1. INTERSTITIAL PULMONARY FIBROSIS
By: Dr.Bidhi Chand
Junior Resident Pulmonary Medicine

2. INTERSTITIAL PULMONARY FIBROSIS
ATS Definition
Interstitial Pulmonary Fibrosis is defined as a specific form of chronic fibrosing interstitial pneumonia of unknown causes, limited to the lungs and associated with a histologic pattern of usual interstitial pneumonia (UIP).

3. EPIDEMIOLOGY
Estimated to affect approximated 5 million people world wide.
The most common (and deadly) interstitial lung disease.
Most cases are sporadic, but rare cases of familial IPF have been described.
15 % of pulmonary physician’s practice.
Mortality from IPF continues to increase in many countries.
Earlier, considered to be rare in India.
In 1979, Jindal et al published 65 cases of DPLD seen over a period of 5 years. Recently the same center published data on 76 patients with IPF diagnosed over a 16 months period- increase in frequency of diagnosis.
Increase in number of studies in India due to increase in incidence or due to availability of better diagnostic facilities like HRCT and fibreoptic bronchoscopy.

4. RISK FACTOR OF IPF
Cigarette smoking.
Environmental Exposure – metal dust, wood dust, solvents associated with increased risk of developing pulmonary fibrosis.
Viruses (EBV, influenza, CMV, HCV), chronic aspiration secondary to GERD.
Hereditary factors do contribute but no specific genetic marker has been identified.
Familial IPF – autosomal dominant – variable penetrance.

5. PATHOLOGY
Interstitial pneumonia classified by Hamman and Rich followed by Liebow.
Pathological Classification
Usual interstitial pneumonia.
Desquamative interstitial pneumonia.
Respiratory Bronchiolitis Interstitial Lung Diseases.
Acute Interstitial pneumonia (Hamman-Rich Disease)
Non-specific Interstitial pneumonia.

6. PATHOLOGY (Contd.)
Pathological changes characterized by UIP – distinguished by variation in location and age of lesions, with predilection for peripheral subpleural parenchyma.
Fibrotic zones with associated honey-combing alternate with areas of relatively unaffected Lung tissue. Fibrotic areas vary in age and activity.

7. Multiple Hypotheses for the Pathogenesis of IPF
Inflammation causes fibrosis
Noninflammatory (multiple hit) hypothesis: fibrosis results from epithelial injury and abnormal wound healing in the absence of chronic inflammation
Vascular remodeling: aberrant vascular remodeling supports fibrosis, and may contribute to increased shunt and hypoxemia
Multiple Hypotheses for the Pathogenesis of IPF
The exact mechanisms underlying the development of IPF remain unknown. While no theory of disease pathogenesis has been proven, several hypotheses have been proposed and are currently being studied. This slide provides a summary of 3 prevailing hypotheses for the pathogenesis of IPF.
Noble PW, Homer RJ. Idiopathic pulmonary fibrosis: new insights into pathogenesis. Clin Chest Med. 2004;25: , vii.
Raghu G, Chang J. Idiopathic pulmonary fibrosis:current trends in management Clin Chest Med. 2004;25: , v.
Strieter RM, Belperio JA, Keane MP. CXC chemokines in vascular remodeling related to pulmonary fibrosis. Am J Respir Cell Mol Biol. 2003;29(3 suppl):S67-S69.

8. Inflammatory Hypothesis
Inflammation causes fibrosis
Inflammatory concept was dominant in the 1970s and 1980s
IPF resulted from unremitting inflammatory response to injury culminating in progressive fibrosis
Role of inflammation remains controversial
Lack of efficacy of corticosteroids
Inflammatory Hypothesis
In the 1970s and 1980s, the dominant hypothesis regarding IPF pathogenesis held that IPF resulted from an unremitting inflammatory response to injury culminating in progressive fibrosis. At that time, many patients with diseases that we now recognize as distinct clinical entities other than IPF were lumped under the diagnosis of IPF. As we have learned more about IPF and improved our ability to diagnose IPF, the role of inflammation and the efficacy of corticosteroids in the treatment of IPF have become increasingly questionable.
Noble PW, Homer RJ. Idiopathic pulmonary fibrosis: new insights into pathogenesis. Clin Chest Med. 2004;25: , vii.
Raghu G, Chang J. Idiopathic pulmonary fibrosis: current trends in management. Clin Chest Med. 2004;25: , v.
Injury
Inflammation
Fibrosis

