introduction to tuberculosis prof.dr. monica pop
TRANSCRIPT
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INTRODUCTION TOTUBERCULOSIS
PROF.DR. MONICA POP
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Definition
• Infectious-contagious disease
• Endemic disease
• Mycobacterium tuberculosis (Koch’s bacillus )
• Granuloma + inflammation + destruction
• Localization: lung, possibly extrapulmonary
• Chronic evolution, consumption and frequently
fatal
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Etiology
• Mycobacterium tuberculosis Complex (MTB):– M. tuberculosis– M. bovis – rarely (digestive transmission)– M. africanum – rarely (in Central and Western Africa)
• Other mycobacteria:– pathogen: M. leprae (leprae)– opportunist pathogen: M. kansasii, M. scrofulaceum,
MAI complex (M. avium-intracellulare), etc.– saprophyte
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Characteristics of MTB
• Resistant to coloration / decoloration (acid-alcohol resistant bacillus = BAAR)
• Slow growth – time required to develop a new generation is between 18-24 h (3 weeks on a solid medium)
• They need O2
• Intracellular Parasite• Destroyed by UV
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TBTransmission - sources of infection
• The patients with pulmonary TB, especially patients with smear sputum with positive microscopy
• The degree of positivity:– Number of bacilli in smear (M+ >>> M-)– The frequency of coughing
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TB Transmission
Patient with pulmonary TB
Coughing, sneezing, talking
Small droplets
Drops’ Nucleus
Sanitise Host???
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TB Transmission
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Risk of infection
• Density of infection sources (TBP/M+)
• Proximity to M.t. sources ( time, proximity)
• Virulence of M.t• Resistance of persons to infection
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LOW RISK OF INFECTION
• Precocious treatment (= precocious diagnose), a correct and a complete treatment of infection sources
• Providing good living conditions (home and food)
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The cycle of TB transmission
Infected personPulmonary TB
Extrapulmonary TB
M+
M-
Noninfected person
Infected person
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Disease Risk to the host with TB infection
Risk Factor Incidence of TB (100.000 pop)
recent TB infection (< 1 year) 2000 – 8000
recent TB infection 1-7 years 200
HIV infection 3500 – 14000
toxicomany iv + HIV infection 4000 – 10000
toxicomany iv without HIV 1000
silicosis 3000 – 7000
Abnormal chest x-ray: disabling TB 200 – 400
Kidney failure 400 – 900
Diabetes mellitus 300
underweight 200 – 260
The absence of any factors 100
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DIMINUATING THE RISK’S DISEASE TO PERSONS WITH TB INFECTION
• The treatment of latent TB infection (= chemoprophylactic therapy)
• BCG vaccination
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TB Infection
Inhaling the particle with MT The multiplication of MTB
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TB Infection
Meninx
Apex of lung
Liver, spleen
Adrenal gland
Lymphatic nodes
Bone, joint
Haematogenous Dissemination
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Immunological modification in TB
Presentation of Ag
Clonal ProliferationLTh1 (CD4+)
LTc (CD8+)
IL-2
IFN-
M bactericide for MTB
Destruction of M parasity
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The Evolution of primary infection
• Reduction of M.t. population:– Complete elimination– Persistence of some dormant bacilli
• The resorption of tb inflammation, sometimes followed by caseous necrosis
• Fibrosis and/or calcification of the tb multiplication
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TB disease - mechanisms
• The Evolution tb infection – disease primoinf. – rarely
• Reactivation by endogenous mechanisms = the MTB multiplication starting with dormant bacilli,– The mechanism is important in countries with low incidence of
TB
• Exogenous Reinfection = reinfection of an infected person, followed by TB disease,– The mechanism is important in countries with high incidence of
TB
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Diagnosis
• Bacteriological
• Histopathological
• Tuberculin Skin Test with PPD
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Bacteriological test
• Smear sputum (BAAR test)– Sensibility 10000 bacilli / ml
• Culture of MT and identification:– The most important method– Sensibility 100 bacilli / ml
• Inoculation to Guinea pigs:– Expensive, slow, experimental,– Sensibility 1-10 bacilli / ml
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Specimen tests
• PulmonaryTB (with Mt):– Sputum after coughing/or aerosols– After bronchial endoscopy
• Extrapulmonary TB (without Mt):– Pleural effusion, peritoneal, pericardial– LCR– Articular liquid– Urine– Bioptic fragments
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Smear sputum
Ziehl-Neelsen Coloration
• Standard analysis
• In mycrobiological laboratory (microscopic interpretation of the slides)
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Results
Number of BAAR Results
absent negative
1-9 BAAR / 100 fields no. of BAAR
10-99 BAAR / 100 fields +
1-9 BAAR / 1 field ++
10 BAAR / 1 field +++
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Microscopic Exam
Fluorescent Colorations
• Fast
• The positive result needs confirmation by Z-N
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The culture of Mycobacterium
• Is the standard method for TB diagnosis• Solid medium Lowenstein-Jensen:
– Standard– Growing in 4-6 weeks
• Liquid medium: – fast (starting in a few days)– More expensive
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The sensitivity to drugs
• It is an expensive method, with many errors
• The MTB Resistance to antiTB drugs quantitatively defined (> 1% resistant bacilli)
• It is imperative:– For isoniazid and rifampin– For re-treatment or in case of initial suspicion of
chemoresistance
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Histopathologic Examination
Clinical material
• Pleural biopsy (biopsy by needle, rarely by thoracoscopy)
• Lymph nodes• Pericardial or peritoneal biopsy• Bone or synovial membrane• Bronchial, laryngeal, lung biopsy
• Rarely - others
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Tuberculinic skin test
