INTRODUCTION TO TUBERCULOSIS PROF.DR. MONICA POP

Definition Infectious-contagious disease Endemic disease Mycobacterium tuberculosis (Koch’s bacillus ) Granuloma + inflammation + destruction Localization: lung, possibly extrapulmonary Chronic evolution, consumption and frequently fatal precizati ca evolutia este cronica, consumptiva si deseori fatala IN ABSENTA TRATAMENTULUI EFICIENT

Etiology Mycobacterium tuberculosis Complex (MTB): Other mycobacteria: 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

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

TB Transmission - 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 Trebuie intens subliniat rolul crucial al tuberculozei pulmonare microscopic pozitive in transmiterea tuberculozei, de aici si tinta programelor de control; pot fi amintite surse alternative (si cai alternative) cum ar fi cea digestiva, dar subliniind rolul extrem de modest

TB Transmission Patient with pulmonary TB Coughing, sneezing, talking Small droplets Drops’ Nucleus Sanitise Host??? etapele transmiterii tuberculozei, figurate in slide-ul urmator

TB Transmission in stanga se observa prin iluminare numarul imens de picaturi generate in cursul unei tuse in dreapta este un desen animat ce este declansat in cursul slide show si arata transmiterea tuberculozei de la individul din stanga (cu pata rosie in plaman) la cel din dreapta (ce va capata o pata rosie pe plaman)

Density of infection sources (TBP/M+) 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 cauzele majore ale riscului de infectie sunt primele doua; ultimele doua sunt scrise cu litere mici pentru a sugera importanta lor relativa mai mica si/sau neconfirmata riscul de infectie poate fi al unei persoane sau al unei populatii; in ultimul caz vorbim de riscul mediu de infectie si exprimat pe un an este un indicator important al endemiei TB in populatie (vezi epidemiologie la sfarsit)

LOW RISK OF INFECTION Precocious treatment (= precocious diagnose), a correct and a complete treatment of infection sources Providing good living conditions (home and food)

The cycle of TB transmission Infected person Pulmonary TB Extrapulmonary TB M+ M- Noninfected person schema arata importanta centrala a tuberculozei pulmonare microscopic pozitive (M+) in transmiterea bolii si in mentinerea bolii in populatie prin mentinerea populatiei de indivizi infectati

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 factorii de risc colorati in rosu cresc riscul de dezvoltare a BOLII tuberculoase de peste 10 ori la cei INFECTATI alti factori de risc nefigurati sunt varstele extreme (< 5 ani) si tratamentele imunosupresoare (frecvent corticosteroizi). corolarul acestui tabel este legat de indicatiile chimioprofilaxiei De precizat pentru exemplificare incidenta TB in Romania si limitele incidentei in judete.

DIMINUATING THE RISK’S DISEASE TO PERSONS WITH TB INFECTION The treatment of latent TB infection (= chemoprophylactic therapy) BCG vaccination trimitere spre capitolul de preventie a tuberculozei

TB Infection Inhaling the particle with MT The multiplication of MTB In stanga se observa inhalarea particulelor infectante ce ajung cel mai frecvent in lobii inferiori In dreapta (dupa clic) apare focarul de mutliplicare al MTB (= primum movens al infectiei) iar ulterior (alt clic) apare adenopatia satelita Inhaling the particle with MT The multiplication of MTB

TB Infection Meninx Apex of lung Liver, spleen Adrenal gland Lymphatic nodes Sunt figurate principalele situri ale diseminarii hematogene. Trebuie facuta precizarea ca orice sediu de multiplicare a MTB (inclusiv după diseminare) poate constitui o viitoare localizare a bolii tuberculoase, fie în continuarea multiplicării iniţiale (prin progresia primoinfecţiei sau a reinfecţiei exogene), fie la distanţă în timp, după oprirea multiplicării iniţiale (reactivare endogenă). Bone, joint Haematogenous Dissemination

