TUBERKULOSIS PADA

ANAK

Definisi

• Tuberkulosis: suatu penyakit infeksi oleh Mycobacterium tuberculosis dengan penye- baran sistemik yang mencakup hampir seluruh organ, terutama paru sebagai tempat infeksi primer.

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

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Sejarah • ancient Egypt : gibbus

• 1882, Koch, identification

• management : sanatorium, collapse treatment

• Chemotherapy :– PAS – 1943 – Lehmann

– Streptomycine – 1945 - Waksman & Schats

– Isoniazid – 1952 – Domagk

– Rifampicine - 1957

24 Maret 1882 Robert Koch mengidentifikasi kuman tuberkulosis

Epidemiologi

• WHO : 2 miliar orang terinfeksi oleh M.tuberculosis ( Afrika, Asia, Amerika Latin)

• Masalah negara berkembang, juga negara maju. Sejak 1990 > : strategi pengendalian, infeksi HIV, pertumbuhan populasi cepat.

• Negara berkembang : TB anak <15 th 15%, negara maju : 5 – 7%

Epidemiologi . . .

• Indonesia : 1994 kasus baru TB 0,4 juta ( 10% < 15 tahun). Th.1999 TB baru 583.000, kematian 140.000 orang/tahun.

• Th 1998 – 2002 di tujuh RS Pendidikan di Indonesia terdapat 1086 kasus TB anak, kematian antara 0% - 14,1%. Kelompok terbanyak usia 12 – 60 bulan (42,9%), untuk bayi < 12 bulan didapatkan 16,5%.

Permasalahan khusus tuberkulosis anak

• Diagnosis : sulit memperoleh spesimen diagnos-tik, jarang ditemukan kuman pd sediaan langsung / kultur.

• Pengobatan : sering drop out• Pencegahan : kontak, gizi, imunisasi• Infeksi HIV : dari orang-tua• Klinis /gejala : sering tidak khas• Program TB Nasional utk.dewasa : anak <

Permasalahan . . .

• Underdiagnosis/overdiagnosis : undertreatment/overtreatment

• Pada anak >TB primer

• Kurang membahayakan /tidak begitu menular. Membahayakan bagi anak sendiri : TB ekstratorakal ( meningitis, tulang )

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Etiologi . . .• Mycobacterium tuberculosis• Mycobacterium bovisfeatures: slender, often slightly curved, rods aerobic, non-motile, non-spore forming acid fail to wash the stain out acid fast bacilli Mycobacteria : found in environments, some strictly

human pathogen (M tb, bovis), others animal pathogen and opportunistic pathogens in human (atypical mycobacteria)

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TB bacilli

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Mycobacterium tuberculosisUnique characteristics :

1. live in weeks in dry condition

2. no endotoxins, no exotoxins

3. hematogenic spread

4. grows slowly (24-32 hr)

5. non specific clinical manifestation

6. aerob, organ predilection - lung

7. wide spectrum of replication: dormant

Etiologi . . .Etiologi . . . • Agen tuberkulosis :

Mycobacterium tuberculosis, Mycobacterium bovis, M. africanum, M.avium . Merupakan ordo Actinomisetales dan famili Mikobacteriaseae.

• Basili tuberkel, batang lengkung,Gram (+) lemah, pleiomorfik, tidak bergerak, tidak membentuk spora, panjang 2-4 um, berkelompok/sendiri, aerob obligat, tahan asam , tumbuh baik 37-41 der.C

Epidemiology 2

M. tuberculosis is a non-motile, rod-shaped bacterium measuring 2-4 x 0.2-0.5 μm. It is an obligate aerobe, which explains why it tends to be found in the well-aerated, upper lobes of the lungs.

It is a slow growing organism (dividing only every 16-20 hours) that lives within tissue macrophages. Humans are the only reservoir of M. tuberculosis. Both cows and humans serve as reservoirs for M. bovis.

The organism does not have the characteristics of either Gram positive or negative bacteria. It has a peculiar cell wall that consists of peptidoglycan and complex lipids. Once stained (e.g. with carbol fuchsin), the organism will retain dyes when treated by acidified organic compounds. Therefore, it is classified as an acid–fast bacterium.

The Ziehl-Neelsen stain is used to demonstrate the presence of the bacilli in a smear. They appear as bright red rods against a contrasting background.

Etiologi . . . Etiologi . . .

M. tuberculosis appearing as bright red bacilli (rods) in a sputum smear stained with the Ziehl-Neelsen stain

Etiologi . . .Etiologi . . .

