nastiti n. rahajoe department of child health medical school university of indonesia jakarta

Nastiti N. Rahajoe

Department of Child Health

Medical School University of Indonesia

Jakarta

Miller FJW. Tuberculosis in children, 1982

A minority of childrenexperience :1. Febrile illness2. Erythema Nodosum3. Phlyctenular Conjunctivitis

EVOLUTION AND TIMETABLE OF UNTREATED PRIMARY TUBERCULOSISIN CHILDREN

Complications of focus1. Effusion2. Cavitation3. Coin shadow

Complications of nodes1. Extension into bronchus2. Consolidation3. Hyperinflation

MENINGITIS OR MILIARYin 4% of children infected

under 5 years of ageLATE COMPLICATIONS

Renal & SkinMost after 5 years

1 2 3 4 5 6

BONE LESIONMost within

3 years

24 months

Resistance reduced :1. Early infection (esp. in first year)2. Malnutrition3. Repeated infections :measles,wwhooping coughstreptococcal infections4. Steroid therapy

infection

BRONCHIAL EROSION

Most childrenbecome tuberculin

sensitive

12 months

DIMINISHING RISK

But still possible90% in first 2 yearsGREATEST RISK OF LOCAL & DISEMINATED LESIONS

Development Of Complex

4-8 weeks 3-4 weeks fever of onset

PRIMARY COMPLEXProgressive HealingMost cases

Uncommon under 5 years of age25% of cases within 3 months75% of cases within 6 months

3-9 monthsIncidence decreasesAs age increased

Smear +Culture +

Smear -Culture +

Smear -Culture -

108

107

106

105

104

103

102

101

100

Start of treatment(isoniazid alone)

Weeks of treatment0 3 6 9 12 15 18 WHO 78351

Sensitive organisms Resistant organisms

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Toman K. Tuberculosis. WHO, 1979

Pathogenesis of tuberculosisInhalation of droplet nuclei

containing M.tb

No infectionDroplets > 10

intact mucosa andupper airway

Droplet < 5 penetrate mucociliary

blanket

Transient alveolar nonspecific inflammatory response

Organism replicates with normalphagocytes (macrophages)

Organism spread by lymphatics locallyOrganism spread by blood to other sites and lung

Development of specificT-cell response

Macrophages are activatedand kill or retard tubercle bacilli

Disease inactiveSmall number of viable

bacilli may persist

Failure adequate cellularimmune response

Active infection = disease(primary lung : 3 week;

disseminated or progressive pulmonary; months to years)

Secondary failure to maintainadequate cellular immunity

3-10 weeks95%

5%

5%reactivation

Jacob RF, et al. Tuberculosis. Pediatr Respir Dis. 1984

Inhalation Alveoli Ingestion by PAM’S

Intracellular multiplicationof bacilli

Destruction of bacilli

Destruction of PAM’S

Tubercle formationResolution Hilar lymph nodes

Calcification

Secondary lung lesions

Ghon Complex Caseation Hematogenous spread

Liquefaction

Lesions in liver, spleen, kidneys, bone, brain, other organs

Pathogenesis of tuberculosis. PAM’S, pulmonary alveolar macrophages

Inselman LS. Tuberculosis in children : An Update. Pediatr Pulmonol 1996; 21:101-20

DrugsDaily dose

(mg/Kg/day) Adverse reactions2 Time/week

dose(mg/Kg/dose)

3 Time/week dose

(mg/Kg/dose)

Isoniazide *(INH)

5-15(300 mg)

Hepatitis, peripheral neuritis,hypersensitivity

15-40(900 mg)

15-40(900 mg)

Rifampicin(RIF)

10-15(600 mg)

Gastrointestinal upset,skin reaction, hepatitis, thrombocytopenia,

hepatic enzymes, inducing orangediscolouration of secretions

10-20(600 mg)

10-20(600 mg)

Pyrazinamide(PZA)

15 - 40(2 g)

Hepatotoxicity, hyperuricaemia,arthralgia, gastrointestinal upset

50-70(4 g)

50-70(3 g)

Ethambutol(EMB)

