Adult type, reactivation or secondary tuberculosis Endogenous reactivation of latent infection. Localized to apical or posterior segments of upper lobes. Extent of involvement varies from small infiltrate to extensive cavitary disease Tubercular pneumonia Highly infectious Clinical features: fever, night sweats, weight loss anorexia, general malaise ,weight loss,sputum production, haemopytsis Pleuritic chest pain, Dyspnea and ARDS Physical findings:
rales Bronchial breathing Fever Pallor Finger clubbing
Extrapulmonary Tuberculosis
Extrapulmonary sites include: lymph nodes, pleura genitourinary tract, bones and joints, meninges peritoneum and pericardium. Lymph nodes Tuberculosis :
Most common extra pulmonary tuberculosis Common in HIV patients Most common posterior cervical and supraclavicular sites (scrofula) Discrete non-tender may be inflamed have a fistulous tract Associated pulmonary disease in > 90%
Diagnosis by FNAC or surgical biopsy
AFB stains +ve in 50% Culture +ve in 70%
Pleural tuberculosis
20% case of extra pulmonary tuberculosis Pleural effusion, chest pain, dyspnea Diagnosis by thoracocentesis Genitourinary tuberculosis: 15% cause of extra pulmonary tuberculosis Urinary frequency, Dysuria , nocturia, haematuria, flank or abdominal pain Urine analysis: pyuria or haematuria IVP, CT abdomen, MRI may show deformities, obstructions, strictures
Skeletal Tuberculosis
10% extra pulmonary causes Wt bearing joints spine, hip and knee Spinal tuberculosis or potts spine
Gibbous formation or cold abscess Aspiration of abscess or bone biopsy confirms the diagnosis
Tuberculosis Meningitis
one of extra pulmonary tuberculosis Diagnosis by CSF examination
Diagnosis
Diagnosis Tuberculosis
AFB Microscopy: 40-60% sensitivety Mycobacterial culture : Takes 4-8 weeks Nucleic Acid Amplification Drug susceptibility testing Radiographic procedure:
CT scan MRI for intracranial tuberculosis
Find persons with LTBI who would benefit from treatment Find persons with TB disease who would benefit from treatment Groups that are not high risk for TB should not be tested routinely
Persons at higher risk for exposure to or infection with TB Close contacts of a person known or suspected to have TB Foreign-borne persons from areas where TB is common Residents and employees of high-risk congregate settings Health care workers (HCWs) who serve highrisk clients
Persons at higher risk for exposure to or infection with TB Medically underserved, low-income populations High-risk racial or ethnic minority populations Children exposed to adults in high-risk categories
Persons at higher risk for TB disease once infected Persons with HIV infection Persons recently infected with M. tuberculosis Persons with certain medical conditions Persons who inject illicit drugs Persons with a history of inadequately
Inject intradermally 0.1 ml of 5 TU PPD tuberculin Produce wheal 6 mm to 10 mm in diameter Do not recap, bend, or break needles, or remove needles from syringes
Read reaction 48-72 hours after injection Measure only induration Record reaction in millimeters
mm is classified as positive in HIV-positive persons Recent contacts of TB case Persons with fibrotic changes on chest radiograph consistent with old healed TB Patients with organ transplants and other immunosuppressed patients
10
mm is classified as positive in
Recent arrivals from high-prevalence countries Injection drug users Residents and employees of high-risk congregate settings Mycobacteriology laboratory personnel Persons with clinical conditions that place them at high risk Children <4 years of age, or children and adolescents
15
mm is classified as positive in
Persons with no known risk factors for TB Targeted skin testing programs should only be conducted among high-risk groups
Type of Reaction Possible Cause False-positive Nontuberculous mycobacteria BCG vaccination Anergy False-negative Recent TB infection Very young age (< 6 months old Live-virus vaccination Overwhelming TB disease
Anergy
Do not rule out diagnosis based on negative skin test result Consider anergy in persons with no reaction if - HIV infected - Overwhelming TB disease - Severe or febrile illness - Viral infections - Live-virus vaccinations - Immunosuppressive therapy. Anergy skin testing no longer routinely recommended
Boosting
Some people with LTBI may have negative after skin test reaction when tested years infection Initial skin test may stimulate (boost) ability to react to tuberculin Positive reactions to subsequent tests
Two-Step Testing
Use two-step testing for initial skin testing of adults who will be retested periodically
Treatment of TB Diseasee
Treatment
Drugs:
Isoniazid 5mg /kg Rifampin 10mg/ kg Pyrazinamidle 20-25 mg/kg Ethambutol 15-20 mg /kg
Regimens
Provide safest, most effective therapy in shortest time Multiple drugs to which the organisms are susceptible Never add single drug to failing regimen Ensure adherence to therapy
Adherence
Nonadherence is a major problem in TB control Use case management and directly observed therapy (DOT) to ensure patients complete treatment
All positive testing activities should be accompanied by a plan for follow-up care.
