INTRODUCTION TOTUBERCULOSIS

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

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

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

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

TB Transmission

Patient with pulmonary TB

Coughing, sneezing, talking

Small droplets

Drops’ Nucleus

Sanitise Host???

TB Transmission

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

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 personPulmonary TB

Extrapulmonary TB

M+

M-

Noninfected person

Infected person

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

DIMINUATING THE RISK’S DISEASE TO PERSONS WITH TB INFECTION

• The treatment of latent TB infection (= chemoprophylactic therapy)

• BCG vaccination

TB Infection

Inhaling the particle with MT The multiplication of MTB

TB Infection

Meninx

Apex of lung

Liver, spleen

Adrenal gland

Lymphatic nodes

Bone, joint

Haematogenous Dissemination

Immunological modification in TB

Presentation of Ag

Clonal ProliferationLTh1 (CD4+)

LTc (CD8+)

IL-2

IFN-

M bactericide for MTB

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

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

Smear sputum

Ziehl-Neelsen Coloration

• Standard analysis

• In mycrobiological laboratory (microscopic interpretation of the slides)

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 +++

Microscopic Exam

Fluorescent Colorations

• Fast

• The positive result needs confirmation by Z-N

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

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

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

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)

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

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– 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 childrenPrimary 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

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

Acute

Haemoptysis

Flue-like

Pseudo-pneumonia

AsymptomaticAsymptomatic Pathological Chest radiography

Insidious General symptoms

Respiratory symptoms

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

symptom)• Mucous expectoration / mucopurulent, possibly

absent• Hemoptysis (sometimes at the beginning)

– haemoptoic sputum– rarely massive (life threatening)

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”)

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)

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

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

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

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

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

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

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)

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 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

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

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

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

Radiological image

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

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

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: 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

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)

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:– efficiency – toxicity ↓– Usable in standard regimes

• Second line:– efficiency ↓– toxicity – Usable in individualised regimes in MDR

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)

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

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

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

Streptomicyn (SM, S)

• Modest Bactericidal effect • No sterilising effect

Ethambutol (EMB, E)

• Modest bacteriostatic Effect• No sterilising effect

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

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

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)

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

Individualised Regimen

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

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

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

1. Adherence to the treatment

2. Efficiency of the treatment

3. 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

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

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

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

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:1. 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

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

 

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