• Injecting directly into the skin MTB antigenes (named PPD-derived from purified proteines)
• It causes a late hypersensitive reaction • It consists of the local accumulation of limfocites
and macrophages • Macroscopically defined as an induration at the
injected place
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Tuberculin skin test (TST)
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Results
• Positive (TB infection) 10 mm 5 mm in HIV-positive host
• Negative (absence of the TB infection)• < 10 mm• < 5 mm in HIV infection
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The results to successive tests
• Tuberculinic conversion = passing from negative to positive skin test
• Diagnosis of recent TB infection
• Tuberculinic jump = min. 10 mm increase in the diameter of skin reaction to tuberculine– uncertain meaning
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False Results
• False pozitive– BCG Vaccination– Contact with atypical mycobacterium
• False negative– Technical Errors– Active Sarcoidosis, haematological malignancy
diseases, acute viral infection, antiviral vaccination with viable virus, HIV infection
– Long-term immunosupressive therapy (including corticotherapy)
– Initial phase of a TB infection
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Tuberculosis in childrenPrimary tuberculosis
Monica Pop
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TB in children
• Suspicion in case of suggestive context :– Child from TB focus– Symptomatic child
• More clinical types• The suspicion is supported by a positive skin
test and chest x-ray exam• Diagnosis is rarely Confirmed by bacteriological
exam
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Primary Tb infection
• Without symptoms in most of the cases
• It goes unnoticed
• TB infection ≠ TB disease
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Primary Pulmonary TB
• Primary infection with clinical-radiological manifestation
• 10% of primary infection cases
• More frequent after the age of 5
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Primary pulmonary TB: symptoms
• General Simptoms :– Fever– Loss of weight– Apathy/indifference
Cutaneous and mucousmembrane manifestations:– Erythema nodosum– Conjunctival blister
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Primary pulmonary TB : radiological signs
• Primary tipical Complex:– Alveolar acinar opacity (3-10 mm)– Hilar lymph nodes and/or mediastinal, sometimes
isolated
• Sometimes segmentary or lobary opacity because of the athelectasy produced by the adenopathy (medium or lingual lobe)
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Primary pulmonary TB :diagnosis
• Epidemiological Context • Skin test (maybe retesting in case of negative
test)• Matching radiological abnormalities• Possible bronchial endoscopy: confirms the
adenopathy
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Primary pulmonary TB evolution
• Usually the evolution is benign, healing even without any treatment
• There is an important risk to develop TB after a variable latent period
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Primary pulmonary TB :complications
• Immediate local complications :– Ganglionic Fistula in a drainage bronchi – risk of
acute bronchial obstruction in children– Primary TB pulmonary cavitation – necrosis on the
pulmonary condensation• Late local complication :– Bronchiectasis– Atelectasis is most frequent in the medium lobe
(by compression of calcified adenopathy)– Haemoptysis
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Primo-secondary pulmonary TB
• Rarely in small children• In teenagers or older children in malnutrition
conditions• Clinical-radiological symptoms – like adult TB• Confirmation by bacteriological exam of sputum,
bronchial or gastric aspirate exam• The treatment is similar to the adult tuberculosis
treatment
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Extrapulmonary TB: severe forms
• TB meningitis
• Milliary tuberculosis
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TB meningitis
• The clinical symptoms - similar to adult meningitis:– Insidious and nonspecific beginning, headackes and
vommiting– Sometime coma and rigidity of the feet and hands
• Thoracic x-ray: normal or aspect of primary tuberculosis or milliary image
• Ex. of the eyes: coroisis tubercullis • LCR: moderate high number of cells, especially
lymphocytes, cultures are usually positive for BK
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TB meningitis
• Possible Diagnosis is:– Epidemiological Context – Criteria of Non-confirmation of another etiology – even when the tuberculin skin test is negative– It is important to institute a DOTS quickly (without the
result of the cultures)
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Milliary Tuberculosis
• Symptoms:– Appears in the first weeks after primary infection– Severe form of disease:
• High fever• Vommiting, diarrhea• Dyspnoea, cyanosis, sometime respiratory
dysfunction • Rdg. of the chest : milliary aspect lymphadenopathy FO
and LCR: dissemination signs• TST: rarely positive
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Milliary TB :diagnosis
• Suspicious in case of:– Epidemiological context – Rx chest: milliary– Excluding other causes of fever with milliary aspect – TST positive
• Start DOTS fast
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The other forms of extrapulmonary TB
• Ggl. Tb: more than 50% of cases of extrapulmonary TB in children
• Skeletal system and articulation TB
• Serous TB: pleura and peritoneum
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Conclusion
• Suspicions in a clinical and epidemiological context
• Confirmed by TST and by occasional isolation of the bacilli
• Frequently the evolution is benign, self-limitative• High risk of developing a secondary disease• Sometime the disseminative forms appear with
severe prognostic in the absence of a treatment
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Pulmonary TB (TBP) in adults
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Pulmonary TB in adults
• Importance:– The most frequent manifestation of TB (5/6 of cases)– Infection source
• Isolated localization in the lung, rarely dissemination
• Precocious diagnosis + correct and complete treatment = the most efficient profilaxis of TB in the community
