IDIOPATHIC PULMONARY FIBROSIS

Dr.AMITH SREEDHARANDept of Pulmonary MedicineSCB Medical College,Cuttack

INTERSTITIAL LUNG DISEASE

ILD OF KNOWN CAUSE IIP GRANULOMATOUS ILD OTHER FORMS

IPF IIP OTHER THAN IPF

DIP

RB ILD

COP

AIP

NSIP LIP

DEFINITION

• A specific form of chronic, progressive fibrosing interstitial pneumonia of unknown cause, occurring primarily in older adults, limited to the lungs, and associated with the histopathologic and/or radiologic pattern of UIP.

• Exclusion of other forms of interstitial pneumonia & ILD associated with environmental exposure, medication, or systemic disease.

• Characterized by progressive worsening of dyspnea and lung function .

• Associated with poor prognosis.

RISK FACTORS

• CIGARETTE SMOKING: > 20 Pack years• ENVIRONMENTAL EXPOSURE: metal dust,wood dust,farming,hair dressing,stone cutting,livestock exposure• MICROBIAL AGENTS: EBV,CMV,HHV 7,HHV 8• GER: microaspiration

GENETIC FACTORS

• FAMILIAL IPF: Less than 5%Autosomal dominant with variable penetranceChr 14 linkageSFT PA₂ mutation• SPORADIC IPF GENETICS:Polymorphism of genes encoding cytokines.

PATHOGENESIS- HYPOTHESIS

• PREVAILING:• INFLAMMATION LEADS TO FIBROSIS

• EVOLVING :• FIBROSIS RESULTS FROM EPITHELIAL INJURY

AND ABNORMAL WOUND HEALING• Inflammation does not play major role.

CLINICAL FEATURESSYMPTOMS• Adults – 6th & 7th decade.• Men > Women• Unexplained C/C EXERTIONAL DYSPNEA with DRY COUGH with H/O

Smoking• Constitutional symptoms• Fever rare.

SIGNS• CLUBBING 25 – 50%• CYANOSIS• PERIPHERAL EDEMA• CHEST AUSCULTATION: Dry end inspiratory “VELCRO” rales(80%

Pts),prevalent in LUNG BASES.• Accentuated pulmonic second sound,right ventricular heave.• Cor pulmonale

RADIOLOGY

CHEST RADIOGRAPH• Peripheral reticular opacities,mostly at lung

bases,usually bilateral & assymetric with decreased lung volumes.

• If clinical deterioration• To assess progression • To identify superimposed infection/malignancy

Diagnosis of IPF requires:

a. Exclusion of other known causes of interstitial lung disease (ILD) (e.g., domestic and occupational environmental exposures, connective tissue disease, and drug toxicity).b. The presence of a UIP pattern on high-resolution computed tomography (HRCT) in patients not subjected to surgical lung biopsy.c. Specific combinations of HRCT and surgical lung biopsy pattern in patients subjected to surgical lung biopsy

RADIOLOGY - HRCT

• Determine ACTIVITY of IPF.• Patchy predominantly peripheral,sub pleural,bibasilar

reticular abnormalities,with architectural distortion & honey combing,referred to as UIP PATTERN.

• Honey combing: Clustered cystic airspaces typically comparable diameters 3-10 mm.

• Traction bronchiectasis/bronchiolectasis (severe)• Variable amount of GROUND GLASS OPACITY.• 90% accuracy with UIP in HRCT.• Coexistant pleural abnormalities,micronodules,extensive

GGO,periBV distribution – alternative diagnosis.

HRCT CRITERIA FOR UIP PATTERN

LUNG BIOPSY

• Should be obtained from more than one lobe• VATS/OPEN THORACOTOMY?• Diagnostic yield similar• VATS – low morbidity & length of stay• Decided based on individual patients

HISTOPATHOLOGICAL CRITERIA FOR UIP

COMBINATION OF HRCT & HP FOR DIAGNOSIS OF IPF

PULMONARY FUNCTION TESTING

• TLC,FRC,RV reduced.• Pressure volume curve downward & right –

stiff,non compliant Lung.• FEV₁,FVC often reduced,FEV₁/FVC ratio N or ↑• Body plethysmography: ↓VC, ↓TLC• DLCO REDUCED,decline precede lung volume ↓• ABG : normal/Hypoxemia,Resp.Alkalosis.• VD/VT ratio ↑ at rest,decrease with EXERCISE.