Epidemiology 3

The cell wall is a major factor in the virulence of the organism. It resists destruction by many antibiotics, acids, alkalis, osmotic lysis and oxidation and enables the organism to survive inside macrophages.

M. tuberculosis grows in Lowenstein Jensen medium, an egg-based medium, which contains inhibitors to keep contaminants from outgrowing the organism. Because of its slow growth, it takes 4-6 weeks before small buff-coloured colonies are visible on the medium.

Typical small, buff coloured colonies of M. tuberculosis on Lowenstein Jensen medium

Etiologi Etiologi . . . .. . . .((Sel kuman tbc dan koloni Sel kuman tbc dan koloni ))Etiologi Etiologi . . . .. . . .((Sel kuman tbc dan koloni Sel kuman tbc dan koloni ))

PenularanPenularan

• Lewat udara/droplet, dapat juga (jarang) mel.kontak langsung kulit/luka/lecet, dan (kongenital), minum susu terkontaminasi basil (M.bovis).

• Basil tetap hidup dan virulen dlm keadaan kering bbrp minggu, mati dlm cairan 60.C 15-20 menit.

• Basil tidak membentuk toksin.

Penularan . . . Umumnya dari TB dewasa dengan BTA (+)

Cara penularan :

• airborne : >90%, droplet nuclei 1-5 • orally : drink infected cow milk

• direct contact : skin wound

• congenital : during pregnancy, very rare

Nearly all TB infection is acquired by inhalation of respiratory droplets from an infectious contact.

Air droplets 3-5 μm diameter coughed, sneezed or spat out by an “open” case of TB. The droplets are inhaled by a close contact. This may lead to a lung infection which then may go on to develop into disease – in the lungs

and/or in other organs.

NB. Abdominal TB can also result from drinking unpasteurised cow’s milk infected with M. bovis.

Transmission 1

Penularan . . .Penularan . . .

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Penularan . . .

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Penularan . . . ( faktor yg berpengaruh)

• doses / numbers

• concentration in the air

• virulence

• exposure duration

• host immune state

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Penularan . (tingkat transmisi) (Shaw ’54)

adultTB patient

AFB(+) AFB(-)culture(+)

culture(-)CXR (+)

65% 26% 17%

Patogenesis (1)Patogenesis (1)

• M.tbc udara fokus primer di paru (susceptible) di alveolus fagositosis oleh makrofagkembang biak/menghancurkan makrofageksudasi konsolidasituberkel

• Fokus primerkel.limfe hiluslimfadenitis/ limfangitismembentuk kompleks primer

• K.primerpeny.organ tsb atau menetap non-aktifdpt.aktif bertahun-tahun kmd. -

Pathogenesis of tuberculosis (2)

Inhalation of droplet nucleicontaining 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

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.tb

Granuloma 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

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

04/22/23 30Figure. Pathogenesis of primary tuberculosis

droplet nuclei inhalation alveoli ingestion by PAM’S

intracellular replicationof bacilli

destruction of bacillidestruction of PAM’S

Tubercle formation Hilar lymph nodes

hematogenic spread

multiple organs remote foci

Lymphogenic spread

disseminated primary TB

acute hematogenic spread

occult hematogenic spread

Fokus primer lymphangitis lymphadenitis

Kompleksprimer

CMI

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lymphadenitis

lymphangitis

Fokus primer

Patogenesis . . Patogenesis . . ..

– Primary Complex

– Ghon Complex

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Kompleks primer

• end of incubation period • TB infection establishment• tuberculin sensitivity (DTH)• cell mediated immunity • end of hematogenic spread• end of TB bacilli proliferation• small amount, live dormant in granuloma• new exogenous TB bacilli: destroyed / localized

Patogenesis (3)Patogenesis (3)

PatogenesisPatogenesis (4) (4)

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Masa inkubasi

• first implantation primary complex• 4-6 weeks (2-12 weeks) incubation period

• first weeks: logaritmic growth, : 103-104 elicit cellular response

• end of incubation period:– primary complex formation

– cell mediated immunity

– tuberculin sensitivity

PrimaryTB infection has established

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Penyebaran hematogen

• during incubation period, before TB infection establishment: – lymphogenic spread

– hematogenic spread

• hematogenic spread (HS):– occult HS

– acute generalized HS

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Penyebaran hematogen .”occult” /tersembunyi

• most common• sporadic, small number• no immediate clinical manifestation• remote foci in almost every organ• rich vascularization: brain, liver, bones &

joints, kidney• including: lung – apex region• CMI (+): silent foci - dormant, potential

for reactivation

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Penyebaran hematogen . . .