9. Progression of Lung Fibrosis
Injury
Epithelial cells ?
Endothelial
cells
Capillary
Progression of Lung Fibrosis
While the etiology of IPF remains unknown, several recent observations have led to a theory that IPF is the result of an aberrant wound healing process.
According to this theory, injury to the alveolar epithelial and capillary wall lining stimulates the release of molecules that damage the basement membrane. In the absence of an appropriate substrate, re-epithelialization and re-endothelialization cannot occur. In an attempt to “wall off” the exposed area, chemokines and growth factors recruit fibroblasts and endothelial cells. Recruited fibroblasts/myofibroblasts are then stimulated to produce collagen and other matrix components.
Slide courtesy of Paul Noble, MD.

10. Tissue Model of Lung Fibrosis
Cell death
Epithelial cells
Endothelial
cells
Growth factors and other
products of epithelial
cell Injury
Capillary
Myofibroblast
Tissue Model of Lung Fibrosis
Specifically, injury to the alveolar-capillary walls leads to tissue damage and cell death. This cell death is accompanied by damage to the basement membrane and the release of a variety of factors, including growth factors and cytokines. Many of these factors stimulate fibroblasts/myofibroblasts to produce extracellular matrix components (particularly collagen), and can lead to dysregulated repair of the epithelial/endothelial barrier. In the end, the formation of fibrotic regions of extracellular matrix proteins and myofibroblasts impedes the recovery of the normal alveolar wall.
Slide courtesy of Paul Noble, MD.
Collagen

11. Non inflammatory (multiple hit) Hypothesis
Fibrosis results from epithelial/endothelial injury and abnormal wound healing in the absence of chronic inflammation
Recurrent, unknown injury to distal pulmonary parenchyma causes repeated epithelial cell injury and apoptosis
Loss of alveolar epithelium exposes basement membrane to oxidative injury and degradation
Failure of re-epithelialization/re-endothelialization provides stimulus for persistent profibrotic growth factor production, persistent fibroblast proliferation, excessive deposition of ECM, and progressive fibrosis
Noninflammatory (multiple hit) Hypothesis
The model of aberrant wound healing described on the previous 2 slides forms the basis for the second prevailing hypothesis of the pathogenesis of IPF. This hypothesis postulates that pulmonary fibrosis results from epithelial injury and abnormal wound repair in the absence of inflammation. Initial injury to the distal pulmonary parenchyma causes repeated injury to the epithelium and endothelium, and epithelial and endothelial apoptosis. The loss of the alveolar epithelium and endothelium exposes the basement membrane to oxidative injury and degradation. Failure of re-epithelialization and re-endothelialization provides the stimulus for persistent production of profibrotic growth factors, persistent fibroblast proliferation, excessive ECM deposition, and progressive fibrosis.
Noble PW, Homer RJ. Idiopathic pulmonary fibrosis: new insights into pathogenesis. Clin Chest Med. 2004;25: , vii.
Raghu G, Chang J. Idiopathic pulmonary fibrosis: current trends in management. Clin Chest Med. 2004;25: , v.
Selman M, Thannickal VJ, Pardo A, Zisman DA, Martinez FJ, Lynch JI 3rd. Idiopathic pulmonary fibrosis: pathogenesis and therapeutic approaches. Drugs. 2004;64:

12. Noninflammatory (multiple hit) Hypothesis
Recurrent pulmonary injury
Epithelial/
endothelial injury and apoptosis
TGF-b = transforming growth factor-beta
PDGF = platelet derived growth factor
IGF-1 = insulin-like growth factor-1
Loss of basement membrane
Failure of re-epithelialization/ re-endothelialization
Release of profibrotic growth factors (TGF-b, PDGF, IGF-1)
Noninflammatory (multiple hit) Hypothesis
This is a simple schematic representation of the non-inflammatory (multiple hit) hypothesis discussed on the previous slide.
Recurrent pulmonary injury leads to epithelial cell injury and apoptosis, resulting in loss of the basement membrane integrity, and ultimately leading to failure of re-epithelialization and re-endothelialization. This process stimulates the release of profibrotic growth factors including TGF-, PDGF, and IGF-1, as well as proliferation of fibroblasts and excessive deposition of extracellular matrix components. These events ultimately lead to progressive fibrosis with the loss of lung architecture.
Noble PW, Homer RJ. Idiopathic pulmonary fibrosis: new insights into pathogenesis. Clin Chest Med. 2004;25: , vii.
Raghu G, Chang J. Idiopathic pulmonary fibrosis: current trends in management. Clin Chest Med. 2004;25: , v.
Selman M, Thannickal VJ, Pardo A, Zisman DA, Martinez FJ, Lynch JP 3rd. Idiopathic pulmonary fibrosis: pathogenesis and therapeutic approaches. Drugs. 2004;64:
Fibroblast proliferation
ECM deposition
Progressive fibrosis with loss of lung architecture

