BRONCHIECTASIS(brong-kee-ECK-tah-sis)

PRASENOHADI

Department of Pulmonolgy and Respiratory MedicineFaculty of Medicine, University of Indonesia

BRONKIEKTASIS = BE Proses patologi yang ditandai dengan dilatasi ireversibel dan destruksi dinding bronkus

SEJARAH

1819 René Théophile Hyacinthe Laënnec “suppurative phlegm” 1922 Jean Athanase Sicard bronkografi kontras kerusakan 1950 Lynne Reid bronkografi, patologi, prevelensi (imunisasi)

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PATOFISIOLOGIBronkiektasis (BE) penyakit bronkus dan bronkiolus infeksi dan inflamasi disertai pelepasan mediator mengakibatkan obstruksi dan kerusakan saluran napas serta infeksi berulang

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Perubahan respons selular dan mediator infiltrasi netrofil dan limfosit T peningkatan elastase dan kemoatraktan, interleukin–8, interleukin–1β, tumor necrosis factor–α (TNF–α) dan prostanoid (leukotrien B4) endotelin–1 meningkatkan CD18 dan CB11b ?desmosin dan isodesmosin urin nitrit oksida, hidrogen peroksidase, karbon monoksida

kolonisasi kumanjumlah kuman

host (pasien)respons inflamasi

gangguanbersihan bronkus

kerusakan paru

THE “VICIOUS CIRCLE” HYPOTHESIS

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TOTAL DIFFERENTIAL CELL COUNTS AND CYTOKINELEVELS IN BALF OF PATIENTS WITH BRONCHIECTASIS

AND CONTROL SUBJECTS

Am J Respir Crit Care Med 2001

Relationship betweenairway bacterial load(cfu/ml) and the % ofneutrophils andTNF–α, IL–1, IL–8concentrations inBALF

Am J Respir Crit Care Med2001

COMPARISON OF BRONCHIAL AND SYSTEMICINFLAMMATORY RESPONSE IN PATIENTS WITH

BRONCHIECTASIS

Am J Respir Crit Care Med 2001

GAMBARAN FOKAL DAN DIFUS

BE dapat dibagi menjadi 2 bentuk Proses lokal atau fokal obstruksi di lobus atau segmen Proses luas pada kedua paru dan sering berhubungan sinusitis and asthma

3 jenis sumbatan jalan napas fokal BE 1. Sumbatan benda asing (broncholith) atau tumor yang yang tumbuh lambat (biasanya jinak) 2. Sumbatan dari luar oleh pembesaran kelenjar getah bening middle lobe syndrome mikobakterium

jamur 3. Sumbatan pasca bedah

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PATOLOGI/PATOGENESISUtama dilatasi jalan napas di paru 3 bentuk dilatasi jalan napas silindrik varikosa sakular

Dilatasi bronkus Inflamasi

Kerusakan jalan napas

Gangguan mukosiliar

Gangguan bersihanJalan napas

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3 mekanisme utama terlibat pada kerusakanjaringan bronkus :

Infeksi dan inflamasi Kemoatraktan sel inflamasi (netrofil, makrofag) bahan sitotoksik kerusakan dinding bronkus / silia

Obstruksi jalan napas dan gangguan silia Gangguan silia sumbatan mukus dan infeksi

Fibrosis peribronkial Lisis jaringan elastis dinding bronkus penebalan

fibrosis

PATOLOGI/PATOGENESIS

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Normal Bronchiectasis

A Scanning ElectronMicrograph of the Surfaceof Human BronchusShowing Dense Ciliation

Outer armInner arm

Nexin link

Radial spoke

Cell membrane

Dynein arm

Absence of outer dynein arm

Normal

Bronchiectasis

CONDITIONS ASSOCIATED WITHBRONCHIECTASIS

Pasca infeksiBakteri (pseudomonas, haemophilus)Mycobacterium tuberculosisAspergillus speciesVirus (adenovirus, measles virus, influenzavirus, human immunodeficiency virus)

Kongenital (Bawaan)Primary ciliary dyskinesiaAlpha 1–antitrypsin deficiencyCystic fibrosisTracheobronchomegaly (Mounier–Kuhn syndrome)Cartilage deficiency (Williams–Campbell syndrome)Pulmonary sequestrationMarfan’s syndrome

ImunodefisiensiPrimer

HypogammaglobulinemiaSekunder

Kanker (chronic lymphatic leukemia),kemoterapi, or imunomodulator(pasca transplantasi)