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Penyebaran hematogen .”acute generalized”/nyata

• less common

• large number

• immediate clinical manifestation: disseminated TB

• milliary TB, meningitis TB

• tubercle in same size, special appearance in CXR

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Tuberkulosis miliaris

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

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

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Manifestasi klinis

• vary, wide spectrum

• factors: – TB bacilli: numbers, virulence– host: age, immune state

• clinical manifestation– general manifestation– organ specific manifestation

Manifestasi klinis . . Gejala umum

• Chronic fever

• Anorexia dan BB / tidak naik

• Malnutrition

• Malaise

• Chronic cough

• Chronic / recurrent diarrhea

• Others

Manifestasi klinis . .. .gejala spesifik

• Respiratorik : batuk, sesak, mengi• Nerologik : kejang, kaku kuduk• Ortopedik : gibbus, pincang• Kelenjar : membesar, skrofuloderma• Gastrointestinal : diare berlanjut• Lain-lain

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Manifestasi klinis . . .klasifikasi• Infection:

TST (+), clinical (-), radiographic (-)

• Disease:– Pulmonary:

• primary pulmonary TB• milliary TB• pleuritis TB• progr primary pulm TB: pneumonia, endobr TB

– Extrapulmonary:• lymph nodes• brain & meninges• bone & joint• gastrointestinal• other organs

Manifestasi klinis . . . . . . klasifikasiInfection

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)

I

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Fever of Onset

Tuberculin Test Positive

Primary pulmonary TBTB Meningitis

Miliary TBTB Pleural effusion

Osteo-articular TB

Renal TB

Ph

lycte

nu

lar co

nju

nctiv

itis

Ery

them

a n

od

osu

m2 – 3 months

3 – 12 months

6 – 24 months

> 5 years

Time after primary infection

Manifestasi klinis . . . .

Figure 5. The Timetable of TuberculosisDonald PR et.al. In: Madkour MM, ed. Tuberculosis. Berlin; Springer;2003.p.243-64

Manifestasi / gambaran klinis

• 5-10% anak terinfeksi tbc sakit tbc• Gambaran klinis tbc tgt : jumlah basil tbc,

virulensi, umur penderita, imunokompe – tensi, kerentanan pend.saat infeksi

• Pd.permulaan tak ada gejala/tanda, kmd dapat batuk, anoreksi, penurunan BB, pa-nas subfebril. Selanjutnya gejala umum dan spesifik tgt alat yg terkena (paru, dll.)

Manifestasi klinis ( lanjutan )

• Permulaan tbc primer sukar diketahui, se-bagian besar gambaran rontgen normal, tak ada tanda fisik dan laboratorik, hanya tes tuberculin (+)/Mantoux test.

• Panas kadang menyerupai tifus abdomina-lis, atau malaria

• Dapat menunjukkan gjl=bronkopneumoni

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Diagnosis (1). . . . . .The main problems

• Diagnosis– Clinical manifestations : not specific both

over/under diagnosis & over/under treatment

– diagnostic specimen : difficult to obtain– No other definitive diagnostic tools– TB infection or TB disease ? no diagnostic

tool to distinguish

• Adherence / compliance – Drug discontinuation treatment failure

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Diagnosis (2)1. Anamnesis - Clinical manifestation2. Tuberculin skin test3. Chest X ray4. Microbiologic5. Pathology6. Hematological 7. Known infection source8. Others : serologic, lung function,

bronchoscopy

Sumber penularanSumber penularan : :

Sulit

Penting :

Untuk dx

Berhasil/tidaknya tx

AnamnesisAnamnesis Febris lama

Batuk lama

BB

Lesu

Aktifitas

Tbc primer : sering asymptomatik

Gx. Paru/rö : ~ INFEKSI LAIN

Conjunctivitis phlyctenularis

Tbc extrathoracal

Scrofuloderma

Pembesaran kelenjar

Men-ser

Cold absces

Tbc tulang/Sendi

Cari

Phisik DiagnostikPhisik Diagnostik

Mantoux TestMantoux Test (1) (1)Sangat penting untuk diagnostik

Dipakai :

Ot 0,9 mg

Ppd 5 tuRÖ

Tidak spesifik

Foto bersih : tidak menyangkal ada proses

Dx. TBC TIDAK DAPAT DIBUAT ATAS DASAR rö

Persangkaan kuat tbc :

Gbr miliair

Pembesaran kelenjar paratracheal

Mantoux Test (Mantoux Test (22) ) (UJI TUBERKULIN)(UJI TUBERKULIN)

• Tuberkulin :komponen protein kuman tuberkulosis yg mempunyai sifat anti- genik yg kuat.

