TUBERCULOSİS

Prof.Dr.Yıldız Camcıoğlu

Tuberculosis(TB)

• Mycobacterium tuberculosis • Mycobacterium bovis• Mycobacterium tuberculosis infects millions of

children every year and yet exact rate of morbidity and mortality is not known in developing countries due to difficulties in diagnose of diseases in childhood. Poverty, overcrowding, inadequate tuberculous control programmes, MDR tuberculosis and HIV infection have all contributed to spread of Tuberculosis worldwide

Childhood TB

• It has been estimated that 3.1 million children under 15 years of age are infected with TB worldwide.

• According to the World Health Organization (WHO), children with TB represent 10 % to 20 % of all TB cases.

M.tuberculosis and M.bovis

0,3-0,6 micron x 2-4 micron aerobic Celll wall;A)Plasma membrane;

Peptidoglicans Arabinogalactan Micolik aside B)Complex polymers

Antigens; 38 kd, 88kd, Antigen 5, Antigen A6, Lipoarabinomannan(LAM), Cord Factor

Transmission

95% TB is an airborne disease, transmitted by particles, or droplet nuclei that are expelled when persons who have pulmonary or laryngeal TB sneeze, cough, speak or sing

1.4% By drinking infected milk1.4% Inoculation of bacilli by skin and mucosal contusions• Congenital TB

Features of The TB in Childhood• Pulmonary TB in children has a low bacillary load and

cavities are also rarely present.• Children also lack the forceful cough mechanism seen in

adults • Adolescents and older children are important exceptions

since their disease closely resembles that of adults• The disease more often progresses from an initial or

primary infection. • 50 % of pediatric patients may remain asymptomatic with

subtle abnormalities on the chest radiograph• Children younger than five years old may develop

disseminated TB in the form of miliary disease or tuberculous meningoencephalitis

Stage I• Droplet nuclei containing between one to 10 bacilli and

a diameter close to 10 μm are expelled with the cough, suspended in the air and transported by air currents.

• Some of these droplet nuclei, usually larger than 10 μm, are inhaled and anchored in the upper respiratory tract

• The mucus and the ciliary system of the respiratory tract avoid further progression of mycobacteria.

Dannenberg, Jr AM Immunol Today 1991

Stage II:Symbiotic stage• Subsequently, alveolar macrophages

phagocytose the inhaled bacilli

• These first macrophages are unable to kill mycobacteria

• The bacilli continue their replication inside these cells

• Logarithmic multiplication of the mycobacteria takes place within the macrophage at the primary infection site.

Stage III: CMI and DTH

• Two or three weeks after the initial M. tuberculosis infection, a cell-mediated immune response is fully established

• While CD4+ T helper cells activate the macrophages

to kill the intracellular bacteria and finally cause epithelioid granuloma formation,

• CD8+ suppressor T cells lyse the infected macrophages, resulting in the formation of caseous granulomas with central necrosis

• The only evidence of a real and effective infection is a positive TST

•Symptoms vary according to the degree of airway irritation and obstruction•Frequently a persistent cough that may mimic pertussis and Mild fever•70 % of the primary foci are subpleural•25% of cases have multiple parenchymal foci• A common radiographic sequence is adenopathy followed by localized hyperinflation and then atelectasis of contiguous parenchyma•Adenopathies are more striking than parenchymal focus• Adenopathies heal with calsification

Primary pulmonary Tuberculosis

Pulmonary Infection•Affected regional lymph nodes attach to the bronchus

• In some children, particularly infants, the lymph nodes continue to enlarge, resulting in lymphobronchial involvement, in which the affected bronchus may become partially or totally obstructed

•The area of caseation may discharge into a bronchus, resulting in the formation of a cavity with possible endotracheal spread

•Similarly, regional lymph node involvement may accompany marked clinical symptoms

•The most frequently affected lobes are the right upper, the right middle, and the left upper lobe

Differential Diagnosis• Bacterial pneumonia

S.Pneumoniae

TWAR

B.pertussis

• Viral pneumonia

Influenza A, B

Adenovirüs 3, 4,7

RSV

• Fungal pneumonia

H.capsulatum

C.immitis

B.dermatitis

•Astma

•Aspiration; •Chemicals; Drugs

Stage IV:Liquefaction Rapid replication of Bacilli

• Reactivation, liquefaction, cavitation

• Bacilli begins to replicate Extra cellularly

• Airborde spread is possible; Transmission

Progressive primary pulmonary tuberculosis

Progression of the pulmonary parenchymal component leads to enlargement of the caseous area and may lead to pneumonia, atelectasis, and air trapping.