BAL

• Exclusion of CHP (lym >40%)

• ↑Neutrophils 70-90% patients• ↑Eosinophils 40-60% patients• ↑Lymphocytes 10-20% patients

Should BAL cellular analysis be performed in suspected IPF?

• Exclusion of CHP• 8% Pts with HRCT- UIP have BAL S/O

alternative diagnosis• Recommendation(weak): BAL cellular analysis

should not be performed in diagnostic evaluation in majority Pts.

Should Transbronchial lung biopsy be used ?

• Useful in evaluation of granulomatous disorders (Sarcoidosis)

• Recommendation(weak) : should not be used in majority

Serologic testing for CTD be used?

• No reliable data• CTD can present with UIP pattern• Recommendation(weak) : should be

performed in majority of Pts.• Even in the absence of signs/symptoms of

CTD.• RF,anti CCP,ANA

Should mutidisciplinary discussion be used?

• By definition,diagnosis of IPF is multidisciplinary.• pulmonologist,radiologist,pathologist• Recommendation: MDD should be used in

majority.

SERUM & BAL MARKERS

• Largely unavailable for routine clinical use• KL-6,produced by regenerating type II

pneumocytes,elevated in IPF pts• Surfactant protein A & D elevated in serum• BAL SP-A predict survival• Serum CCL18• Serum BNP related to mortality• MMP1 & MMP7 elevated,MMP7 related to disease severity• Presence of circulating FIBROCYTES a/w worse short term

survival

NATURAL HISTORY

ACUTE EXACERBATION

• Acute respiratory worsening in 5-10%.• When cause cannot be identified.• Data do not suggest infectious etiology.• Unexplained worsening of DYSPNEA within 1

month,evidence of HYPOXEMIA or impaired GAS EXCHANGE,new radiographic alveolar infiltrates with Pneumonia,PNX,PE,HF ruled out.

• No known risk factors• ↑ after BAL,thoarcic surgery• Histology: acute/organising DAD

VITAL STATISTICS

• US – 61/1000000 men,54/1000000 women• Japan – 33/1000000 men,24/1000000 women• Mortality burden higher than CANCERS• M/C CAUSE: progressive lung disease-60%• Others: CAD,PE,LUNG CA

STAGING & PROGNOSIS• Identifying patients with increased risk of mortality within 2 years to

consider LUNG TRANSPLANTATION• Presence of one or more – Advanced/End stage Baseline factors• Level of dyspnea• DLCO <40% predicted• Desaturation < 88% during 6MWT• Extent of honeycombing on HRCT• Pulmonary hypertension Longitudinal factors• Increase in level of dyspnea • Decrease in Forced Vital Capacity by > 10% absolute value• Decrease in DLCO by > 15% absolute value• Worsening of fibrosis on HRCT

BACK

Should IPF be treated with CS monotherapy?

• No RCT conducted,no survival benefit in retrospective studies.

• Recommendation(strong): CS monotherapy should not be used

• High value on treatment related morbidity

Should COLCHICINE be used?

• Inhibit fibroblast proliferation,collagen synthesis

• Prospective clinical trials without any benefit• Recommendation(strong): should not be used• Low quality evidence

Should CYCLOSPORIN A be used?

• Recent studies shows no benefit• Recommendation(strong): not to be used• Prevention of side effects & cost

Combination CS & Immunomodulator?(azathioprine/cyclophosphamide)

• Recent studies shows no survival benefit.• Recommendation(strong): should not be

treated with CS/Immunomodulator• Preventing treatment related morbidity

CS/AZATHIOPRINE/NAC triple therapy?