• Uji tuberkulin : alat diagnostik TB yg sudah sangat lama dikenal. Mempunyai nilai diagnostik dg sensi-tifitas dan spesifisitas > 90%.

• Tuberkulin yg tersedia di Indonesia : PPD RT 23 2TU dan PPD S 5TU.

Mantoux Test (3)Mantoux Test (3)

• Children for whom immediate Tuberculin Skin Test (TST) is indicated

1. Contacts with confirmed or suspected TB

2. Radiographic/clinical findings suggestive of TB

3. Children from endemic regions (Asia, Lat. America, Africa, Middle East)

4. Children with travel to those regions or contact with someone from those regions

Mantoux Test (4):Mantoux Test (4):

• The TST is the only practical tool for TB diagnosis when asymptomatic

• 5 tuberculin units of purified protein derivative (PPD) is the only acceptable method

• 27 ga. TB syringe

intradermally on the

volar surface

Mantoux Test (5)Mantoux Test (5):: TSTTST interpretationinterpretation

• Read induration (not erythema) at 48-72o

– transverse to the long axis of the arm

• Ball point pen-method (Sokal) is preferred

• Self interpretation is unacceptable

• + tests sometimes persist for several wk

Mantoux Test (6)Mantoux Test (6) Positive PPD definedPositive PPD defined (infants, children, adolescents)(infants, children, adolescents)

• Induration 5 mm– Children in close contact with known/suspected

case of TB

– Children suspected to have TB• CXR findings

• Clinical findings c/w TB

– Children receiving immunosuppressive Tx or with immunosuppressive conditions (e.g. HIV)

Mantoux TestMantoux Test (7)(7) Positive PPD definedPositive PPD defined (infants, children, adolescents)(infants, children, adolescents)

• Induration 10 mm– Children at inc. risk of disseminated Dz

• < 4 y/o

• Those with Hodgkin's, lymphoma, DM CRF, malnutrition

– Children w/ increased exposure (travel, country of origin, exposure to high-risk adult)

Mantoux Test (8)Mantoux Test (8) Positive PPD definedPositive PPD defined (infants, children, adolescents)(infants, children, adolescents)

• Induration 15 mm– Children > 4 y/o with no risk factor (i.e. all

patients)

INTERPRESTASI mtxINTERPRESTASI mtxINTERPRESTASI mtxINTERPRESTASI mtx

0-4 mm NEGATIF 5-9 ragu

> 10 mm

POSITIF

Klinis : infeksi θ

Klinis : sedang/pernah terinfeksi

Tidak perlu diulang, kecuali ada dugaan keras tbc Klinis :

-Teknik salah-Ada infeksi-Cross reaksiPsot bcg/crp

Aktif, bila :

< 6 thTx θ

Bcg θ

Konverse :Θ Dlm 1 thTx θBcg θ

Infeksi Cross reaksi post bcg MUNGKIN skl TBC

Ket : konversi :I. 0 – 2 mm

II. BERTAMBAH > 10 mm

> 10 mm

Tetap

Tetap tanda-tanda lain

Diulang dgn dosis sama

Prinsip dasar Uji Tuberkulin (1)Prinsip dasar Uji Tuberkulin (1)

• Infeksi M.tuberculosis sel limfosit T berproliferasi, tersensitisasi masuk ke aliran darah, bersirkulasi berbulan-bulan/tahun.

• Proses sensitisasi terjadi dlm kel.getah bening regional (2-12 jam stl. infeksi).

• Injeksi tuberkulin pd kulit menstimulasi sel limfosit aktivasi rentetan kejadian respons hipersensitivitas tipe lambat (delayed-type hypersensitivity/DTH )/ memerlukan waktu berjam-jam.

PrinsipPrinsip dasar Uji Tuberkulin (2) dasar Uji Tuberkulin (2)

• Reaktivitas kulit : vasodilatasi,edema, infiltrasi sel-sel limfosit, basofil,mono-sit dan netrofil ke lokasi suntikan.