Immunological modification in TB Presentation of Ag IL-2 Clonal Proliferation LTh1 (CD4+) IFN- M bactericide for MTB Prelucrarea antigenului fagocitat de macrofage este urmata de prezentarea acestuia limfocitului T, urmata de proliferarea clonala a lmfocitelor T CD4+ tip Th1 ce vor determina activarea Macrofagelor ce devin bactericide pentru MTB si respectiv a limfocitelor T CD8+ citotoxice ce vor distruge macrofagele parazitate de MTB. Aceste fenomene conduc la contentia infectiei si eliminarea treptata a MTB din organism cu exceptia unui numar mic de bacili dormanti. LTc (CD8+) Destruction of M parasity

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

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

Diagnosis Bacteriological Histopathological Tuberculin Skin Test with PPD

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 Ne vom referi in continuare doar la primele doua

Specimen tests PulmonaryTB (with Mt): Extrapulmonary TB (without Mt): Sputum after coughing/or aerosols After bronchial endoscopy Extrapulmonary TB (without Mt): Pleural effusion, peritoneal, pericardial LCR Articular liquid Urine Bioptic fragments Se va sublinia diferenta dintre secretiile respiratorii contaminate si celelalte produse ce trebuie recoltate steril; in plus se va sublinia importanta cultivarii tuturor fragmentelor bioptice de la pacienti suspecti de TB INAINTEA introducerii in formol.

Ziehl-Neelsen Coloration Smear sputum Ziehl-Neelsen Coloration Standard analysis In mycrobiological laboratory (microscopic interpretation of the slides)

frotiu de sputa ce arata pe langa celule si alte resturi colorate in albastru si numerosi bacili colorati in rosu adica BAAR (Ziehl-Nielsen, 1000x)

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 +++ Se poate preciza ca in cazul gasirii a doar 1-2 bacili pe 100 campuri se mai citesc inca 200 si in cazul in care raman 1-2 bacili pe 300 de campuri (deci sub 3 bacili pe 300 de campuri) rezultatul este considerat neconcludent si se va repeta proba).

Fluorescent Colorations Microscopic Exam Fluorescent Colorations Fast The positive result needs confirmation by Z-N Roll coloratiilor fluorescente in eliminarea lamelor negative, diminuand numarul de lame colorate cu Z-N

coloratie cu auramina O vizualizata in microscopul cu fluorescenta, 1000x

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

Culturi de Mycobacterium tuberculosis pe mediul Lowenstein-Jensen

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 Trimiteri pentru mai tarziu pentru importanta drogurilor majore si respectiv indicatiile testarii sensibilitatii

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 A se reaminti importanta cultivarii unor portiuni din aceste fragmente, INAINTEA introducerii in formol, intrucat cultura MTB constituie cel mai important argument diagnostic pentru TB.

granulom epitelioid la nivel pulmonar (sageata) cu o zona intinsa de necroza cazeoasa (zona amorfa roza din centrul imaginii), 100x pe slide-ul urmator puteti vedea imaginea marita

granulom epitelioid cu celule Langhans in centru, 400x

Fotografie macroscopica pe sectiune de plaman observandu-se o cavitate cu cazeum (alb) in interior

fragment pleural cu un granulom epitelioid fara necroza cazeoasa, 100x

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

Tuberculin skin test (TST) intradermoreactia la tuberculina in stanga puteti observa tehnica de administrare strict intradermic cu formarea unei papule albe (se observa mai bine in imaginea marita din centru) in dreapta citirea cu ajutorul unei rigle a diametrului transversal al induratiei, aici de 12 mm; subliniati importanta masurarii induratiei si nu a eritemului, a diametrului transversal si nu a celui longitudinal si momentul ideal de 72 de ore a citirii, in orice caz nu imediat, precum si necesitatea identificarii cu cat mai mare precizie a marginilor transversale ale induratiei. Tuberculin skin test (TST)

Results Positive (TB infection) Negative (absence of the TB infection)  10 mm  5 mm in HIV-positive host Negative (absence of the TB infection) < 10 mm < 5 mm in HIV infection A se sublinia relativitea interpretarii la populatiile vaccinate BCG si faptul ca sunt numeroase rezultate fals pozitive si fals negative – vezi slide-urile urmatoare.