Sequelae of toxic inhalation or aspirationChlorineOverdose (heroin)Foreign body

CONDITIONS ASSOCIATED WITHBRONCHIECTASIS

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CONDITIONS ASSOCIATED WITHBRONCHIECTASIS

Rematik Rheumatoid arthritisSystemic lupus erythematosusSjögren’s syndromeRelapsing polychondritis

Lain–lain Inflammatory bowel disease(chronic ulcerative colitis or Crohn’s disease)Young’s syndrome (secondary ciliary dyskinesia)Yellow nail syndrome (yellow nails and lymphedema)

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GEJALA DAN TEMUAN KLINIK

Umumnya : batuk dan produksi sputum kronikSputum : mukoid, mukopurulen, kental, tenaciousKerusakan saluran napas akibat infeksi akut Blood–streaked atau hemoptisis Sesak napas (dyspnea) dan mengi (wheezing) : 75% pasienNyeri dada (pleuritic chest pain) : 50% pasien

Pemeriksaan fisis ditemukan suara napas tambahanbronkial (70% pasien), mengi (34%) and ronki (44%)Jari tabuh (digital clubbing) kadang–kadang (3%)

Diagnosis banding PPOK

GEJALA EKSASERBASI AKUTBRONKIEKTASIS

Perubahan produksi sputum Sesak napas (dyspnea) meningkat Batuk meningkat Demam (suhu, >38.0°C) Mengi (wheezing) meningkat Malaise, fatigue, lethargy, atau

penurunan kegiatan Faal paru menurun Radiographic changes consistent with

a new pulmonary process Perubahan suara napas

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PERBEDAAN BRONKIEKTASIS (BE) DANPENYAKIT PARU OBSTRUKTIF KRONIK (PPOK)

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VARIABEL PPOK BE

Penyebab Rokok Infeksi, genetik atau gangguan imun

Peran infeksi Sekunder Primer Organisme sputum Streptococcus H. influenzae,

pneumoniae, PseudomonasHaemophilus aeruginosa

influenzae Obstruksi jalan napas Ada Ada dan hiperesponsif Radiologi Hiperlusen, hiperinflasi, Dilatasi, penebalan,

dilatasi “mucous plugs” Sputum (stabil) Mukoid Purulen, tiga–lapis

DIAGNOSTIC TESTING FOR BRONCHIECTASIS

Appropriate Tests

Blood Imaging Other

Primary Complete and High–resolution Spirometry or differential blood CT bronchodilator test count,

IgG, IgA, IgM

Secondary Rheumatoid factor; Sinus CT Sputum bacterial, IgE, aspergillus mycobacterial, fungal precipitins (ABPA); culture and sensitivity; IgG subclasses; bronchoscopy with

mucosal alpha1-antitrypsin level biopsy, cultures (for focal obstruction, infection, primary ciliary dyskinesia);

(for sweat chloride test analysis cystic fibrosis)

Level ofTesting

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Paru normal Bronkiektasis

A PA radiograph shows extensive increase in linearopacities particularly in the lower lobes suggestive of

ectatic bronchi 

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Cylindrical bronchiectasis withsignet-ring appearance.Note that the luminal airwaydiameter is greater than the diameter of the adjacent vessel

Cystic and cylindricalbronchiectasis of the right lowerlobe on a posterior-anteriorchest radiograph

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Findings:• normal upper and middle lobes• the branches to the lower lobe are slightly dilated and there is a lack of branch filling

The repeated episodes of inflammation can result in scarring,which has resulted in fibrous adhesions between the lobes.Fibrous pleural adhesions are common in persons who havehad past episodes of inflammation of the lung that involve the pleura.With extensive involvement, the pleural space may be obliterated.

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FAAL PARU

- Penurunan rasio volume ekspirasi paksa detik 1 (VEP1) terhadap kapasiti vital paksa (KVP) - Normal atau penurunan KVP - Penurunan VEP1

Penurunan KVP hambatan aliran udara mukus, atelektasis, pneumonitis paru

Merokok memperburuk faal paru gangguan obstruksi

Hiperesponsif jalan napas 40% pasien

CLINICAL CHARACTERISTICS AND SPIROMETRICVALUES OF PATIENTS WITH BRONCHIECTASIS AND

CONTROL SUBJECTS

Am J Respir Crit Care Med 2001

Lung function, Medical Research Council (MRC),five–point flow limitation (FL), high–resolution computed

tomography (HRCT) score and maximal power output (WRmax)in bronchiectatic patients colonised (PA) and not colonised

(non-PA) with Pseudomonas aeruginosa

Eur Respir J 2003 = significant

PENATALAKSANAAN

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ANTIBIOTIKA eksaserbasi akut