• Antigen-spesific limfosit T akan ber-proliferasi dan melepaskan limfokin, yg akan mengundang akumulasi sel-sel lain ke lokasi suntikan terjadi indurasi yg mencerminkan aktivitas DTH.

Prinsip Prinsip dasardasar Uji Tuberkulin (3) Uji Tuberkulin (3) Immune Response to TuberculinImmune Response to Tuberculin

TB infected : TB infected : T lymphocytes proliferate and become T lymphocytes proliferate and become

sensitized.sensitized. Within weeks these sensitized T cells are Within weeks these sensitized T cells are

circulating in the blood stream.circulating in the blood stream.

Sensitized of lymphocytes Sensitized of lymphocytes reach a level adequate to produce a reach a level adequate to produce a

detectable DTH response at 2-10 weeks after detectable DTH response at 2-10 weeks after initial infection with M. tuberculosisinitial infection with M. tuberculosis

This sensitivity may persist for years, This sensitivity may persist for years, although reactivity may wane with although reactivity may wane with increasing age. increasing age.

CID 1993;17:968-75.

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Mantoux tuberculin skin test

Anergi (1)

Uji tuberkulin dapat negatif untuk sementara karena :• TB berat misalnya TB milier• PEM berat• Mendapat kortikosteroid lama• Penyakit virus : morbili, varicella• Penyakit bakteri : typhus abdominalis, difteri, pertusis• Vaksinasi virus : morbili, polio• Penyakit keganasan : penyakit Hodgkin

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Anergy (2)Patient with primary complex do not give reaction to

TST due to supression of CMI :• Severe TB: miliary TB, TB meningitis• Severe malnutrition • Steroid, long term use• Certain viral infection: morbili, varicella• Severe bacterial infection: typhus abdominalis,

diphteria, pertussis• Viral vaccination: morbili, polio• Malignancy: Hodgkin, leukemia, ...

Pemeriksaan radiologis (1)Pemeriksaan radiologis (1)

• Pemeriksaan rontgen saja tidak dapat digunakan untuk mendiagnosis tbc.

• Gambaran rontgen paru tbc anak ti-dak khas.

• Foto rontgen paru yang normal (tidak terdeteksi) tidak dapat menyingkirkan diagnosis TB.

Pemeriksaan radiologis (2)Pemeriksaan radiologis (2)

• Secara umum gambaran radiologis yang sugestif TB adalah sbb.: *pembesaran kel.hilus atau paratrakeal * konsolidasi segmental/lobar *milier *kalsifikasi *atelektasis *kavitas * efusi pleura

PemeriksaanPemeriksaan radiologis (2-A)radiologis (2-A)

Should evaluate AP, Lateral views

Nodal component changes: hilar or mediastinal lymphadenopathy

Lung parenchymal changes: segmental pneumonia: segmental hyperinflation: atelectasis: effusion, cavitation (rare)

Pemeriksaan radiologis (3)Pemeriksaan radiologis (3)

• Jika dijumpai ketidaksesuaian antara gambaran klinis (ringan) dengan gambaran radiologis (berat), harus dicurigai TB.

• Pada keadaan foto rontgen paru tidak jelas, bila perlu dilakukan pencitraan lain seperti CT-scan toraks.

Gambaran radiologi (1) Imaging diagnostic

• routine : chest X ray

• on indication : bone, joint, abdomen

• majority of CXR non suggestive TB

• pitfall in TB diagnostic

Gambaran radiologi ( 2)

• Pembesaran kelenjar• Fokus primer• Atelektasis• Kavitas• Tuberkuloma• Pneumonia• “Air trapping”• Trakeobronkitis• Bronkiektasis• Efusi pleura• Gambaran milier

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Gambaran radiologi (3) Radiographic picture

• primary complex: lymph node enlargement• milliary• atelectasis• cavity• tuberculoma• pneumonia• air trapping - hyperinflation• pleural effusion• honeycombs – bronchiectasis• calcification, fibrosis

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do not always help, particularly in small childrenat times can be confusing

some cases: extensive disease from radiography clinical exam revealed little or nothing

more confusingsuperadded bacterial pneumonia

Osborne CM et.al. Arch Dis Child 1995;72:369-74

Gambaran radiologi (4) Radiographic picture

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• No radiographic picture is typical of TB• Many lung diseases have similar radiographic

appearances mimicking PTB• Cannot distinguish active pulmonary TB –

inactive PTB – previously treated TB• May not detect early stages of TB disease

– under-reading– over-reading– intra-individual inconsistency

Vijayan VK. Indian J Clin Biochem 2002;17(2):96-100.