Case Management
Health care worker watches patient swallow each dose of medication Consider DOT for all patients DOT should be used with all intermittent regimens DOT can lead to reductions in relapse and acquired drug resistance Use DOT with other measures to promote
Include four drugs in initial regimen - Isoniazid (INH) - Rifampin (RIF) - Pyrazinamide (PZA) - Ethambutol (EMB) or streptomycin (SM) Adjust regimen when drug susceptibility results
Care for HIV-related TB should be provided by or in consultation with experts in management of both HIV and TB
RIF-based regimens generally recommended for persons Who have not started antiretroviral therapy For whom PIs or NNRTIs are not recommended Initial treatment phase should consist of Isoniazid (INH)
Rifampi (RIF)
Pyrazinzamide (PZA) Ethambutol (EMB) RIF may be used with some Pls and NNRTIs
For patients receiving PIs or NNRTIs, initial treatment phase may consist of - Isoniazid (INH) - Rifabutin (RFB) - Pyrazinamide (PZA) - Ethambutol (EMB) An alternative non rifampycin regimen includes INH, EMB, PZA, and streptomycin (SM)
Extrapulmonary TB
Pregnant women
9-month regimen of INH, RIF, and EMB PZA and SM are contraindicated PZA not contraindicated in HIV-positive pregnant women
Children
HIV-Negative Persons Carefully supervise and manage treatment to avoid development of MDR TB Discontinue INH and continue RIF, PZA, and EMB or SM for the entire 6 months Or, treat with RIF and EMB for 12 months
Presents difficult treatment problems Treatment must be individualized Clinicians unfamiliar with treatment of MDR TB should seek expert consultation Always use DOT to ensure adherence
Baseline measurements Monitor patients at least monthly Monitoring for adverse reactions must be individualized Instruct patients to immediately report adverse reactions
After 3 months of therapy, if cultures are posit or symptoms do not resolve, reevaluate for - Potential drug-resistant disease - Nonadherence to drug regimen
If cultures do not convert to negative despite 3 months of therapy, consider initiating DOT
HIV-Positive Persons A rifamycin and PZA daily for 2 months May be given twice weekly Administration of rifampin (RIF) contraindicated with some protease inhibitors (PIs) and nonnucleoside reverse transcriptase inhibitors (NNRTIs) HIV-Negative Persons Clinical trials have not been conducted Daily RIF and PZA for 2 months
Contacts of INH-Resistant TB
Treatment with a rifamycin and PZA If unable to tolerate PZA, 4-month regimen of daily RIF HIV-positive persons: 2 month regimen with a rifamycin and PZA
Contacts of Multidrug-Resistant TB
Use 2 drugs to which the infecting organism has demonstrated susceptibility Treat for 6 months or observe without treatment (HIV-negative) Treat HIV-positive persons for 12 months Follow for 2 years regardless of treatment
Fibrotic Lesions
Acceptable regimens include 9 months of INH 2 months RIF plus PZA 4 months of RIF (with or without INH)
Pregnancy and Breast-feeding
Monitoring Patients
Importance of adherence to treatment regime Possible adverse side effects of regimen Establishment of optimal follow-up plan
Baseline laboratory testing Not routinely indicated Baseline hepatic measurements for - Patients whose initial evaluation suggests a liver disorder - Patients with HIV infection - Pregnant women and those in immediate postpartum period - Patients with history of chronic liver disorder
At least monthly, evaluate for Adherence to prescribed regimen Signs and symptoms of active TB disease Signs and symptoms of hepatitis (if receiving isoniazid alone, and at 2, 4, and 8 weeks if receiving RIF and PZA)
Prevention
BCG : Vaccination
BCG Vaccination
Not recommended in immunization programs or TB control programs in the U.S. BCG vaccination undertaken after consultation with health department
Considered for an infant or child with negative skin-test result who Is continually exposed to untreated or ineffectively treated patient Will be continually exposed to multidrugresistant TB
HCWs considered on individual basis in settings in which High percentage of MDR TB patients has been found Transmission of drug-resistant TB strains and subsequent infection are likely, and Comprehensive TB infection-control
BCG Contraindications
Contraindicated in persons with impaired immune response from HIV infection Congenital immunodeficiency Leukemia Lymphoma Generalized malignancy Receiving high-dose steroid therapy Receiving alkylating agents Receiving antimetabolites
Tuberculin skin testing not contraindicated for BCGvaccinate persons LTBI diagnosis and treatment for LTBI considered for any BCG- vaccinated person whose skin test reaction is 10 mm, if any of these circumstances are present: - Was contact of another person with infectious TB - Was born or has resided in a high TB prevalence country - Is continually exposed to populations where
Community TB Control
Identify and treat all persons with TB disease Identify contacts to persons with infectious TB; evaluate and offer therapy Test high-risk groups for LTBI; offer therapy as appropriate