Mucociliary stimulants meningkatkan bersihan

MUKOLITIK kurang efektif

STEROID eksaserbasi akut, kontrofersi

BRONKODILATOR hiperesponsif jalan napas

PEMBEDAHAN

“Airway clearance therapy” pencegahan intervensi dini

PROGNOSIS

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Keistinen et al. (National Hospital Discharge Register) di Finland mengidentifikasi 842 pasien BE usia 35 – 74 tahun antara1982 s/d 1986 dan membandingkan dengan pasien asma dan PPOK

Selama 8.0–12.9 tahun hingga akhir 1993, jumlah pasien BE yang dirawat bervariasi (range, 1 – 51; rerata, 2.2)

239 kematian pasien BE (28%), 165 kematian pasien asma (20%) dan 319 kematian pasien PPOK (38%).

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References : 1. Angrill J, Agustí C, Torres A. Bronchiectasis. Curr Opinion Infect Dis 2001; 14: 193–7. 2. Barker AF. Bronchiectasis. N Eng J Med 2002; 346: 1383–93. 3. Tsang KWT, Zheng L, Tipoe G. Cilliary assessment in bronchiectasis. Respirologi 2000; 5: 91–8. 4. Angrill J, Agustì C, De Celis R, Filella X, Raňó A, Elena M, De La Bellacasa JP, Xaubet A, Torres A. Bronchial inflammation and colonization in patients with clinically stable bronchiectasis. Am J Respir Crit Care Med 2001; 164: 1628–32. 5. Koulouris NG, Retsou S, Kosmas E, Dimakou K, Malagari K, Mantzikopoulos G, Koutsoukou A, Milic-Emili J, Jordanoglou J. Tidal expiratory flow limitation, dyspnoea and exercise capacity in patients with bilateral bronchiectasis. Eur Respir J 2003; 21: 743–8. 6. Greenstone M. Changing paradigms in the diagnosis and management of bronchiectasis. Am J Respir Med 2002; 1: 339–47. 7. Braverman JM. Airway clearance indications in bronchiectasis: An overview. Advanced Respiratory.

IDIOPATHICPULMONARY FIBROSIS

( IPF )

PRASENOHADI

Department of Pulmonolgy and Respiratory MedicineFaculty of Medicine, University of Indonesia

Terbanyak pada “idiopathic interstitial pneumonias”

Tidak respons terhadap pengobatan

= “cryptogenic fibrosing alveolitis”= “chronic fibrosing interstitial pneumonia”

Penyebab tidak diketahui

IPF termasuk dalam “idiopathic interstitial pneumonias”

IDIOPATHIC PULMONARY FIBROSIS

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Prevalensi 1.5–1.8 per 10 000 orang pertahun

Insidens 0.5 per 10 000 orang pertahun

Prevalensi laki–laki : perempuan = 1.4:1.0

Insidens rasio laki–laki : perempuan = 1.3:1.0

Usia 40–70 tahun, kebanyakan diatas 60 tahun

Survival (setelah diagnosis) 3.2–5 tahun

EPIDEMIOLOGI

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ETIOLOGICigarette smokingSeveral occupational factors (farming, hairdressing,

stonecutting, and exposure to livestock, birds,and dust from metals and vegetables)

Viral proteins and antibodies (Epstein–Barr virus,influenza A virus, hepatitis C virus,parainfluenza viruses 1 and 3, HIV-1, herpesvirus 6)

Genetic predisposition to IPF Familial IPF autosomal dominant Inherited abnormalities in surfactant proteins interleukin-1 (IL-1) receptor antagonist, polymorphism of the tumour necrosis factor–α complement receptor 1

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PATOGENESIS (1)

Initial injury recruitment of inflammatory cells release of cytokines and eventually,

increased fibroblast activity,parenchymal remodelling and fibrosis.

Alveolar epithelial cells transforming growth factor–β1 (TGF–β1) platelet-derived growth factor (PDGF) tumour necrosis factor α (TNFα) interleukin–1 (IL–1) insulin–like growth factor 1 (IGF1) basic fibroblast growth factor (bFGF)

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Release of cytokines fibroblast proliferation migration to various sites in the lung differentiation of the fibroblast phenotype

First, differentiated cell to be more resistant to apoptosis (natural cell death) repair of tissue without excessive scarring

Second, the altered cells responsiveness tofibrogenic cytokines (TGF-beta, bFGF)

PATOGENESIS (2)

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Immunological pathogenesis of IPF

Type 2 T–cell response predominates,

Increase IL–4 and IL–13

Elevated circulating autoantibodies antinuclear antibodies, anti–DNA antibodies, anti–cytokeratin 8 antibodies immune complexes