• No observed difference in mortality• Recommendation(weak): TRIPLE therapy

shouldn’t be used in majority.• Treatment related morbidity

Acetyl cysteine monotherapy?

• Recent studies show significantly smaller decline in pulmonary function.

• Recommendation (weak): should not be used in majority

• Potential cost,low quality data,absence of ‘’no therapy’’ arm in study

• More data needed…

IFN-γ1b?

• Antifibrotic and immunomodulator• Studies: no difference in mortality• Recommendation(strong): should not be used

BOSENTAN?

• Dual endothelin receptor (A & B) antagonist• Elevated endothelin in serum & BAL in IPF pts• Studies : ongoing..• Recommendation(strong):should not be used• Potential risk,high cost

ETANERCEPT?

• Recombinant soluble human TNF,binds to TNF receptor & neutralises its activity.

• Studies:no significant trends• Recommendation(strong): should not be used • Potential risk,cost.

Anticoagulants?

• JAPANESE trial: compared oral CS+WARFARIN to CS alone,survival benefit demonstrated

• Low quality study• Recommendation(weak):should not be used in

majority,but reasonable in minority.• Potential risk,low quality data

PIRFENIDONE?

• Antiinflammatory,antifibrotic,antioxidant properties,with TGF-β antagonism.

• JAPANESE trials: RCT significant reduction in decline of VC.

• US trials: favoured PIRFENIDONE over placebo• ADR:significant GI

disturbances,↑LFT,Photosensitivity,rash• Recommendation(weak):should not be used• Side effects,cost

Therapies without recommendations

• SILDENAFIL:No significant difference in endpoint

• IMATINIB(tk inhibitor against PDGF):no meaningful difference in secondary endpoints

Non pharmacological therapies

LONG TERM OXYGEN THERAPY(LTOT)Studies: clear survival benefitRecommendation(STRONG): Pts with significant resting Hypoxemia should be treated with LTOT

LUNG TRANSPLANTATION

• 5 year survival benefit after lung transplantation : 50-56%

• No data to guide precise timing• Recommendation(strong):appropriate Pts

should undergo LUNG TRANSPLANTATION

MV in IPF pts with respiratory failure

• Studies: high hospital mortality rate (96%)• The only survivor in one study underwent lung

transplantation 6 hours after intubation• Recommendation(weak): should not receive

MV,but reasonable choice in a minority of Pts• High mortality rate to be explained to

Pts,caregivers ahead of time• NIPV appropriate in some Pts• Can be used as a BRIDGE to lung transplantation

Pulmonary rehabilitation?

• Aerobic conditioning,strength & flexibility training,nutritional interventions,psychosocial support

• Studies: improvement in walk distance and QOL

• Recommendation(weak):majority should be treated with Pulmonary rehabilitation

Treatment of selected complications & comorbid conditions

• Acute exacerbation• Pulmonary hypertension• Gastroesophageal reflux disease• Obesity• Emphysema• Obstructive sleep apnea• No data to make recommendations for

obesity,emphysema,OSA treatment in IPF setting

Acute exacerbation & CS?

• High dose CS commonly prescribed• No controlled trials to judge efficacy• Recommendation(weak):majority of Pts(Ex)

should be treated with CS.• Specific recommendations regarding

DOSE,ROUTE,DURATION not made• IV CS upto 1 gram/day reported beneficial

PH & IPF

• Mean PAP >25 mmHg on right heart catheterisation

• Recommendation(weak): PH should not be treated in majority of Pts

• Cost & drug related morbidity• Moderate to severe PH(>35 mmHg),trial of

vasomodulatory therapy indicated.• IV EPOPROSTENOL,ORAL BOSENTAN,SILDENAFIL

improved pulmonary hemodynamics

Asymptomatic GER be medically treated?

• Abnormal GER highly prevalent in IPF• 50% asymptomatic• Aspiration risk,pneumonitis• Recommendation(weak): should be medically

treated in majority• Recommendation does not extend to

fundoplication.