13. Vascular Remodeling Hypothesis
Aberrant vascular remodeling supports fibrosis and may contribute to increased shunt and hypoxemia
Increased angiogenesis results from imbalance of pro-angiogenic chemokines (IL-8, ENA-78) and anti-angiogenic, IFN-inducible chemokines (IP-10)
Vascular remodeling leads to anastomoses between the systemic/pulmonary microvasculature, increasing right-to-left shunt, contributing to hypoxemia
Vascular Remodeling Hypothesis
The presence of aberrant vascular remodeling in IPF was originally identified in the 1960s. Early studies demonstrated neovascularization in areas of fibrosis and anastomoses between the systemic and pulmonary microvasculature. These findings underlie the vascular remodeling hypothesis of IPF pathogenesis. The hypothesis postulates that vascular remodeling in areas of fibrosis may support fibroplasia and that development of anastomoses between the systemic and pulmonary microvasculature may contribute to increased right-to-left shunt and hypoxemia in IPF patients upon exertion or in conjunction with secondary pulmonary hypertension.
A fundamental component of this hypothesis is the idea that angiogenesis, which leads to aberrant vascular remodeling, is the result of an imbalance between pro-angiogenic chemokines (IL-8, ENA-78) and angiostatic, IFN-inducible chemokines (IP-10, MIG, ITAC) that favor augmented angiogenic activity.
In animal models, expression of an angiogenic chemokine and the angiostatic chemokine, IP-10 and ITAC, directly and inversely, respectively, correlate with the extent of fibrosis during bleomycin-induced pulmonary fibrosis.
Noble PW, Homer RJ. Idiopathic pulmonary fibrosis: new insights into pathogenesis. Clin Chest Med. 2004;25: , vii.
Strieter RM, Belperio JA, Keane MP. CXC Chemokines in vascular remodeling related to pulmonary fibrosis. Am J Respir Cell Mol Biol. 2003;29(3 suppl):S67-S69.
Fibrosis
Chemokine imbalance
Increased angiogenesis
Aberrant
vascular
remodeling

14. Defects in Host Defense Mechanisms May Contribute to Fibrosis
Defects in endogenous host defense mechanisms (eg, IFN-g, PGE2 production) that limit fibrosis after acute lung injury may contribute to progressive fibrosis
Defects in Host Defense Mechanisms May Contribute to Fibrosis
The temporal heterogeneity of fibrotic lesions in IPF suggests that host factors that limit the extent of fibrosis after lung injury may be an important component of disease pathogenesis. It is suggested that a failure of sufficient antifibrotic responses to injury, such as deficiencies in IFN- or prostaglandin E2, may contribute to disease progression. Therefore, augmentation of host defense mechanisms may be a novel approach to therapy for IPF.
Noble PW, Homer RJ. Idiopathic pulmonary fibrosis: new insights into pathogenesis. Clin Chest Med. 2004;25: , vii.

15. American Thoracic Society (ATS)
Diagnostic Criteria (IPF)
According to ATS, in immunocompetent adult, the presence of all of the major diagnostic criteria as well as at least 3-4 minor criteria increase the likelihood of correct diagnosis of IPF.

16. American Thoracic Society (ATS)
Major Criteria
Exclusion of other known causes of ILD such as certain drug toxicities, environmental exposures and connective tissue disorders.
Abnormal pulmonary function studies that include restriction (reduced VC, increase FEV1 / FVC ratio) and impaired gas exchange.
Bibasilar reticular abnormalities with minimal ground glass opacities on HRCT scan.
Transbronchial Lung biopsy or BAL showing no feature to support alternative diagnosis.

17. Minor Criteria
Age > 50 years.
Insidious onset of otherwise unexplained dyspnoea on exertion.
Duration of illness more or equal to 3 months.
Bibasilar, inspiratory crackles (dry/velcro type in quality)

18. CLINICAL PRESENTATION
Middle age
Progressive dyspnoea on exertion.
Non-productive cough.
Most have symptoms for month prior to definitive evaluation.
Constitutional symptoms are uncommon.
Weight loss, fever, fatigue, myalgias, or arthralgias occasionally present.