PATOGENESIS (3)

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Classification ofIdiopathic Interstitial Pneumonias

GAMBARAN KLINIS Umumnya batuk dengan produksi sputum minimal

Sesak napas (dispnea) progresif dalam 3–4 bulan

Jari tabuh (clubbing finger)

Auskultasi ronki halus (tengah – akhir inspirasi)

Tekanan jantung kanan meningkat Gagal jantung kanan

Diagnostik :anamnesis, pemeriksaan fisis, radiologi,pemeriksaan faal paru, serologi, histopatologi

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• Unclear diagnosis• Age < 50 yr• Systemic complaints• Radiological features atypical of idiopathic

pulmonary fibrosis• Rapid progression of disease• Normal chest radiograph• Recurrent pneumothorax• Benefit of correct diagnosis outweighs the risk of

surgery• Detection of a fibrotic process related to an exposure

that may be important for compensation purposesfor the patient

Suggested Indications for Surgical Biopsyin Patients with Diffuse Interstitial Lung Disease

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Major criteria Exclusion of known causes of interstitial lung disease, such as drug toxicity, exposure to environmental respiratory hazards and the presence of connective tissue disease Evidence of restrictive lung disease such as reduced vital capacity, impaired gas exchange with an increased alveolar– arterial oxygen gradient, decrease in partial arterial pressure of O2 at rest or during exercise, decreased CO gas transfer High–resolution CT showing bibasilar reticulonodular opacities with minimal or no ground-glass appearance A transbronchial biopsy or bronchoalveolar lavage findings that would not support other diagnosis such as sarcoidosis, hypersensitivity pneumonitis, malignant disease, infection, cryptogenic organizing pneumonia or pulmonary alveolar proteinosis

Major and Minor Criteria for the Diagnosis of IPF in the Absence of a Surgical Lung Biopsy (1)

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Major and Minor Criteria for the Diagnosis of IPF in the Absence of a Surgical Lung Biopsy (2)

Minor criteria Age > 50 yr Insidious onset of dyspnea with no discernible cause Duration of symptoms > 3 mo Bilateral inspiratory crackles

Diagnosis requires : all 4 major criteria 3 of the 4 minor criteria

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HISTOPATOLOGI

Bagian paru yang dipisahkan lung saat otopsi pasien denganIPF menunjukkan kista sarang tawon(honeycomb cysts)

HISTOPATOLOGI

Tampak gambaran kista sarang tawon

HISTOPATOLOGI

Potongan paru subpleural dan basal dengan kelainan IPF dansedikit kelainan di bagian sentral.

(1) pleura,(2) lokasi biopsi,(3) area sarang tawon,(4) bagian sentral yang hampir normal

HISTOPATOLOGI

Jaringan paru normal (N), fokus fibroblas (panah) dan

fibrosis interstisial ()

Fibrosis subpleura, kista sarang tawon, bronkiektasis (panah besar) danfibrosis paraseptal (panah kecil) dan perubahan minimal di paru tengah

Gambaran Radiologi IPF dengan high–resolution CT

Pharmacotherapy immunosuppressive agents

antifibrotic agents

Nonpharmacologic

PENATALAKSANAAN (1)

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Single/combined immunosuppressive agentCorticosteroids (standard therapy)

survival ?, side effects and complications

Prednisone (20 mg/d) Azathioprine (3 mg/kg daily, not to exceed 200 mg/d) stabilize lung function monitored for hepatotoxic effects, renal dysfunction and bone marrow suppression osteoporosis prevention with vitamin D and calcium supplementation and bisphosphonates

PENATALAKSANAAN (2)Terapi Imunosupresif

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PENATALAKSANAAN (3)Terapi Antifibrotik

Collagen synthesis (clinical trials) pirfenidone interferon gamma–1b interferon beta–1a colchicine penicillamine

SURVIVAL ?

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Examples of anti-inflammatory and antifibrotic agents as potential therapeutic options for the treatment of IPF

PENATALAKSANAAN (4)Nonpharmacological treatment

Fitness Good nutrition Oxygen supplementation

Lung transplantation improve survival single lung transplantation reduced

the risk of death by 75% comparedwith patients with IPF on the transplantwaiting list

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IPF adalah penyakit paru interstisial progresif yang tidak diketahui sebabnya dan sulit diobati

Pengobatan yang telah ada perlu dikombinasi dengan obat baru meskipun dalam tahap uji klinik

Pasien IPF membutuhkan penanganan secara klinik spesialistik dan kemungkinan untuk dilakukan transplantasi paru

KESIMPULAN

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