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Clinical Manifestion – the beginning
Acute
Haemoptysis
Flue-like
Pseudo-pneumonia
AsymptomaticAsymptomatic Pathological Chest radiography
Insidious General symptoms
Respiratory symptoms
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General symptoms
• Physical asthenia • Annorexia• Weight loss (significant > 10% for the initial
mass)• Perspiration• Fever (variably - possibly without fever)
• Amenorrhoea (women)
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Respiratory symptoms
• Persistent cough (almost 3 weeks = central
symptom)• Mucous expectoration / mucopurulent, possibly
absent• Hemoptysis (sometimes at the beginning)
– haemoptoic sputum– rarely massive (life threatening)
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Physical Thoracic Exam
• Is frequently poor
• Localised rales (crepitant or sibilant/ronflant)
• Condensation Syndrom – rarely
• Amphoric breath – exceptionally (cavern localisation superficially)
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Clinical Manifestations
• Non-specific
• Sometimes without symptoms
• Persistent cough = the most important sign for a call in pulmonary TB
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Thoracic Chest radiography
• Is the most important piece in persistent cough
diagnosis
• It is not conclusive for a positive diagnosis
• It is an element for diagnosis orientation
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Radiological diagnosis• Alveolar opacities • Different sizes (subsegmental lobar)
– Homogenous or non-homogenous (transparency zone inside)
• Cavity Image- Relatively thin wall- Without horizontal level– +/- unique bronchi drainage, rarely multiple
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Cavitation Image
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Extensive Form (“bronchopneumonia”)
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Radiological nodular lessions
• Micronodules (<3mm) = hematogenous dissemination
• Acinar Nodes (4-10mm) – sometimes confluences
• (same dimensions cm) =bronchogenic dissemination
• Macronodules (>10mm), sometimes with calcification,
no evolution in time (tuberculoma)
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Tuberculoma
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Other radiological lessions
• Sequellary:
– Primary Complex calcification
– Localized fibrosis
– Extended Fibrosis (fibrothorax)
• Complications
– Pneumothorax / pyopneumothorax
– Pleural effusion
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Radiological Criteria for TB suspicion
• Localization of the main lesion, especially in:– Apical and posterior segments of the superior lobe– Apical segment of the inferior lobe
• Association of different lesions on the same radiography (cavitation, nodules, fibrous lesions)
• Association of lesions at a distance (two lobs / both lungs)
• Slow evolution of the lesions in time
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Differential Dg. – persistent cough
Coughing > 3 weeks
Bronchial asthmaORL Pathologygastroesophagealreflux disease
Bronchiectasis
COPD? Chronical bronchitis
Bronchopulmonary cancer
Pneumoconiosis
Mitral Stenosis / IVS
Normal chest
Purulente Bronchorrhea Infectious exacerbations
Progressive Dispnea
obstructive Syndrom
Smoke historyRx +/- bronchoscopysuggestive
Professional exposure, Rx image
Clinical signs,
ECG, EcoCG
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Differential Dg - cavity imagine
Pulmonary abscess
Pulmonay cancer
Hydatid cyst
Insidious beginningCough and chronic expectorationFetid SputumChest Rdg: hydroaeric image
Smoking historychest Rdg: cavitation with thick wallsFrequently nodules reaction
History of clear vomical liquidChest Rdg: cavitation with thin wallsProligerous membrane
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Differential dgs. of alveolar condensation
Pulmonary Tb must constitute a differential diagnosis for any pneumonia with poor response
– no response after AB treatment !!
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Pulmonary TB Diagnosis
The decision to begin antitb treatment – the arguments:
• Epidemiological• Clinical• Radiological• Positive Smear sputum
2 positive smear sputum 1 positive smear sputum with a clinical-radiological suggestive aspect
– Negative (3-6 samples) with suggestive clinical-radiological aspect (the pneumologist’s decision)
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Pulmonary TB Diagnosis
The confirmation of pulmonary TB diagnosis:
• Smear positive culture
• Favourable clinical-radiological evolution after treatment, in absence of an alternative diagnosis
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The Evolution of the disease (TB)
• In absence of correct treatment:– Progressive worsening with lesional extension– Frequently death– Persistent bacilli elimination by (infection source)
• After correct treatment – Slow resorption of infiltrates– The reduction in sizes and the closure of cavities– Localised fibrosis– Stop in the elimination of bacilli
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TB complications during treatment
• Hemoptysis (massive) – the erosion of the arterial bronchial wall
• Pneumothorax – air in the pleural space (pyothorax)
• Pleuresy of vicinity
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Sequela and late complications
• Hemoptysis – breaking the scarred aneurysm • Secundary bronchiectasis • Hemoptysis Recurrente infections• Chronic respiratory failure• Extensive destructions of the pulmonary parenchyma Secundary pulmonary Fibrosis Aspergilloma: residual cavity (hemoptysis)
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Extrapulmonary Tuberculosis (TBEP)
Prof.Dr. Monica Pop
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Extrapulmonary Tuberculosis
• It represents 1/6 of TB cases ( HIV–)• It summarizes all localisations – except the lung • It is more frequent in HIV infected patients • The origin – blood stream invasion• Paucibacillary lesions• Positive diagnosis: bacteriological and/or
histopathological
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Dissemination of TB
• The display: – miliary acute and chronic TB– disseminative and non-reactive TB– dissemination: a severe form of TB ( high mortality)
• Frequently IDR to PPD is negative – does not exclude the diagnosis (the tuberculin turn during the treatment = retrospective positive dg.)