19. PHYSICAL EXAMINATION
Bibasilar late inspiratory fine crackles (velcro rales).
Tachypnea.
Clubbing 40-70% late in disease course.
Cardiac examination normal until middle-late stages – augmental P2, Right sided heave, S3 gallop.
Cyanosis

20. Diagnosis of Pulmonary Fibrosis
Investigation:
FBC show mild anemia.
ESR and C-reactive protein may be raised.
Autoantibodies including antinuclear antibodies, RA factors.
Arterial blood gases – Oxygen desaturation is common.
Lung Function Test :
Shows Restrictive Pattern (But obstructive of airway may also be present)
Reduced total lung capacity.
Reduced residual capacity.
Reduced residual volume.
Reduced gas transfer.

21. X-ray Chest
Bilateral basal symmetrical peripheral reticular opacities with decreased lung volumes.
Volume loss evident by diaphragmatic elevation and depression of fissures.
Progressive fibrosis ultimately leads to cystic dilatation of distal air spaces, which is visible as peripheral honey combing.
Alternative diagnosis/ super-imposed complicated illness should be suspected if X-ray shows bronchogram, confluent shadows or hilar adenopathy.
Most of patient with IPF have abnormalities on X-ray. Rarely patients can have a normal X-ray, but have evidence of IPF either in HRCT or surgical lung biopsy.

22. HRCT
Patchy, predominantly peripheral, sub-pleural, bibasilar reticular abnormalities and area of traction bronchiectasis with limited amount of ground glass opacity.
The areas of severe involvement show sub-pleural honeycombing.
When certain diagnosis is not able to made by HRCT then a lung biopsy is needed for diagnosis.

23. This 50-year-old man presented with end-stage lung fibrosis
PA chest radiograph shows medium to coarse reticular
B: CT scan shows multiple small cysts (honeycombing) involving predominantly the subpleural peripheral regions of lung. Traction bronchiectasis, another sign of end-stage lung fibrosis.

24. Classic idiopathic pulmonary fibrosis in 70-year-old man
Classic idiopathic pulmonary fibrosis in 70-year-old man. High-resolution CT shows bilateral subpleural reticulation, traction bronchiectasis (curved arrow), and honeycombing (straight arrows).

25. 42-year-old woman with biopsy-proven idiopathic pulmonary fibrosis
42-year-old woman with biopsy-proven idiopathic pulmonary fibrosis. High-resolution CT shows patchy bilateral ground-glass opacities and mild predominantly subpleural reticulation.

26. 57-year-old man with biopsy-proven idiopathic pulmonary fibrosis
57-year-old man with biopsy-proven idiopathic pulmonary fibrosis. High-resolution CT (HRCT) shows patchy bilateral areas of ground-glass opacity. Fine reticulation is observed in subpleural regions.

27. BRONCHOALVEOLAR LAVAGE
Increase in Polymorphonuclear leucocytes, neutrophil products, eosinophils, activated alveolar macrophage, alveolar macrophages products, cytokines, growth factors.
BAL-useful research tool but its diagnostic usefulness is limited.
Increase in neutrophils/ eosinophils in BAL fluid – worse prgonosis.
BAL lymphocytosis – less honey combing and greater responsiveness to treatment.

28. TBLB (Transbronchial Lung Biopsy)
Not helpful in making a diagnosis of IPF as limited Lung tissue is obtained. But can exclude by identifying an alternative specific diagnosis.

29. Surgical Lung Biopsy
By open or video assisted thoracoscopic methods – gold standard for diagnosis of IPF. Large piece of Lung parenchyma is required, optimally from several sites.

30. USUAL INTERSTITIAL PNEUMONIA PATTERN
2 fibroblastic foci adjacent to dense fibrosis
Arrows – dense subpleural fibrosis with collapse of alveoli
Dense scarring by areas of normal lung – characteristic of IPF
Note no necrosis or substantial inflammation
Mason: Murray & Nadel's Textbook of Respiratory Medicine, 4th ed.
Idiopathic Pulmonary Fibrosis, Gross and Huninghake, NEJM, 2001.