Gambaran radiologi (5) Radiographic picture

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Commonly found: enlargement of hilar/ paratracheal nodes sometimes difficult to interpret requires thorax CT with contrast

Thorax CT reveals enlargement of lymph node in 60% children with TB infection and normal Chest röntgenogram

Delacourt C et.al. Arch Dis Child 1993;69:430-2.

Gambaran radiologi (6)

Gambaran CT toraksGambaran CT toraks

NOT ROUTINELY RECOMMENDED

More useful in highly suspected PTB but normal CXR,

: endobronchial TB: early cavitation: bronchiectasis

Very useful in TB meningitis, Tuberculoma,intrathoracic mass, intraabdominal mass intraspinal mass

Pleural effusion

Milliary tuberculosis

A 1-year-old with endobronchial TB

with pulmonary consolidation.

3 mo old with TB. –Presented as fever. CXR—RUL consolidation. PPD was positive.

Mycobacterium tuberculosis grew from gastric aspirate culture.

• Primary pulmonary TB with pleural effusion (right lung). The possibility of TB should routinely be considered in children with a pleural effusion

Pemeriksaan mikrobiologis

• Memastikan D/ TB

• Hasil negatif tidak menyingkirkan D/ TB

• Hasil positif : 10 - 62 % (cara lama)

• Cara : – cara lama,– radiometrik, – PCR

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Pemeriksaan mikrobiologis • culture (Lowenstein Jensen)• confirm the diagnosis • negative result do not rule out TB• positive result : 10 - 62 % (old method)• methods:

– old method– radiometric (Bactec) – PCR

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Pemeriksaan mikrobiologiss

• PCR (Polymerase chain reaction )from gastric aspirate diagnosis of TB in children Sensitivity: 44 – 90%Specificity: 94 – 96,8%Compared to MTB culture

Lodha R et.al. Indian J Pediatr 2004;71:221-7.

PCR technique using primer containing IS6110 better results

Khan EA and Starke JR. Emerg Infect Dis 1995;1:115-23.

May help in early detection of resistant strain of MTBLodha R et.al. Indian J Pediatr 2004;71:221-7.

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Sensitivity: 19 – 68%Specificity: 40 – 98%

Disadvantagesresults affected by factors such as- age- history of BCG vaccination - exposure to atypical Mycobacteria- unable to differentiate between infection and disease

Khan EA and Starke JR. Emerg Infect Dis 1995;1:115-23.

Depends on:Type of antigen usedType of infection

Pemeriksaan serologis

Pemeriksaan hematologis

• Not specific

• BSR could elevate

• Limphocyte could increase

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Pemeriksaan patologis

• complicated pathogenesis varied pathology

clinical manifestation

radiologic appearance• lung represent• tubercle, granuloma, tuberculoma, fibrosis,

fistula, cavity, atelectasis• complication of primary focus: so many

possibilities

Pemeriksaan patologis 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

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

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tubercle formationresolution

primary focus

calcification

2nd lung lesions

caseation

liquefaction

granuloma

Pathology junglePathology jungle

remote focireg lymph node

tuberculoma

cavity

milliary seed

erodes airway

compresses airway

rupt to pleura rupt to airway bronchiectasis

fibrosis

br pl fistula

Pemeriksaan lain-lain

• Uji faal paru

• Bronkoskopi

• Bronkografi

• Serologi

• MPB64

Komplikasi tuberkulosis primer

1. Komplikasi komplex primer– Fokus primer : kavitas, efusi pleura, dll– Kelenjar : menekan bronkus, dll

2. Penyebaran hematogen– Tuberkulosis milier– Meningitis TB– TB tulang dan sendi– TB ginjal– Lain-lain

3. Penyebaran limfogen4. Per kontinuitatum

Tuberkulosis milier

• Penyebaran hematogen akut dan menyeluruh• Dapat menjadi kronik• Tanpa obat bisa fatal• Lesi-lesi ke seluruh tubuh• Demam, hepatomegali, splenomegali, tuberkel koroid

mata• Pungsi lumbal

Pleuritis TB dengan efusi

• Pleuritis TB biasanya dengan efusi

• Terjadi karena :– Perluasan fokus TB dekat pleura– Penyebaran hematogen

• Hipersensitivitas terhadap tuberkulin efusi pleura

• Pungsi pleura

• Dapat berupa empyema

Akibat pembesaran kelenjar

• Menekan bronkus :– Atelektasis– Emfisema

• Menembus bronkus :– Penyebaran bronkogen– Fistula

TB Tulang dan Sendi

• Spondilitis

• Koksitis

• Gonitis

• Daktilitis (Spina ventosa)