Health care providers should work with health department in the following areas: Overall planning and policy development Identification of persons with clinically active TB Management of persons with disease or TB suspects Identification and management of persons with LTBI Laboratory and diagnostic services Data collection and analysis Training and education
Develop overall TB control strategy Review local laws, regulations, and policies Guide and oversee TB control efforts of local institutions and practitioners Provide consultations in TB treatment, contact investigations, and infection control practices Seek out necessary funding and resources Educate policymakers
Health department has ultimate responsibility for ensuring TB patients do not transmit TB
Contact Investigation
Have TB disease so treatment can be given, and furth transmission stopped Have LTBI so treatment can be given
Are at high risk of developing TB disease and require treatment until LTBI excluded
Management involves range of services, which include Developing a treatment plan Promoting and ensuring adherence
Providing a referral system for other medical problems Providing clinical consultation services Providing inpatient care when necessary Providing appropriate facilities to isolate and treat patients with infectious TB Maintaining an infection control program
Readily accessible AFB results within 24 hours of specimen collection Clinicians promptly report all TB cases and suspected cases All TB smear and culture results reported by laboratories
TB reporting required in every state All new cases and suspected cases promptly reported to health department All drug susceptibility results sent to health department
TB control programs should Provide training for program staff Provide leadership in TB education to the community Ensure community leaders, clinicians, and policymakers are knowledgeable about TB Educate the public
SARCOIDOSIS
Multisystem granulomatous disorder. Commonly affecting young adults. Usually presenting with:- bilateral hilar lymphadenopathy - Pulmonary infiltrates - Skin or eye lesions. Most common in colder climates.
Lesion are histologically similar to tuberculous follicles. The differerences are:-absence of caseation. -absence of tubercule bacilli
Chronic beryillium poisoning produces a disease which mimics sarcoidosis clinically and pathologically. Ocasionally sarcoidosis reactions seen carcinoma, fungal infection.
Aetiology
-Unknown -No evidence of role of typical or atypical mycobacteria,fungi,viruses. -Disturbances in cell mediated immunity
Depressed reactivity to tuberculin * Lymphopenia * Increase in the lymphocytes in bonchoaleolarlavage flui,particularly CD4 helper cells.
*
* Transbronchial biopsies of lung show infiltration of alveolar walls,interstitial spaces with leucocytes especially T cells prior to granuloma formation.
Clinical features
Clinical features
Peak incidence:third and fourth decades. Female Preponderance. Multisystem inholvement-variable Presentation Clinical Presentation of sarcoidosis. 1. ASYMPTOMATIC : Bilateral hilar lymphadenopathy. 2. ACUTE PRESENTATION HEERFORDT-WALDENSTROM SYNDROME: (uveoparotid fever) parotid enlargement, anterior uveitis, facial nerve palsy.
LOFGRENS SYNDROME : erythema nodosum,X-ray finding of bilateral hilar adenopathy,arthritis. 3. INSIDIOUS FORM :respiratory manifestations without constitutional symptoms;progressive exertional dyspnea,dry cough.On exam-initially no positive findings.Later-fine basal insp.crackles.
Investigation
Chest xray-is abnormal in 90% of cases stage 1- Bilateral hilar enlargement spontaneous resolution within 1year Stage2- Combination of hilar glanduar enlargement plus pulmonary opacities Dyspnea & dry cough. Spontaneous impoovement in majoity Stage3 diffuse pulmonary shadows without hilar adenopathy. Progressive course
Stage 4-pulmonary fibrosis. Progressive ventilatory failure ,pulmonary hypertension and corpulmonale 1.Imaging chest x-ray / high resolution CT scan (HRCT) of chest is useful in the assessment of diffuse lung involvement 2.Transbronchial biopsy the most useful investigation. Positive results are seen in 90% cases pulmonary sarcoidosis with or without x-ray evidence of lung involvement. Non censating granuloma (NCGS) are seen in 50% cases with clinically typical extrapulmonary sarcoidosis with normal looking chest x-ray.
3. Lung Function Tests:- show a restrictive defect earliest decreased gas transfer factor (DLCO) TLC in both FEV1 & FVC 4.CBC:- Mild normocytic and normochromic anaemia with ESR 5.S.biochemistry:- Hypercalcemia, hyper gammaglobulinemia, hypercalciuria 6.Serum level of angiotensin converting enzyme (ACE) is raised. Not specific to sarcoidosis. Useful in assessing the activity of the disease. 7.Tuberculin test:- is negative, useful as a
SARCOIDOSIS - Management
Stage I & II No treatment is required Patients with EN, pyrexia, joint pains can be treated with NSAIDs Short course of steroids Stage III Long term corticosteroid therapy Methotrexate Hydroxychloroquine