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Miliary Tuberculosis
• The most frequent form of TB dissemination• Small active lesions (<3mm) spread in the body• Frequently: lung, liver, spleen• Sometimes: bone marrow, serous, kidneys, CNS
(central nervous system), CSR
• Miliary: diffuse localisation (not predominantly pulmonary)
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Miliary acute TB
• Child and the young adult (possible at any age)
• Rapid progression
• Fatal without treatment
• High mortality (28%) in spite of correct treatment
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Miliary acute TB – clinical features-
• General symptoms – clinical chart is important :– fever 38-40°C – trembling– extreme physical asthenia– anorexia – weight loss– cough
• Progressive dyspnoea → respiratory distress• Physical exam: tachycardia, hepatomegaly,
splenomegaly
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Radiological exam
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Positive Diagnosis - difficult
• Expectoration (sputum, LBA) are paucibacillary• Biopsy exam:• Transbronchial pulmonary biopsy – difficult to
obtain– Liver biopsiy - is not specified– Bone marrow biopsy – diagnosis
! Low degree of TB suspicion – given by the severity of the disease
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Differential Diagnosis
• Other infectious causes– Cytomegalovirus– S. aureus– Pn. carinii
• Miliary carcinomatosis• Hypersensitive pneumonitis• Sarcoidosis
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Miliary chronic Tuberculosis• Old patients• Insidious clinical form• Clinical symptoms: fever, consumptive syndrom
• Miliary chest radiography
• Positive diagnosis difficult, frequent after death
• Differential diagnosis – other interstitial diseases
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Non-reactive disseminated TB
• Insidious, rare clinical form
• Frequently in immunosuppressed host
• Histologically: important area of necrosis with
bacillus, without specific granuloma
• Clinically: fast or chronic evolution
• Unfavourable evolution, without an efficient
treatment
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TB Meningitis
• Origin: hematogenous dissemination focus of primary infection
• It occurs in childhood
• Often in miliary tuberculosis
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Clinical Manifestation
• Subacute onset• Initially: - fever and malaise
- irritability/physical asthenia - headache - +/- nausea-vomiting
• Afterwards: - coma - signs of paralysis (cranial)
• Late: - antalgic position - sensitivity to light
- coma
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Investigations
• Chest Radiography: - normally
- milliary image
- the aspect of primary lesion
• TST to PPD negative (starts to be positive during treatment = is a retrospective dg. argument)
• Ex. FO: choroid tubercule
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LCR Exam (lumbar puncture)
• Clear/ opalescent
• High pressure
• Low glucose (< 40 mg/dl)
• High proteins (0,6-2 g/dl)
• High cells, mostly lymphocytes
• BAAR – negative, usually + in culture
• Molecular Diagnosis (PCR)
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Positive Diagnosis
! Probability – it is necessary to start treatment fast
• Age < 5 years• Children unvaccinated BCG• Contact with a patient with active pulmonary
tuberculosis• LCR – clear liquid with lymphocytes and high
proteins
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Differential Diagnosis on LCR ExamEtiology Cells Proteins Bacteriological
exam
TB 30-300/mm3
Lymphocytes
>0,6 g/dl BAAR (-)
Cultures BK (+), PCR
Bacterium Hundred- thousands/mm3
Neutrophils
>0,6 g/dl Smear sputum, cultures
Viral >300/mm3
Lymfocites
<0,5 g/l Negative
Meningism <10/mm3 <0,5 g/dl Negative
Cryptococcus Neutrophils ↑
Lymphocytes ↑
High Parasites in specific
coloration
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TB Pleurisy
• Is the most frequent form of extrapulmonary TB
• Young adult, adolescent
• Origin: – Rarely, hematogen dissemination, breaking of a pulmonary
subpleural nodule within the pleura
• Mechanism – intense inflammatory granulomatous reaction to the presence of mycobacterium Ag
• It may be a pulmonary TB complication
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Clinical Manifestation
Acute debut• Intense pain with pleural character (twinge)• Fever • Cough without expectoration• +/- polypnea
previous general signs• Physical asthenia• Loss of appetite• Weight loss
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Clinical examination
Pleural Liquid Syndrome :• Intensive basal mobile dullness• Absence of vocale vibrations• Absence of vesicular murmur +/- pleural breath
to the la superior margin ofmall dullness
• Positive Hirtz in small pleuresis
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Paraclinical examinations
1. Chest x-Ray: liquid-type opacity
2. TST to PPD negative; it might be positive during treatment = retrospective dg. argument
3. Examination of the pleural liquid :– Serocytrin– Exsudate (proteins > 3g/dl, LDH > 2/3 of plasmatic LDH)– Numerous lymphocyte (> 90%) – Crossing of ADA
4. Histopatological Ex. – pleural biopsy (+) in 80% of cases; crossing rudimental when ssociate with positive culture of biopsy fragments
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Radiological image
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Differential DiagnosisEtiology Clinical Liquid + Diagnostic
TBC Fever, cough, thoracic pain
Serocytrin,exsudate, lymphocites ↑
Granuloma TB (pleura) cultures + liquid or fragment
Mycoplasma Cough, headaches, muscle pain
Serocitrin,exsudate,monocytes
+ Cultures
Virus Thoracic pain, after IACRS
Serocitrin,exsudate,mononuclear