31. HONEYCOMB PATTERN

32. COMPLICATIONS OF IPF
Interstitial lung disease can lead to series of life-threatening complications, including :-
Pulmonary Hypertension
Unlike systemic high Blood Pressure, this condition affects only the artries in Lungs. It begins when scar tissue retricts the smaller blood vessels, limiting blood flow in Lungs. This in turn raises pressure within the Pulmonary arteries. Pulmonary hypertension is a serious illness that becomes progressively worse.
Cont…..

33. Right sided heart failure (cor-pulmonale) : This is serious condition occur when heart’s lower chamber (right ventricle) : which is less muscular than the left- has to pump harder than usual to move blood through obstructed pulmonary arteries Eventually the right ventricle fails from the extra strain.
Respiratory failure : In the end stage of chronic interstitial lung disease, respiratory failure occurs when severely low blood oxygen levels along with rising pressure in the pulmonary arteries and right ventricle causes heart failure.

34. The Course of IPF
Although the course of idiopathic pulmonary fibrosis varies greatly from person to person, the disease usually develops slowly, sometimes over years.
The early stages are marked by alveolitis, an inflammation of the air sacs called alveoli, in the lungs. The job of the air sacs is to allow the transfer of O2 from Lungs into the blood and elimination of CO2 from Lungs and out of the body.
Contd…

35. As IPF progresses, the alveoli become damaged and scarred, the stiffening of the lungs, makes breathing difficult and bring on a feeling of breathlessness, especially during activities that require extra effort.
In addition, scarring of the alveoli reduces the ability of lungs to transfer oxygen. The resulting lack of O2 in to the blood (hypoxemia) may cause increase in the blood vessels of the lungs, a situation known as pulmonary hypertension. The high blood pressure in the lungs then puts a strain on right ventricle the lower right side of the heart, which pumps the oxygen – poor blood into the lungs.

36. TREATMENT AND DRUGS Cont…..
The Lung Scarring that occurs in pulmonary fibrosis cannot be reversed, and no current treatment has proved effective in stopping the ultimate progression of the disease. Some treatments, may improve symptoms temporarily or slow the disease’s progress. Other improve quality of life.
Cont…..

37. Specific Treatment Options are:
Medications
Oxygen Therapy
Pulmonary Rehabilitation
Lung Transplantation
Cont…..

38. Cont….. Medications : Corticosteroids
Immunosupressant/ Cytotoxic agents
Antifibrotic agents in along or combination
Anti-oxidant agents
Cont…..

39. Cont….. Corticosteroids:
The main stay of treatment for idiopathic pulmonary fibrosis is medication that help to reduce inflammation. Inflammation is thought to play a role in the injury and fibrosis of Lung tissue. So corticosteroids that stop the inflammation are thought to have an effect on the resulting damage.
Despite their widespread use only 10-30% of pateint with IPF improve on quantitative assessment when treated with corticosteroids.
Cont…..

40. If response is to occur, it is usually noted with three months.
Prolonged treatment for a minimum of 1-2 years and sometimes indefinitely is reasonable for patient exhibiting unequivocal response to therapy.
High dose IV pulse methylprednisolone has no proven advantage over oral corticosteriods.
Now, treatment with steroid alone is considered in appropriate, corticosteroids, should be used in conjuction with cytotoxic agents.
Favorable response to combination is seen in 15-50% of cases.
Cont…..

41. CYTOTOXIC / IMMUNOSUPPRESSANT
Azothioprine
Cyclophosphamide
Azothioprine : is a medicine that effects the immune system. Because it can cause serious side effects, it may be prescribed with corticosteroids – is associated with improvement and enhanced survival in some patient.
Cyclophosphamide : High dose IV administered every 2-4 weeks ( mg) – tried in open trial result were un-impressive. A recent study suggested that combined corticosteroid and cyclophosphamide therapy has no impact on the survival of patient with IPF.

42. AGENTS THAT AFFECT COLLAGEN SYNTHESIS OR FIBROSIS
Colchicine
D-Pencillamine
Interferon Gamma
Pirfenidone
Interferon gamma : inhibits proliferation of lung fibroblasts in dose dependent manner and a reduce protein synthesis in fibroblasts.
- In an open randomized study with 18 patients who had not respondend to glucocorticoids and other immunosupressive agents – 200mg interferon gamma 1b , 3 times/wk for 12 month along with predinsolone resulted in improvement in TLC and partial pressure of O2.
Cont…..