TB kelenjar superfisial

• Akibat penyebaran limfogen dan hematogen • Dapat sembuh sendiri, dapat progresif• Dapat merupakan bagian dari TB milier• Biasanya multipel• Lokasi : leher, axilla, inguinal, supraklavikuler,

submandibula• Abses

TB Mata

• TB primer konjungtivapembesaran kelenjar preaurikuler

• TB koroid funduskopi• Conjunctivitis phluctenularis :

– Fenomena hipersensitivitas– Sakit, sangat mengganggu– Rekuren– Terjadi dalam 5-15 tahun

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Masalah dalam diagnosis TB anak

• If you find the diagnosis of TB in children easy, you probably overdiagnosing TB

• If you find the diagnosis of TB in children difficult, you are not alone

• It is easy to over-diagnose TB in children• It is also easy to miss TB in children• Carefully assess all the evidence, before making the

diagnosis

Anthony Harries & Dermot Maher, 1997

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Pengobatan Objectives of treatment

• Rapid reduction of the number of bacilli

• Preventing acquired drug resistance

• Sterilization to prevent relapses

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Pengobatan Treatment principles Drug combination, not single drug

risk of fall and rise phenomenon each TB drug has special action to certain

TB bacilli population Two phases :

Initial phase (2 months) – intensive, bactericidal effect

Maintenance phase (4 months / more) – ‘sterilizing’ effect, prevent relaps

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Pengobatan Treatment principles

Long duration problem of adherence (compliance)

Other aspects : Nutrition improvement prevent / search & treat other

disease

Pengobatan TB

• Permulaan intensif

• Kombinasi 3 atau lebih OAT

• Teratur dan lama

• Pemberian gizi yang baik

• Pengobatan dan pencegahan penyakit lain

Obat Anti Tuberkulosis (OAT)

1. Isoniazid (INH) : 5 - 15 mg/Kg BB/hari, max. 300 mg/hari

oral 1 - 2 x / hari

2. Rifampisin : 10 - 20 mg/Kg BB/hari, max. 600 mg/hari

oral 1 - 2 x / hari, perut kosong

3. Pirazinamid : 15 - 30 mg/Kg BB/hari, max. 2 gram/hari

oral 1 - 2 x / hari (20 - 40 mg/Kg BB/hari)

4. Streptomisin : 20 - 40 mg /Kg BB/hari, max. 1gram/hari

intramuskulus

5. Etambutol : 15 - 20 mg/Kg BB/hari, max. 1,5 gram/hari

oral 1 x /hari, perut kosong

6. Lain-lain : Ethionamide, Kanamycin, Cycloserin, Ciprofloxacin

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Drugs Daily dose(mg/Kg/day) Adverse reactions

2 Time/weekdose

(mg/Kg/dose))

Isoniazid(INH)

5-15(300 mg))

Hepatitis, peripheral neuritis,hypersensitivity

15-40(900 mg))

Rifampicin(RIF)

10-15(600 mg))

Gastrointestinal upset,skin reaction, hepatitis, thrombocytopenia,

hepatic enzymes, including orangediscolouraution of secretions

10-20(600 mg)

Pyrazinamide(PZA)

15 - 40(2 g)

Hepatotoxicity, hyperuricamia,arthralgia, gastrointestinal upset

50-70(4 g)

Ethambutol(EMB)

15-25(2,5 g)

Optic neuritis, decreased visualacuity, decreased red-green colour

discrimination, hypersensitivity,gastrointestinal upset

50(2,5 g)

Streptomycin(SM)

15 - 40(1 g)

Ototoxicity nephrotoxicity25-40(1,5 g)

When INH and RIF are used concurrently, the daily doses of the drugs are reduced

National consensus of tuberculosis in children, 2001

Dosage of antituberculosis drug

Daftar obat dan dosisnya

Nama Obat BB < 10 Kg BB 10-20 Kg BB 20-33 Kg

INH (H) 50 mg 100 mg 200 mg

Rifampisin (R) 75 mg 150 mg 300 mg

PZA (Z) 150 mg 300 mg 600 mg

Bila BB > 33 kg dimasukkan golongan dewasa

Bila BB < 5 kg sebaiknya dirujuk ke Rumah sakit

Bila dikombinasikan H dan R, H tidak boleh lebih dari 10 mg/Kg BB/hari, R tidak boleh lebih dari 15 mg/Kg