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

False Results False pozitive False negative 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

Tuberculosis in children Primary tuberculosis Monica Pop

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

Primary Tb infection Without symptoms in most of the cases It goes unnoticed TB infection ≠ TB disease

Primary Pulmonary TB Primary infection with clinical-radiological manifestation 10% of primary infection cases More frequent after the age of 5

Primary pulmonary TB: symptoms General Simptoms : Fever Loss of weight Apathy/indifference Cutaneous and mucousmembrane manifestations: Erythema nodosum Conjunctival blister

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)

Primary pulmonary TB : diagnosis Epidemiological Context Skin test (maybe retesting in case of negative test) Matching radiological abnormalities Possible bronchial endoscopy: confirms the adenopathy

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

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

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

Extrapulmonary TB: severe forms TB meningitis Milliary tuberculosis Vezi si tuberculoza extrapulmonara

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

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)

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

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

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

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

Pulmonary TB (TBP) in adults

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

Clinical Manifestion – the beginning Insidious General symptoms Respiratory symptoms Acute Haemoptysis Flue-like Pseudo-pneumonia Frecventa este descrescanda: insidios = frecvent, acut = uneori, asimptomatic = rar Asymptomatic Pathological Chest radiography

General symptoms Physical asthenia Annorexia Weight loss (significant > 10% for the initial mass) Perspiration Fever (variably - possibly without fever) Amenorrhoea (women)

Respiratory symptoms Persistent cough (almost 3 weeks = central Mucous expectoration / mucopurulent, possibly absent Hemoptysis (sometimes at the beginning) haemoptoic sputum rarely massive (life threatening) Tusea persistenta reprezinta elementul central, vezi si diagnosticul diferential

Physical Thoracic Exam Is frequently poor Localised rales (crepitant or sibilant/ronflant) Condensation Syndrom – rarely Amphoric breath – exceptionally (cavern localisation superficially)

Clinical Manifestations Non-specific Sometimes without symptoms Persistent cough = the most important sign for a call in pulmonary TB

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

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

Cavitation Image

Extensive Form (“bronchopneumonia”) Condensari multiple bilaterale difuze cu crutarea relativa a jumatatii superioare stangi

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) Pentru micronoduli vezi TB miliara

Tuberculoma

Other radiological lessions Sequellary: Primary Complex calcification Localized fibrosis Extended Fibrosis (fibrothorax) Complications Pneumothorax / pyopneumothorax Pleural effusion

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 Prezenta a mai multor criterii creste suspiciunea; dinamica lenta in timp este atat in evolutia naturala spre agravare cat si in evolutia sub tratament spre ameliorare / vindecare

Differential Dg. – persistent cough Normal chest Bronchial asthma ORL Pathology gastroesophagealreflux disease Purulente Bronchorrhea Infectious exacerbations Bronchiectasis Coughing > 3 weeks Progressive Dispnea obstructive Syndrom COPD? Chronical bronchitis Smoke history Rx +/- bronchoscopy suggestive Bronchopulmonary cancer Professional exposure, Rx image Pneumoconiosis Clinical signs, ECG, EcoCG Mitral Stenosis / IVS

Differential Dg - cavity imagine Insidious beginning Cough and chronic expectoration Fetid Sputum Chest Rdg: hydroaeric image Pulmonary abscess Smoking history chest Rdg: cavitation with thick walls Frequently nodules reaction Pulmonay cancer History of clear vomical liquid Chest Rdg: cavitation with thin walls Proligerous membrane Hydatid cyst

Differential dgs. of alveolar condensation Pulmonary Tb must constitute a differential diagnosis for any pneumonia with poor response – no response after AB treatment !!