43. Subsequent studies dampened hopes, when Honore et al reported 4 cases of IPF who developed irreversible respiratory failure following treatment with Interferon Gamma.
Increased level of IL-18 in induced sputum of patient with IPF have been found to decrease after treatment with interferon gamma.
A recent meta analysis showed interferon therapy – reduced mortality.

44. Pirfenidone – Anti Fibrotic Agents
A larged well controlled multinational clinical trial programme has been demonstrated the effectiveness and safety of pirfenidone in the treatment of IPF. Study present in American Thoracic Society International Conference, Tronoto. Daily consumption of pirfenidone can slow down the progression of IPF by improving the lung capacity. Study conducted on 275 patient by Takashi Ogura in Japanese patients with mild-moderate IPF patient was randomly divided into three groups were administered 1800mg/ day (High dose) or 1200mg/day (low dose) of pirfenidone or placebo for 52 weeks.
Cont…..

45. Then vital capacity assessed at week 52, the researchers found that the loss of vital capacity in high dose regimen group was significantly lower when compared with the low dose regime and with the placebo group.
The rate of deterioration IPF was reduced in patients taking pirfenidone. The drug was relatively well tolerated. The only side effect of the drug to be noticed was photosensitivity, which as mild severity.

46. Cont….. Anti Oxidant Agents
Glutathione , taurine, niacin, inhibit development of fibrosis in animal models.
Acetyle cysteine – a precurser of glutathione, can replenish pulmonary glutathione levels.
In study with 18 patients with IPF treated with 600mg N-acetyl cysteine TID for 12 weeks in addition to their latest immunosupressant therapy – significant improvement PFT.
A recent double blind, randomized, placebo controlled multicenter study assessed the effectiveness over 1 year of high dose oral acetyl cysteine added to standard therapy with prednisolone and azothioprine – show acetyl cysteine slowed deterioration of vital capacity at the end of 1 year.
Cont…..

47. Pulmonary Rehabilitation / General Supportive measures :
The aim of the pulmonary rehabilitation is not only to improve daily functioning, but also to help people with interstitial lung disease to live fully satisfying life. Pulmonary rehabilitation program focus on:
Physical exercise, to improve your endurance.
Breathing techniques that improve lung efficiency.
Emotional Support
Nutritional Counselling

48. General Supportive measures :
Smoking cessation
Avoidance of any other environmental (including occupational) causes.
Stopping any medication thought to be causing or contributing to pulmonary fibrosis.
Treating any respiratory tract infections promptly.
Patients should be encouraged to receive influenza or vaccination and pneumococal vaccine.
Good pulmonary hygiene is important.

49. Lung Transplantation :
Lung transplantation is a treatment option for selected patients with advanced disease refractory to medical therapy. Lung transplant improves long term survival. Survival rates worldwide after single lung transplantation are approximately :
74% at 1 year
58% at 3 years
47% at 5 years
and 42% at 10 years

50. PROGNOSIS :
The prognosis variable and depends on the specific diagnosis and severity. Some disease are insidious in onset and gradual progression, while other disease are acute in onset but responsive to therapy. Idiopathic pulmonary fibrosis is progressive illness, producing increasingly severe symptoms, and generally has a poor prognosis.
Mortality data for 3 year and 5 year mortality rate are approximately 50% and 80% respectively. Although IPF occurs in older patients with co-morbid diseases, most patients with IPF die as direct consequence of the Lung fibrosis. However, some patients with IPF remain stable for a number of years. The median survival rate of biopsy – proven IPF is less than three years. Most will die as a result of respiratory failure, but other will develop infections secondary to steroid therapy or right heart failure.

51. Poor outcome is associated with:
Older age
Male gender
Severe dyspnoea
History of Cigarette Smoking
Severe loss of Lung function
Appearance and severity of fibrosis on radiological studies
Lack of response to therapy.
Prominent Fibroblastic foci on histopathological evaluation.

52. CONCLUSION
IPF is a severe condition with a worse prognosis than all other ILDs.
The accuracy and timeliness of IPF diagnosis must be improved in order to improve treatment opportunities and outcomes.
However, there is often a long delay before a diagnosis is made and today the diagnosis is too often insufficiently secure or accurate.

53. issues need to be addressed
The guidelines (exclusion of alternate diagnosis, optimal interpretation of CT, combination CT and histopathological evaluation with a multidisciplinary discussion implying a pulmonologist, a radiologist and a pathologist expert on ILD) have to be strictly applied.

54. Thanks……………..