15-25(2,5 g)

Optic neuritis, decreased visualacuity, decreased red-green colour

discrimination, hypersensitivity,gastrointestinal upset

50(2,5 g)

50(2,5 g)

Streptomycin(SM)

15 - 40(1 g)

Ototoxicity nephrotoxicity25-40(1,5 g)

25-40(1,5 g)

Values in parentheses are maximum doses* In combination with rifampicin, doses < 10 mg/kg/dayWhen INH and RIF are used concurrently, the daily doses of the drugs are reduced

National Concensus of tuberculosis in children, 2001

Cell mediated immunity Delayed-type hypersensitivity

CD4+ T-lymphocytes proliferation Promoted activity of cytotoxic CD4+ & CD8+ T- lymphocytes & Killer cells

Th1 T-lymphocytes Th2 T-lymphocytes

Activate macrophages Augment humoral antibody synthesis

Destroys local non-activated macrophages with M.tb &

surrounding tissue

Attract & activate blood-borne monocytes

Produce cytokines (TNF a, IFN g)

Caseation necrosis, tissue damage,

dormancy of M.tbGranuloma formation

Cavity formation & spread of M.tb

Produce lysosomal enzymes oxygen radicals, nitrogen intermediates, IL-2

Kill M.tb

Cell mediated immunity and delayed-type hypersensitivity in tuberculosis; M.tb, mycobacterium tuberculosis,

TNF-, tumor necrosis factor-alpha; IFN-; gamma interferon; IL-2, interleukin-2


Location of primary focus in 2,114 cases, 1909-1928

Location %Lung 95.93Intestine 1.14Skin 0.14Nose 0.09Tonsil 0.09Middle ear (Eustachian tube) 0.09Parotid 0.05Conjungtiva 0.05Undetermined 2.41

Source: Adapted from Ghon and Kudlich, in Engel and Pirquet (eds.),“Handbuch de Kindertuberkulose,” Georg Thieme Verlag, Stuttgart, 1930, Vol 1

Lesions of pulmonary tuberculosis

Lymph nodes--hilar, paratracheal, and mediastinal adenopathy

Parenchyma--primary parenchymal focus, pneumonia, atelectasis, tuberculoma, cavitary

Airway--air trapping, endobronchial disease, tracheobronchitis, bronchial stenosis, bronchopleural fistula, bronchiectasis, bronchoesophageal fistula

Pleura--effusion, bronchoplueral fistula, empyema, pneumothorax, hemothorax

Blood vessels--miliary, pulmonary hemorrhage


Clinical types of tuberculosis in childrenInfection

Positive tuberculin skin test reaction without clinical, radiographic, or laboratory evidence of disease

Disease

PulmonaryPrimary pulmonary tuberculosis (hilar adenopathy with or without primary parenchymal disease

Progressive primary pulmonary tuberculosis (pneumonia, endobronchial disease)

Chronic pulmonary tuberculosis (cavitary, fibrotic, tuberculoma)

Miliary tuberculosis

Tuberculous pleural effusion

ExtrapulmonaryLymph nodes

Brain and meninges

Skeleton (bone and joint)

Gastrointestinal tract, including liver, gall bladder, and pancreas

Genitourinary tract, including kidneys

Skin

Eyes

Ears and mastoids

Heart

Serous membranes (peritoneum, percardium)

Endocrine glands (adrenal)

Upper respiratory tract (tonsil, larynx, salivary glands)Inselman LS. Tuberculosis in children : An Update. Pediatr Pulmonol 1996; 21:101-20

Positive Mantoux tuberculin test reactions as determined by risk categories for exposure and size of induration of skin test

Risk category Size of induration

None > 15 mm

Moderate > 10 mm

High > 5 mm

Received BCG immunization > 15 mm


Causes of false-positive and false-negative Mantoux tuberculin skin test reaction

False-positiveIncorrect application of tuberculin

Incorrect interpretation

Cross-reactivity with nontuberculous mycobacteria

False-negativeIncubation period

Incorrect storage and application of tuberculosis

Incorrect interpretation

Widespread tuberculous disease

Coexistence of viral infections (measles, rubella, varicella, influenza, human immunodeficiency)