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)

Pulmonary TB Diagnosis The confirmation of pulmonary TB diagnosis: Smear positive culture Favourable clinical-radiological evolution after treatment, in absence of an alternative diagnosis Sublinierea importantei obtinerii confirmarii bacteriologice in cat mai multe cazuri

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

TB complications during treatment Hemoptysis (massive) – the erosion of the arterial bronchial wall Pneumothorax – air in the pleural space (pyothorax) Pleuresy of vicinity

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)

Extrapulmonary Tuberculosis (TBEP) Prof.Dr. Monica Pop

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

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.)

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)

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

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

Radiological exam Poate fi normala la debut

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 Se subliniaza importanta tratamentului precoce, cu un prag scazut de suspiciune diagnostica datorita prognosticului grav, chiar in absenta unei confirmari bacteriologice sau de alta natura

Differential Diagnosis Other infectious causes Cytomegalovirus S. aureus Pn. carinii Miliary carcinomatosis Hypersensitive pneumonitis Sarcoidosis

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

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

TB Meningitis Origin: hematogenous dissemination focus of primary infection It occurs in childhood Often in miliary tuberculosis

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

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

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) Principalul test diagnostic

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

Differential Diagnosis on LCR Exam Etiology Cells Proteins Bacteriological exam TB 30-300/mm3 Lymphocytes >0,6 g/dl BAAR (-) Cultures BK (+), PCR Bacterium Hundred- thousands/mm3 Neutrophils Smear sputum, cultures Viral >300/mm3 Lymfocites <0,5 g/l Negative Meningism <10/mm3 <0,5 g/dl Cryptococcus Neutrophils ↑ Lymphocytes ↑ High Parasites in specific coloration

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

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 Debutul este acut, dar uneori pot fi identificate semne generale prezente anterior debutului acut

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 Se va explica semnul Hirtz

Paraclinical examinations Chest x-Ray: liquid-type opacity TST to PPD negative; it might be positive during treatment = retrospective dg. argument Examination of the pleural liquid : Serocytrin Exsudate (proteins > 3g/dl, LDH > 2/3 of plasmatic LDH) Numerous lymphocyte (> 90%) Crossing of ADA Histopatological Ex. – pleural biopsy (+) in 80% of cases; crossing rudimental when ssociate with positive culture of biopsy fragments

Radiological image

Differential Diagnosis Etiology 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 Lupic cells Rheumathoid Arthritis, subcutaneous nodules Purulent, exsudate FR present

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

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 +

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 De precizat rezistenta la antituberculoase a altor micobacterii si evolutia lor favorabila cu vindecare spontana la pubertate

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

Tuberculous Spondylitis (morbus Pott) Clincal presentation: pain in a single area, it’s worsened by touching the affected zone rarely: general symptoms advanced stage: hunchback Lateral x-ray: the erossion of the anterior part of the vertebral body narrowing of the vertebral spaces Positive diagnostic: bacteriologic exam from the externalized caseum biopsy of the affected bone Differential diagnostic: - infectious spondylitis, spondylosis, bone metastasis

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

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

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

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

Very rarely Localisations Cerebral Tuberculoma Skin TB Intestinal TB Hepatosplenic TB Auricular TB OcularTB Thyroid TB CSR TB ( with CSR insufficiency) De dezvoltat putin tuberculoza intestinala care nu este foarte rara

HIV and Tuberculosis Infection Prof.dr. Monica Pop

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

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

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

Pulmonary TB Diagnosis TB confirmation is necessary It is important to exclude the other cases of pneumonia to immunodepressive

Extrapulmonary Tuberculosis Ggl, Serous (pleuresia, peritonitis, pericarditis) Meningitis More frequent in HIV-positive persons !!

