IDIOPATHIC PULMONARY FIBROSIS Dr.AMITH SREEDHARAN Dept of Pulmonary Medicine SCB Medical College,Cuttack
INTERSTITIAL LUNG DISEASEILD OF KNOWN IIP GRANULOMATOUS ILD OTHER FORMS CAUSE IPF IIP OTHER THAN IPF AIP RB ILD NSIP LIP DIP COP
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.
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
RADIOLOGYCHEST 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 IPFrequires:a. Exclusion of other known causes of interstitial lungdisease (ILD) (e.g., domestic and occupationalenvironmental exposures, connective tissue disease,and drug toxicity).b. The presence of a UIP pattern on high-resolutioncomputed tomography (HRCT) in patients notsubjected to surgical lung biopsy.c. Specific combinations of HRCT and surgicallung biopsy pattern in patients subjected to surgicallung 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.
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.
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
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 significantresting 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 for progressive diseaseAny of the following changes consistent withprogressive disease: Progressive dyspnea (objectively assessed) Progressive, sustained decrease from baseline in absolute FVC Progressive, sustained decrease from baseline in absolute DLCO (corrected for hemoglobin) Progression of fibrosis from baseline on HRCT Acute exacerbation Death 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
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 gradualworsening of lung function over years; a minorityof patients remains stable or declines rapidly.b. Some patients may experience episodes of acuterespiratory 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 L U INCREASED RISK N LUNG TRANSPLANTATION G DISEASE PROGRESSION MONITOR 3-6 MONTHS T R NON PHARMACOLOGICAL AIPF O₂ SUPPLEMENTATION N PULMONARY REHABILITATION S ACUTE EXACERBATION P CS L PHARMACOLOGICAL A N COMORBIDITIES RESPIRATORY T PH FAILURE A GER T I O TIME N