PALLIATIVE CARE

• Psychological & spiritual support• COUGH- CS & Thalidomide• Opioids – for severe dyspnea & cough

MONITORING CLINICAL COURSE

• Progressive disease• Worsening symptoms• Worsening oxygenation• Complications & comorbidities

Monitoring for progressive disease

Any of the following changes consistent with progressive disease:Progressive dyspnea (objectively assessed)Progressive, sustained decrease from baseline in

absolute FVCProgressive, sustained decrease from baseline in

absolute DLCO (corrected for hemoglobin)Progression of fibrosis from baseline on HRCTAcute exacerbationDeath from respiratory failure

Monitoring for worsening symptoms

• Eg: Dyspnea worsening has important management implications

• Dyspnea scoring (california university SOB questionaire)

• Assessment of oxygenation• Detection of 2⁰ complications (DVT,PE)

Monitoring for worsening oxygenation

• Pulse oximetry @ rest & exertion• Desaturation below 88% during 6MWT require

supplemental oxygen• Should be performed at baseline and 3-6 month

intervals.• Absolute FVC change of 10%• Absolute DLCO change of 15% surrogate marker of

mortality & disease progression• Others:TLC,P(A-a)02

Monitoring complications & comorbidities

• PH,PE,LUNG CA,CAD• PH – consider lung transplantation• Echocardiography inaccurate in estimating

pulmonary hemodynamics in fibrotic lung disease

• Right heart catheterisation preferred• BNP correlate with mod to severe PH

TREATMENT ASSESMENT PLAN

CONCLUSION

• A specific form of chronic, progressive fibrosing interstitial pneumonia of unknown cause, occurring primarily in older adults, limited to the lungs, and associated with the histopathologic and/or radiologic pattern of UIP.

• The accuracy of the diagnosis of IPF increases with multidisciplinary discussion between pulmonologists, radiologists, and pathologists experienced in the diagnosis of ILD.

• IPF is a fatal lung disease; the natural history is variable and unpredictable:

a. Most patients with IPF demonstrate a gradual worsening of lung function over years; a minority of patients remains stable or declines rapidly.b. Some patients may experience episodes of acute respiratory worsening despite previous stability.

• sub-clinical or overt comorbid conditions pulmonary hypertension,gastroesophageal reflux, obstructive sleep apnea, obesity, and emphysema.

• The impact of these conditions on the outcome of patients with IPF is unclear

• The recommendation against the use of the following agents for the treatment of IPF is strong:

• CS MONOTHERAPY• COLCHICINE• CYCLOSPORIN A• COMBINED CS & IMMUNOMODULATOR• IFN γ 1b• BOSENTAN• ETANERCEPT

• Following therapies may be a reasonable choice in a minority:

• Combined ACETYL CYSTEINE,AZATHIOPRINE,PREDNISONE

• PIRFENIDONE• ACETYLCYSTEINE MONOTHERAPY• ANTICOAGULANTS

• Long-term oxygen therapy recommended in patients with IPF

• The recommendation for lung transplantation in appropriate patients with IPF is strong.

• Mechanical ventilation should not be used in the majority of patients with IPF.

• Pulmonary rehabilitation should be used in the majority of patients with IPF.

• Corticosteroids should be used in the majority of patients with acute exacerbation of IPF.

• Pulmonary hypertension should not be treated in the majority of patients with IPF.

• Asymptomatic gastroesophageal reflux should be treated in the majority of patients with IPF.

SUMMARY

IPF

INCREASED RISKLUNG TRANSPLANTATION

NON PHARMACOLOGICALO₂ SUPPLEMENTATION

PULMONARY REHABILITATION

PHARMACOLOGICAL

COMORBIDITIESPH

GER

DISEASE PROGRESSIONMONITOR 3-6 MONTHS

ACUTE EXACERBATIONCS

RESPIRATORY FAILURE

LUNG TRANSP LANTAT I ONTIME

THANK YOU