Rapid resorption
Bacterial Initially/
concomitent
Pneumonia
Serocitrin,exsudate,neutrophile PMN
Purulent liquid
Cancer Neoplasic signs Seros/ hemorrhagic exsudat
+ cytology
Mesothelioma Thoracic pain, dyspnoea
Seros/hemorrhagic, exsudat
Pleural fragment histology +
LES Diagnostic LES Thoracic pain
Seros/hemorrhagic, exsudat
Lupic cells
Rheumathoid Arthritis, subcutaneous
nodules
Purulent, exsudate FR present
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Evolution
• Spontaneus:– Spontaneus resorption, patient healed without (per
primam) sequals; – Risk of pulmonary TB in the next 5 years
• Antituberculosis TB treatment: completely healing in all cases– Without risk of a pulmonary TB
• Corticosteroids – without any effect
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Lymph node tuberculosis
• Children and young adults• Mechanisms – lympho-hematogenic
dissemination • Frequently laterocervical and supraclavicular
nodules
Clinically:– elastic adenopathy unpainful,non-adherent– rare + general signs and symptoms
• TST to PPD frequently +
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Lymph nodule tuberculosis
• Diagnosis:– BK culture positive: lymph nodule point, lymph node
fragment– Histological: lymph node fragment – Differential diagnosis: abscessed nodes, sarcoidosis,
neoplasia, malignant lymphoma– The other mycobacteria: M. scrofulaceum, M.
intracelular
• Variable evolution after anti-tuberculosis drugs, sometimes they need surgery treatment
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Tuberculous Spondylitis(morbus Pott)
• Children and adults• Mechanism - hematogenic dissemination
between primary infection, rarely lymphatic dissemination
• Thoracic/ lumbar Vertebrae• Lesion:
– initially: the anterior part of the vertebral body (erossion)
– advanced stage: vertebral narrowing and eventually vertebral collapse and spinal damage
• -breaking lesions in paravertebral tissue
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Tuberculous Spondylitis (morbus Pott)
Clincal presentation:- pain in a single area, it’s worsened by touching the affected zone - rarely: general symptoms- advanced stage: hunchbackLateral x-ray: - the erossion of the anterior part of the vertebral body - narrowing of the vertebral spacesPositive diagnostic:- bacteriologic exam from the externalized caseum - biopsy of the affected boneDifferential diagnostic:- infectious spondylitis, spondylosis, bone metastasis
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Articular Tuberculosis
• Big joints • Frequently monoarticular • Clinical exam: painless tumefaction
→ progressive amyotrophy → joint destruction• joints X-ray : epiphysis lesion + articular space growing
• TST to PPD +
• Diagnosis: culture by + of the sinovial liquid
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Renal tuberculosis
• Mechanism: reactivation of dissemination hematogenic focus
• Ureteral, urinare vesice by later afection• Clinical:
– Lumbar pain, painful urination, tumefaction, hematuria– Rarely general manifestation
• TST to PPD frequently + • Diagnosis: urine cultures bK +• Complications: ureteral structures, chronic renal
insufficiency
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Tuberculous Pericarditis
• Rarely, usually associate with HIV infection• Mechanism: hematogenic reactivation of primary
infection focus
• Symptoms: fever, chest pain, progressive dyspnea • Objective: pericarditis friction, cardiac noise, • Chest Rx: cardiac silhoutte enlarged,• EKG: difuse modifications of the end phase• Diagnosis: pericarditis biopsy• Complications: cardiac coliision
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Other localisations
Peritoneal Tuberculosis
Insidious evolution
Clinical signs: ascitis; rarely acute abdomen
Diagnosis: exploratory laparotomy with histological exam + bacteriological exam of peritoneal fragments
Tuberculosis of the larynx• Rare form• Very contagious• Is associate with extensive pulmonary TB • Clinical: dysphonia, sometimes obstruction of the larynx
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Very rarely Localisations
• Cerebral Tuberculoma• Skin TB • Intestinal TB• Hepatosplenic TB • Auricular TB • OcularTB • Thyroid TB • CSR TB ( with CSR insufficiency)
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HIV and Tuberculosis Infection
Prof.dr. Monica Pop
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MTB – HIV
• HIV Infection: the most strongest risk factor is tb appearance in a person previously infected with M. tuberculosis
• Tuberculosis + HIV infection = AIDS
• Tuberculosis = the most frequent opportunist infection in HIV infection, in the country, with high endemic malady
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Diagnosis circumstances
• Patient with HIV infection:– Persistent cough
• Tuberculosis like first sign HIV infection:– To persons with risk of HIV infection– Patients with antitb (DOTS) treatment who present
loss in weigh or the clinical signs to develop SIDA disease
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Pulmonary Tuberculosis
• CD4 > 200/mm3:– Clinical-radiological signs similar to the patients
without HIV infection– Is predominant in cases BAAR (+)– High frequence in a high endemic TB county
• CD4 < 200/mm3:– Atypical clinical form: TB dissemination (miliary),
absence of cavity TB lesions– Mediastinal nodes presents
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Pulmonary TB Diagnosis
• TB confirmation is necessary
• It is important to exclude the other cases of pneumonia to immunodepressive
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Extrapulmonary Tuberculosis
• Ggl,• Serous (pleuresia, peritonitis, pericarditis)• Meningitis
More frequent in HIV-positive persons !!