This is more likely to occur in young children than in adolescents

The child usually appears ill with symptoms of fever, cough, malaise and weight loss

This form presents classic signs of pneumonia, including tachypnea, dullness to percussion, nasal flaring, grunting, egophony, decreased breath sounds, and crackles

Pleural Involvement

Pleural involvement

85 % acute onset of fever, 52 % chest pain on deep inspiration28 % shortness of breath

Pleural effusion due to TB usually occurs in older children The pain accompanies the onset of the pleural effusion, but after that the pleural involvement is painless. Fever usually persists for 14-21 days.The signs of pleural effusion include tachypnea, respiratory distress, decreased breath sounds, dullness to percussion,and occasionally, features of mediastinalshift.

TB Pericarditis

• Directly dissemination or by lymphatic drainage from subcarinal lymph nodes

• Fever, cough, weight loss, malaise, chest pain • Physical exam ; Dyspnea and ortopnea Edema at ankle Pericardial rubbing • Pericardial fluid; Serofibrinous or mild hemoragic 30-70 % bacilli yielded• Constrictive pericarditis

Miliary Tuberculosis

100 % Fever 63 % Cough 25 % Dyspnea 24 % Malaise 23% Vomiting 16 % weight loss 13 % Abdominal pain 11 % Convulsions 11 % Diarrhea 8 % Wheezing 5 % Headache

Lymph Node Involvement • 17 % of those all TB cases• 9 billion new cases • Drinking of infected cow milk ; M.bovis or M.avium, M.intracellulare, M.scrofulaceum • M.tuberculosis• 30-70 % primary focus is at lung• Patients with scrofula may complain of enlarged nodes • Fever, weight loss, fatigue,and malaise are usually

absent or minimal• Lymph node involvement typically occurs between six

to nine months following the initial infection.

TB Meningitis

• Pathology: meningoencephalitis

• Caseous focusus(Rich focus) at Cerebral cortex or basal meninges

• Dissemination of subarachnoid area

• Thick exudate enriched of lympocytes and plasma cells covers interpedincular and pontin cisterna

• Disseminates lateral sulcus and cisterna ambiens, cisterna magna and chiasmatik cisterna

TB Meningitis• Cerebral vessel, nerves , choroid plexus in ventriculles

are alll covered by thick exudate

Cerebral vessel damage and brain infarcts

Vasculitis, aneurisma, trombosis and

Focal hemoragic infarcts• Thick exudate result in(early stage);

Impairment of CSF flow

in late stage; Adhesions and hydrocephaly• Hyponatremia• Inapproprite ADH release(%70)

TB MeningitisI. Onset: insidious onset of the disease, 1-2 weeks, low-grade

persistent fever, malaise, anorexia, weight loss,fatigue, hepatomegaly, splenomegaly and generalized lymphadenopathy

II.Meninges irritation: vomiting,headache, nuchal rigidity, seizures,hypertonia, minor neurological changes; mild consciousness ,anisochory,double vision, loss of abdominal reflexes, convulsion

III.The final stage:Alteration in consciousness and sensorium, III, VI ,VII nerve involvement comprises major neurological

defects, including coma, seizures,and abnormal movements (e.g. choreoathetosis, paresis, paralysis of one or more extremities) , decerebrated or decorticated posturing, opisthotonus

intestinal TB

• Drinking unpasteurised milk or milk infected with M.bovis

• mesenteric lymph nodes and peritoneum infection occurs by lymphatic drainage

• 60 % ulsers occurs • Jejunum, ileum and appendices • Sığ ülserler pain, tenesmus,

diarrhea or constipationveya kabızlık, abdominal distension, weight loss , low set fever Diag; Biopsy

• Gastrointestinal TB

• At every site of GIS• Rare at oral cavity

lympadenopathies accompanies painless ulsers at the mucosa of month, gums, tonsils

• Eosophagal TB

Trachea-eosophagal fistula at infants

Gastrointestinal TB

Mesenteric TB

• Hematogenous dissemination

• Lymphoma ?