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

TB Prevention

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

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)

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

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,

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)

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)

TB Treatment

TB Treatament = Administration of antibiotics with MTB effect (antituberculosis chemotherapies) The Decision of treatment administration – arguments: epidemiological clinical radiological + Smear sputum ( M)

Mycobacterium Populations Localisation intracellular extracellular Multiplication Rhythm Rapid slow intermittent

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

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)

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

Chemoresistance Primary Chemoresistance – monotherapie with one antiTB drug Secondary Chemoresistance – infection with already persistent stem

Necessity of an antiTB treatment Association of minimum 3 efficient antiTB drugs + Bactericidal Effect + Anti-sterilisation Effect Sufficient Time  Organisms’ Sterilisation  prevention of relapse

AntiTB DRUGS First linie: Second line: efficiency  toxicity ↓ Usable in standard regimes Second line: efficiency ↓ toxicity  Usable in individualised regimes in MDR

Isoniazides (INH, I) Rifampicin (RMP, R) 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)

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 relapses INH RMP

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

INH + RMP + PZM INH RMP  PZM INH RMP INH RMP

Streptomicyn (SM, S) Ethambutol (EMB, E) Modest Bactericidal effect No sterilising effect Ethambutol (EMB, E) Modest bacteriostatic Effect No sterilising effect

 INH + RMP + PZM + EMB/SM INH RMP PZM INH RMP PZM EMB/SM Etambutol sau streptomicina previn instalarea chimiorezistentei atunci cand sunt asociate la regimul HRZ la pacientii cu chimiorezistenta initiala (frecvent la hidrazida). Dupa doua luni se poate afla gradul de rezistenta si se individualizeaza regimul terapeutic. Altfel asocierea EMB sau SM nu aduce beneficii suplimentare in TB cu germeni chimiosensibili PZM INH RMP EMB/SM

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 Z 30 2000 40 2500 E 25 1500-1600 S 20 1000

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,

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

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) Regimul I: 2 HRZE (S)7 + 4 HR3

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 Rergimul II (retratament) 2 HRZSE7 + 1 HRZE7 + 5 HRE3

Individualised Regimen TBP with resistance of M.t. Importante\severe side effects Intolerance

Individual scheme of treatment Refigure therapeutic Regimen Therapeutic regime TBP BAAR+ with resistance of M.t. Individual scheme of treatment PZM INH RMP EMB/SM PZM INH RMP EMB SM PZM INH RMP

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

Treatment Monitoring Adherence to the treatment Efficiency of the treatment Adverse effects of the Monitoring

Adherence of treatment DOT (directly observed therapy) – usually used in first phase of treatment Combination of drugs in one (HR /HRZ)

Efficiency of the treatment Clinical Monitoring Loss/disappearance of fever Loss/disappearance of cough Recurrence of appetite Bacteriological Monitoring – is the most important!!!!!

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,

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)

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

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)

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)

Epidemiology of Tuberculosis

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

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

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

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

TB incidence in the world in 2002

TB Incidence in Romania %000

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

Death due to TB in Romania %000

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

Tuberculosis Control in the community

Tuberculosis control in the community Elaboration of strategies in a National TB Control Program Objectives: Negativization aprox. 85% of positive smear sputum of positive cases. 2. Diagnosis a minimum 70% of tb cases in the community.

Components of the TB control program The role of governmental authorities The role of bacteriological diagnosis Organising antitb treatment Ensuring the drug requirements Periodic assessment of the program’s efficiency  

Organising the treatment Short Standardized Regimes Direct observation Using drug combinations DOTS Program

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

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)

Organising screenings Passive screening ex.e: with symptoms Bacteriologically: minim 3 sputums Radiological ex. Active hunting out: in the risk groups of the populations

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

Others objectives of the tb program control Surveillance of mycobacterial resistance Surveillance of HIV infection prevalence Control of the bacteriological laboratory’s quality

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