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TB Evolution
• After treatment the evolution is similar to HIV (-) cases
• Adverse reactions are most frequent• Mortality is greater by complications between
HIV infection• It is not possible to administate:
– Rifampicin (in cases of concomitant administration of antiretrovirals)
– Thioacetazone: severe skin reaction
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TB Prevention
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TB Prevention
• Primary TB: isolation and active TB pulmonary treatment
• Secondary (prevention TB development of TB disease):
• Tracing and TB latent infectious treatment– BCG Vaccination
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Risk Groups
• exposes Persons to infectious tb sources– Familiar Contacts– Medical institutions (patient, personal)
• Immunocompromised persons– HIV infection– Occupational diseases, lymphoma, mellitus diabetes,
organs transplant, etc
• Social persons (penitenciaries, asylums, homeless persons, immigrants)
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Latent tb Infection
• Tracing: TST to PPD (difficult diagnosis in countries where BGC vaccination to the newborn children is compulsory)
• Treatment (chemoprophylaxis): isoniazid 5 mg/kgcorp/zi (max. 300 mg) 6 months
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Chemoprophilaxis - indications
• Familiar Contacts < 5 years without the result of TST to PPD,
• HIV infected persons with TST to PPD positive (> 5 mm)
• Other categories:– other familiar contact of TBP/M+of patients (especially with
tuberculinic turn and/or < 35 years old)– other immunocompromised categories with positive TST to PPD,
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BCG Vaccination
• Attenuation in live Vaccine (Calmette-Guerin bacilli from M. bovis)
• Effect:– Partial Protection (20-60%) against developing TB
disease – Prevents serious tb disease in children (dissemination
TB, meningeal TB)
• Indications: newborns in the first 5 days or in their first year of live
• Contraindications: congenital immunocompromise (without HIV infection, only AIDS disease)
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Post-vaccination Evolution
• Normal Evolution: red induration (3-4 weeks), sometimes with ulceration, finally scars user retractile with 5 mm diameter
• Local complications : satelite nodes, sometimes with fistulisation, local prolongated ulceration
• General Complications: BCG-itis (= disseminated infection, like disseminated TB, to immunocompromised)
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TB Treatment
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TB Treatament
= Administration of antibiotics with MTB effect (antituberculosis chemotherapies)
• The Decision of treatment administration – arguments:– epidemiological – clinical– radiological– + Smear sputum ( M)
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Mycobacterium Populations
• Localisation – intracellular– extracellular
• Multiplication Rhythm – Rapid– slow– intermittent
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The Effect of antiTB drugs
• Bactericidal Effect - on rapid multiplication populations
– the Mycobacterium t↓ disappears rapidly (the contagion level disappears)
– ↓ the time of treatment – the duration– favourable to pass to the slow/intermittent phase of
multiplication
• Sterilisation Effect – on the population with slow/intermittent multiplication– Relapse prevention– It is important to ↓ treatment duration– It is important to be administrated at the beginning
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The Effect of TB drugs
• Slow Dynamic of Mt multiplication
+• Antibiotic post-effect of antiTB drugs
• Drugs Administration– in the morning, once a day, – intermittent (2-3 or weekly)
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Chemoresistance
• Appears due to spontaneous genetic mutation in wild Mycobacterium tb population (1 la 105-108)
• Resistant mutant to 2 antiTB – 1 la 1010-1013 (independent mutation between themselves)
• Cavity lesions - 108-109 insufficient mycobacterium population to appear spontaneously multidrug resistant
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Chemoresistance
• Primary Chemoresistance – monotherapie with one antiTB drug
• Secondary Chemoresistance – infection with already persistent stem
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Necessity of an antiTB treatment
Association of minimum 3 efficient antiTB drugs
+Bactericidal Effect + Anti-sterilisation Effect
+ Sufficient Time
Organisms’ Sterilisation prevention of relapse
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AntiTB DRUGS
• First linie:– efficiency – toxicity ↓– Usable in standard regimes
• Second line:– efficiency ↓– toxicity – Usable in individualised regimes in MDR
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Isoniazides (INH, I)• The most important bactericidal activity
• It is active, especially on TB populations:– With rapid multiplication– Intracellular population
• Intense bactericidy• Potent sterilising effect • It is active for all mycobacterial populations
Rifampicin (RMP, R)
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INH + RMP
• The most important Antituberculosis drug
• It is important to have an antiTB drug association for 9 months:– Negativization with TB sensitive bacilli– It is important to prevent TB chemoresistance and
relapsesINH
RMP
INH INH INH INH INH INH INH INH
RMP RMP RMP RMP RMP RMP RMP RMP
RMP
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Pyrasinamid (PZM, Z)
• Modest bactericidal• Potent steriling effect • Action is taken at an intracellular level, an
action per population to acid pH• Associate PZM in the first 2 months of treatment
the duration of treatment is 6 months
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INH + RMP + PZM
INH
RMP
INH INH INH INH INH INH INH INH
RMP RMP RMP RMP RMP RMP RMP RMP
PZM PZM
INH
RMP
INH INH INH INH INH
RMP RMP RMP RMP RMP
INH
INH
INHRMP
RMP
RMP
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Streptomicyn (SM, S)
• Modest Bactericidal effect • No sterilising effect
Ethambutol (EMB, E)
• Modest bacteriostatic Effect• No sterilising effect
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INH + RMP + PZM + EMB/SM
INH INH INH INH INH INH
PZM PZM
RMP RMP RMP RMP RMP RMP
PZM PZM
INH
RMP
INH INH INH INH INH
RMP RMP RMP RMP RMP
EMB/SM EMB/SM
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Posology of antiTB drugs
Time of Administration
Every day (6/7 sau 7/7) inttermitent dose(3/7)
Usual Dose (mg/kC/prise)
Max.dose. (mg) Usual dose (mg/kC/prise)
Max. Dose.