• Pain at exercise

• Intestinal obstruction, peritonitis

Peritonitis

• Disseminate from adjacent tissues

• Palpable lymph nodes, omentum and periton klamps each other and resembles irregular abdominal masses

• Mild fever, abdominal distension, loss of appetite,, weight loss and serous effussion(asite) may occur

Osteoarticular TB• Appear in 1 % to 6 % of untreated primary infections• Clinical and radiographic presentations vary widely and depend upon

the stage of the disease at the time of diagnosis• Skeletal TB may remain unrecognized for months to years because of

its lack of specific signs and symptoms and indolent nature• Bone or joint TB may present acutely or subacutely • Sites commonly involved are the large weight-bearing bones or joints

including the vertebrae (50 %), hips (15 %), and knees (15 %)• Less common skeletal sites are the femur, tibia, and fibula. • Destruction of the bones with deformity is a late sign of TB • Manifestations may include angulation of the spine or “gibbus

deformity” and/or the severe kyphosis with destruction of the vertebral bodies or “Pott’s disease”

• Cervical spine involvement may result in atlantoaxial subluxation, which may lead to paraplegia or quadriplegia

• TB of the skeletal system may also lead to involvement of the inguinal, epitrochlear, or axillary lymph nodes

Osteoarticular TB

TB Dactilitis (spina ventoza).

Distal endarteritis No pain Cystic enlargement Rarely occurs abscess

Cutaneous Tuberculosis Hypersensitvity or haematogenous dissemination Cutaneous papules3-8 weeks later regional lymphadenopathies No systemic symptoms Papulonecrotic tuberculide Miliary lesions on skin On face, trunk, Upper extremitiesVerrucosa cutis Wart like lesion On extremities Dif.diag; Letterer-siwe diseases and urticary

Congenital TBA very rare event in the whole spectrum of TB

presentations.This infection is caused by lymphohematogenous

spread during pregnancy from an infected placenta or aspiration of contaminated amniotic fluid.

Symptoms typically develop during the second or third week of life

Poor feeding, poor weight gain, cough, lethargy, and irritability

Other symptoms include fever, ear discharge, and skin lesions, failure to thrive, icterus, hepatosplenomegaly,tachypnea, and lymphadenopathy.

Congenital TB diagnosisCongenital TB diagnosis is based on clinical features and

the infant should have at least one of the following proven TB Lesions

• Skin lesions during the first week of life, including papular lesions or petechiae, necrotic or purpuric lesions

• Choroidal tubercles in the retina• Documentation of TB infection of the placenta or the

maternal genital tract• Presence of a primary hepatic complex (liver and

regional lymph-node involvement)• Exclusion of the possibility of postnatal transmission

Suspicion Of TB

• Symptoms: persistent cough, fever, night sweats, weight loss

• Risk factors for exposure to TB: close contact of case, residence/travel in high prevalence country, congregate living with other high risk individuals

• Risk factors for development of active disease if infected: recent infection, HIV/AIDS, other underlying medical condition

Blood Cells

Mild anemia Monocytosis High ESR

Radiological Studies(80-85% of TB Cases)

• Chest x-ray – Standard PA and lateral films; apical lordotic views may be

helpful– Infiltrates, nodular densities, cavities, +/- hilar adenopathy– Abnormalities may be subtle in immunocompromised patients – Previous x-rays for comparison may be useful

• CT scans– Often obtained– Nice to have but rarely critical to diagnosis– Expensive

Diagnosis of Pulmonary TB

• TST– Positive supports but does not make diagnosis– Negative does not exclude TB as possible

diagnosis

• Quantiferon– Screening test only, not diagnostic

TST> 5mm

• Contact with infectious cases

• Abnormal Chest X ray

• HIV infection and other immunocompromise

>10 mm

• Age ≤ 4years of age

• Certain medical risk factors: Hodgkin, diabetes Mellitus , renal diseases, malnutrion

• Member of local high –risk group

• Birth or previous residence in high prevalence

• Occupation in health care field, exposure to patients with TB

• Close contact with a high –risk adult

• Residence in long term care or correction facilities

>15mm

No risk factor

CSF, synovial Fluid;

High Protein level

Lymphocytes 500/ mm3

Pleural ve peritoneal fluid ;

Exudate

Dansity >1016

Protein level >3 gr/dl

Lymphocytes 500/mm3

Glycose LOW

Lactic dehidrogenase HİGH

Adenosine deaminase HİGH

Biochemical results

SCAN and US *CT SCAN;

TB meningitis; Tuberculoma and hydrosefaly •Ultrasonography;

Peritonitis, mesenteric adenitis

Laboratory Tests for M.tb

• Culture and Identification of Isolate– “Gold standard” for TB diagnosis– Usually complete in 2-4 weeks– Not signed out as negative until 8 weeks– Traditional identification based on growth characteristics,

biochemical tests– ID by “probe” now standard

• Requires isolate (2-4 weeks)• Tests DNA – can ID M.tb complex, M.avium, +/-

others• More rapid than chemicals, just as accurate• Cannot distinguish among M.tb complex species