Cellular immunoincompetence, including use of corticosteroids

Complement depletion

Fever

Leukocytosis

Malnutrition

Sacoidosis

Psoriasis

Jejunoileal bypass

Ultraviolet light exposure (sun, solaria)

Zinc deficiency

Pernicious anemia

Uremia Inselman LS. Tuberculosis in children : An Update. Pediatr Pulmonol 1996; 21:101-20

Rapid culture with Bactec®

Polymerase chain reaction (PCR)

Restriction fragment-length polymorphism (RFLP)

Luciferase assay

Immunologic assay (ELISA, latexparticle agglutination, radioimmunoassay, immunoblotting)

Adenosine deaminase levels

BAL fluid levels of CD4+ T-lymphocytes, immunoglobulins, and fibronectin

Newer laboratory studies for the diagnosis of tuberculosis


Chemotherapy for tuberculosis in children

6-month regimen

INH + RIF + PZA daily for 2 months

plus

INH + RIF daily or 2 times/week with DOT for 4 months

If initial drug resistance is suspected : add EMB or SM

For hilar adenopathy without drug resistance : use INH + RIF for 6 months

9-month regimen

INH + RIF daily for 9 months

or

INH + RIF daily for 1 month (or 2 months)

Plus

INH + RIF 2 times/week with DOT for 8 months (or 7 months)


Chemotherapy for tuberculosis in children in special situations

Tuberculosis meningitis, miliary tuberculosis, bone and joint tuberculosis, and congenital tuberculosis

INH + RIF + PZA + SM daily for 2 months

plus

INH + RIF daily or 2 times/week with DOT for 10 months

Mutiple drug-resistant tuberculosis

INH + RIF + PZA + SM

(or high-dose EMB) with DOT for 12-18 months

HIV infection

INH + RIF + PZA for 9 months

May add SM or EMB for initial 2 months


Prophylaxis of tuberculosis infection in children

Isoniazid-suspectible organisms

INH for 9 months

10 mg/kg/day, max 300 mg/day, daily

or

10 mg/kg/day, max 300 mg/day, daily 1 month

plus

20-30 mg/kg/dose, max 900 mg/dose, 2 times/week with DOT for 8 months

Isoniazid-resistant organisms

RIF + INH for 9 months

RIF 10 mg/kg/day, max 600 mg/day, daily

+ INH 10 mg/kg/day, max 300 mg/day, daily

HIV infection

INH for 12 months

INH 10 mg/kg/day, max 300 mg/day, daily


Regimen OAT 2 bl 6 bl 9 bl 12bl

INHRIFPZA

EMBSTREP

PRED

Directly Observed Treatment Short course (DOT’S)

DOTS with a SMILE

S : SupervisedM : MedicationI : InL : a LovingE: Environment

(Grange JM. Int J Tuberc Lung Dis 1999; 3:360-362)

A. Focus and complication

Primary complexFocus and Reg. glands

Rupture of focus intro pleura space with effusion; serous occ. purulen

Rupture of focus intobronchus cavitation

Enlarged focus sometime laminated “round” or “coin” shadow

B. Mediastinal (regional) nodes and complication

Incomplete bronchialObstruction (Ball-valve)

inflation of Middle & lower lobus

Collapsed right lower lobe afterComplete bronchial obstruction

Without consolidation

Collapsed after partialConsolidation segmental

lesion

Erosion into bronchus, inhalarionAnd areas of Tub.

Bronchopneumonia Pericardial effusion post rupture

of node through percardium

Stricture of bronchus

C. Sequelae of bronchial complication

Cylindrical bronchiectasis in area Of old collapse

Wedge shadow with fibrosis andbronchiectasis following contracture

of segmental lesion

Linear scar of fibrosis followingsegmental lesion

nastiti n. rahajoe department of child health medical school university of indonesia jakarta

Documents

children infectedunder

maximum doses

daily doses

diseaseprimary lung

droplet nucleicontaining

cell responsemacrophages

years of age25

early infection