(mg)
H 5 300 10 600
R 10 600 10 600
Z 30 2000 40 2500
E 25 1500-1600 30 2000
S 20 1000 20 1000
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Anti TB - Principles of treatment
• Association with antiTB active drugs:• 2 phases:
– Initial (intensive) – to rapidly reduce a Mycobacterium population
– continuation – to destroy the multiplication of mycobacterium t.
• Duration of treatment – long (sterilization of the organisms + preview of the relapses)
• Rhythm of administration:– Every days/intermittent– Unique dose, a jeun,
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AntiTB Principles of treatment
• H + R (6 months) + Z (in the first 2 months) – Sterilisation of the tb lesions > 95% of TB with
sensible germens– It is the basis regime of antiTB treatment
• Association of S/E – protection between initial monoresistance
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Regimul I: 2 HRZE (S)7 + 4 HR3
Indications
Pulmonary TB- intensive contagious BAAR forms positive at the microscopic exam (M+)-presumtive contagious BAAR negative at the microscopic exam, but with clear cavitary pulmonary images (M-)
Extrapulmonary TB with a serious clinical evolution and a lethal risk(meningites,pericardites,miliary).
Observation- Slide still positive at two months-prelonging the HRZE
with one month 3 HRZE (S)7 + 3 HR3 - Prelonging to eight months in special situations-morbide
associate conditions(mellitus diabetis, silicosis, HIV infections or AIDS)
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Rergimul II (retratament) 2 HRZSE7 + 1 HRZE7 + 5 HRE3
Indications-patients at first retreatment-relapses, failure of initial
chimotherapy, starting the treatment after abandoning it
~ 80% of patients are treatable by applying the eight months regime
Obs.-fixable pretherapeutical antibiograms are necessary even
at T3 positive cases
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Individualised Regimen
• TBP with resistance of M.t. • Importante\severe side effects• Intolerance
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Refigure therapeutic
Regimen Therapeutic regime
TBP BAAR+ with resistance of M.t.
Individual scheme of treatment
PZM PZM
INHRMP
INH INH INH INH INHRMP RMP RMP RMP RMP
PZM PZM
INHRMP
INH INH INH INH INHRMP RMP RMP RMP RMP
EMB/SMEMB/SM
PZM PZM
INHRMP
INH INH INH INH INHRMP RMP RMP RMP RMP
EMB EMB
INH INHRMP RMP
SM SM
PZMEMB
EMB EMB EMB EMB EMB
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Initial Evaluation of the patient
• TB localisation: pulmonary, extrapulmonary• Anterior antiTB Treatment,• other factors:
– pregnancy (H,R,Z,E may to be administrate)– Concomitant of medical of administration
(contraception, oral anticoagulation)– Association diseases:
• Mellitus diabetes• Chronic Kidney Insufficiency • Chronic hepatitis• HIV/AIDS infection
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Treatment Monitoring
1. Adherence to the treatment
2. Efficiency of the treatment
3. Adverse effects of the Monitoring
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Adherence of treatment
• DOT (directly observed therapy) – usually used in first phase of treatment
• Combination of drugs in one (HR /HRZ)
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Efficiency of the treatment
• Clinical Monitoring– Loss/disappearance of fever– Loss/disappearance of cough– Recurrence of appetite
• Bacteriological Monitoring – is the most important!!!!!