(M.tb vs. M.bovis)

Laboratory Tests for M.tb

• Antimicrobial susceptibility testing– Requires isolate– 2-4 weeks after isolate available– IREZ +/- S testing standard– Second line drug testing only on request– 3-10% of VA TB isolates resistant to > 1 first line

TB drug• Continue IREZ until susceptibility results available

BiopsySkinLymph nodesBonePleura

Granuloma formation

Treatment of TB Disease

• The first rules of TB treatment are:– Enough drugs (4 to start)– The right drugs (antimicrobial sensitivities)– Enough milligrams of each drug (patient

weight)– Enough doses (count doses)– Enough attention to detail (monitoring of

laboratory studies and clinical course)

Antituberculosis Drugs Currently in Use

• First-line Drugs– Isoniazid

– Rifampin

– Rifapentine

– Rifabutin

– Ethambutol

– Pyrazinamide

• Second-line Drugs– Cycloserine– Ethionamide– Levofloxacin– Moxifloxacin– Gatifloxacin– P-Aminosalicylic acid– Streptomycin– Amikacin/kanamycin– Capreomycin– Linezolid

DrugDaily dose

mg/kg (max)

Weekly 2 times a week

mg/kg(max)

Side effect

Isoniazid5–10 (300 mg)

20–40 (900 mg)

hepatitis , neuritishypersensitivity

Rifampin10–20 (600 mg)

10–20 (600 mg)

Orange coulor of urine, vomiting, hepatitis, influenza like syndrome, trhombocytopenia,

Pyrazinamide2540  (2000 mg)

50–70  (4000 mg)

Hepatotoxick hiperürisemi,artralgia,GİS symptoms

Ethambutol15-25(2500mg)

50 (2500mg)

Optic neuritis, GİS symptoms after 7 years of age

Streptomycin20- 40 (1000 mg)

Ototoxidity , nefrotoxic

Ethionamide10–20(1000mg)

-GİS symptoms, hepatotoxic,, hypothroidy

Preventive therapyPreventive therapy may be given to persons who have a negative skin

test reaction

– High-risk contacts

– Children younger than 6 months of age who have been exposed to TB

Persons receiving preventive therapy are those who have a positive skin test, and those who are:

• more likely to be exposed to or infected with M. tuberculosis

• more likely to develop TB disease once infected

All persons receiving preventive therapy should receive a medical evaluation to:

– Exclude the possibility of TB disease

– Determine whether they have ever been treated for TB infection or disease

– Identify any medical problems that may complicate therapy or require more careful monitoring

Features of Childhood TB

• Farmacokinetic effects of drugs vary • Few bacilli found in caseous lesion• Development of secondary resistance ratio is low• Extrapulmonary diseases are frequent • Drug tolerance is better than adults • Low side effects against drugs• Drugs are for adults • For that reason children have problems to swallow

the tablets, taste are not good

Treatment

Asymptomatic infection TTS(+) INH 6-9 m NO Disease Pulmonary TB INH+RIF 9-12 m or INH+RIF+SM

or INH+RIF+PZA or INH+RIF+ETB

(DOT) INH+RIF 2 months daily + 7 months 2 days weekly

Hilar adenopathy Same as PulmonaryExtratorasic TB Same as Pulmonary (Except Miliary, meningitis, osteoarticular )

Miliary, meningitis, INH+RIF+PZA+SM 2 months daily + osteoarticular + INH+RIF 10 months daily

+or INH+RIF 10 months 2 days weekly

Risk of Drug Resistance

• Treated patients with Active TB• Contact with patients who have drug resistant

TB• Contact with immigrants• Living in the population with INH resistance

higher than 4%• The patients with bacilli(+) sputum after 2

months of antituberculous treatment and contact with those patients

STEROİD

• Meningitis• Pleural involvement• Pericarditis• Peritonitis• Severe Miliary TB• Atelectasis or obstruction

2 mg/kg/day for 15 days. than in decreased doses, Stop 4-6 weeks after

Diagnosis/Follow-up of Pulmonary vs. Extra-Pulmonary TB

• Pulmonary – Sputum for AFB smear and

culture

– Chest x-ray helpful

– Follow-up sputum smears and cultures useful to monitor treatment

• Extra-pulmonary– More variability in presentation;

may be more difficult to diagnose

– AFB smear and culture done on tissue or fluid

– Follow-up smears/cultures may not be possible

– Must evaluate for pulmonary disease

– Chest x-ray may be normal; x-rays/scans may be helpful