INH dan rifampisin tidak boleh diracik dalam satu puyer, tetapi boleh dicampur saat meminumnya

Fixed Dose CombinationFixed Dose Combination

Regimen of Antituberculosis drugs

2 mo 6 mo 9 mo 12 mo

INHRIFPZA

EMBSTREP

PRED

Directly Observed Treatment Short course (DOT’S)

Corticosteroid• Anti inflammation

• prednison : 1 - 3 mg/kg BB/hari, 3x/hari oral 2 - 4 minggu, tapering

off

• Indications :– TB milier– Meningitis TB– Pleuritis TB with effusion

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Evaluasi pengobatan

• Clear improvement in clinical and supporting examination, especially in the first 2 month

• Main : clinical

• supporting exam as adjuvant

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Evaluasi pengobatan

• Clinical improvement :– Increased body weight – Increased appetite– Diminished / reduced symptoms (fever, cough,

etc)

• Supporting examination : – Chest X rays : 2 / 6 month (on indication)– Blood : BSR – Tuberculin test : once positive, do not needed to

repeat !

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Kegagalan pengobatan

• Inadequate response, despite adequate therapy :– Review the diagnosis, not a TB case ?– Review other aspects : nutrition, other

disease– MDR – rarely in children

• Treatment discontinuation

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Permasalahan dlm pengobatan

• The main : compliance / adherence (kebutuhan / dosis /ketaatan)

• The factors :– Long duration– Drug side effect– Initial improvement – misinterpreted by patients /

parents– Inconvenient health service– Socio-economic-cultural factors

• The following : drug resistance

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Penanganan masalah kegagalan pengobatan

• DOTS : Directly Observe Treatment Shortcourse

• FDC : Fixed dose combination i.e. >2 drugs in one tablet in a fixed dose formulation

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DOTS with a SMILE

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

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

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

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

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Fixed Dose Combination

FDC: >2 drugs in one tablet in a fixed dose formulation

• simple dosing• patient friendly, doctor friendly• increase adherence• reduce MDR• easier drug supplying• easier drug monitoring

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FDC tablet formulation

WHO

• H : 30 mg

• R : 60 mg

• Z : 150 mg

IDAI

• H : 50 mg

• R : 75 mg

• Z : 150 mg

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WHO FDC (H/R/Z:30/60/150 & H/R:30/60)

BW(kg)

Intensive, 2 mo(tablet)

Continuation, 4 mo(tablet)

<7 1 1

8-9 1,5 1,5

10-14 2 2

15-19 3 3

20-24 4 4

25-29 5 5

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IDAI FDC (H/R/Z:50/75/150 & H/R:50/75)

BW (kg)

Intensive, 2 mo

(tablet)

Continuation, 4 mo(tablet)

5-9 1 1

10-19 2 2

20-33 4 4

Note: BW < 5kg should be referred and need tailored dosing

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WHO vs IDAI fdc formulation

• WHO:– INH: 4-6 mg/kgBW

– BW grouping: too many

– not practical

– hard to remember

– a gap for BW 30-33 kg

• IDAI– INH: 5-10 mg/kgBW

– simple BW grouping

– more friendly both for doctor and patient

Pencegahan

• Perbaikan sosio ekonomi

• Kemoprofilaksis

• Imunisasi BCG

Kemoprofilaksis primer

• Mencegah infeksi• Anak kontak dengan pasien TB aktif, tetapi belum

terinfeksi (uji tuberkulin negatif)• Obat : INH 5 - 10 mg/kg BB/hari

Kemoprofilaksis sekunderMencegah penyakit TB pada anak yang terinfeksi :

1. Mantoux (+), Rö (-), klinis (-) :• Umur < 5 th• Kortikosteroid lama• Limfoma, Hodgkin, lekemi• Morbili, pertusis• Akil baliq

2. Konversi Mt (-) menjadi (+) dalam 12 bl, Rö (-), klinis (-)

Obat INH 5 - 10 mg/kg BB/hari

Imunisasi BCG

• Imunitas spesifik

• Uji tuberkulin menjadi (+)

• Mt (-) baru BCG

• Masal : langsung BCG tanpa Mt

• Reaksi lokal : membantu screening

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