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Treatment’s efficiency
• Negative Smear sputum by microscopy at the end of the intensive phase (absence of negativization to extend intensive phase with 3 month)
• Persistent Negative in cultures a sputum between treatment, beginning of the end of 4th of treatment
• It is important to Complete certain of all treatment, even in absence of bacteriological examns,
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Inefficient Treatment
• bacteriologically positive Exam of the sputum (microscopy / culture) at beginning of the end of the 4th months of treatment
• Premature stopping of the treatment
• Restart treatment (retreatment) – Bacteriological confirmation is the rule – Antibiogram is the rule (high suspicion of
chemoresistance)
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Monitoring adverse effects
Hepatitis drugs• The main adverse effect • It is determined by H, R and/or Z• more frequent in chronic alcoholic patients, chronic
hepatitis diseases • Monitoring of the hepatitis enzymes (TGO, TGP) in
patients with risk factors with high level of enzymes at the beginning of the treatment
• tracing: clinical (symptoms) or by hepatic cystolisis • attitude: 5x stop H,R,Z (SE to severe patients or
very contagious), than is to sequentially taking again to tested to identifying the drug and to stop it then
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Monitoring adverse effects
• Cutaneous Eruptions (S, E)
• Peripheral Neuropathy (H) – pyridoxine
• Deafness, vertigo (S)
• Optic retrobulbar neuritis (E)
• Thrombocytopenic Purpura, hemolytic anemia,
acute renal insufficiency (R)
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Complementary Treatment
• Corticotherapie 0.5mg/kC/zi, 5-6 weeks– meningitis TB – pericarditis TB No effect in pulmonary and pleural TB
• Surgery Treatment – TB complications
– pulmonary TB with resistant bacilli ( antiTB drugs)
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Epidemiology of Tuberculosis
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Definitions
• Tuberculosis Infection = latent infection with MTB, without clinical manifestation, Rx or / and bacteriological
• Active Tuberculosis (disease) = presence of clinical manifestations and/or Rx determinates by MTB multiplication and the organisms’ reaction
• Tuberculosis case = patient with active TB bacteriological confirmation / dg. by a doctor and we decide to initiate an antituberculosis treatment
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Epidemiology
• Tuberculosis = infectious-contagious disease– The most spread disease in human disease– The most persistent
• Endemic – Reduces the infection level – Relative immunity - 10% of infected persons develop
the disease throughout the life (max. in primary 2 years)
– Long period of latency
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Epidemiology
• 1/3 of the world’s population is infected with MTB (~1.9 billion in 1997)
• 8 million new cases of active TB per year
• 3 million deaths a year
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TB Morbidity
• Incidence = number of new TB cases diagnosed in a year reported to 100.000 persons
• Prevalence = TB cases existent in the community at a certain moment by 100.000 persons
• Mortality = TB death number throughout 1 year by 100.000 persons
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TB incidence in the world in 2002
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TB Incidence in Romania
142.2134.1121.9
102.6
7053.255.861
110152.1
184.4135.6
492.7
0
100
200
300
400
500
600
1950 1965 1970 1975 1980 1985 1987 1990 1995 2000 2001 2002 2003
%000
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TB Incidence
• According to OMS, Romania is on the 3th place in European region, after Kazakstan and Kyrgystan
• The Incidence is higher in:– men – 25-29 years to 60-64 years
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Death due to TB in Romania
9.5
180.2
44.935.1
24 18.5 6.7 3.7 4.2 6.9 11.3
0
50
100
150
200
1950 1955 1960 1965 1970 1975 1980 1985 1990 1995 2000
%000
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Co-infection HIV-MTB
• HIV Infection – the most important risk factor for progression latent TB infection to active TB
– Infection MTB and HIV – risk of 8-10% per year to develop active TB
– HIV Infected who are MTB infection – they are more exposed to the risk of having active TB
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Tuberculosis Control in the community
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Tuberculosis control in the community
• Elaboration of strategies in a National TB Control Program
• Objectives:1. Negativization aprox. 85% of positive smear
sputum of positive cases.
2. Diagnosis a minimum 70% of tb cases in the community.
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Components of the TB control program
1. The role of governmental authorities
2. The role of bacteriological diagnosis
3. Organising antitb treatment
4. Ensuring the drug requirements
5. Periodic assessment of the program’s efficiency
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Organising the treatment
• Short Standardized Regimes• Direct observation• Using drug combinations
DOTS Program
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Individual assessment of the treatment
• Cured: correct treatment, 2 negative bacteriological• Controls
• A finished Treatment : correct treatment, without bacteriological control
• Therapeutic Relapse : BK positive after 4h months of treatment
• Death: death due to any cause
• Abandon: interruption for min. 2 month of the treatment
• Lost: the patient can not be assessed
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Periodical Program Assessment
Assessment by cohort analysis • Proportion of bacteriologically confirmed cases• Proportion of cured cases• Proportion of negative cases after 2 months of
treatment (precocious indicator efficiently)
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Organising screenings
• Passive screening ex.e: with symptoms– Bacteriologically: minim 3 sputums– Radiological ex.
• Active hunting out: in the risk groups of the populations
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TB prevention and tb infection
• Free treatment administration • Chemoprophilactic Administration :
– contacts under 5 years of age– selection for persons between 5-35 years of age– HIV Infecteted
• BCG Vaccination
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Others objectives of the tb program control
• Surveillance of mycobacterial resistance
• Surveillance of HIV infection prevalence
• Control of the bacteriological laboratory’s quality
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Conclusions
• Tuberculosis: a public health issue• It is necessary to have a national control
program• The effort of all doctors and nurses is required
to reach the objectives• Periodical assessments are necessary