Idiopathic Pulmonary Fibrosis

James Allen, MD

I. Pathogenesis Of Interstitial Lung Disease:

A. Anatomic considerations within the lung:

1. interstitial components

2. alveolar components

3. small airway components

4. blood vessel components

B. Differential diagnosis:

1. general principles:

a) inhaled insult - alveolitis - interstitial fibrosis

b) circulating insult - endothelial injury - interstitial fibrosis

2. common identifiable causes:

a) infectious causes, e.g.: non-tuberculous mycobacteria & certain fungal infections

b) occupational causes, e.g.: asbestos & silica

c) drug reactions, e.g.: methotrexate & amiodarone

d) neoplastic causes, e.g.: metastatic cancer, bronchoalveolar cell carcinoma (a form of lung cancer)

e) radiation pneumonitis

f) hypersensitivity pneumonitis

(1) this is a frequently unrecognized cause of interstitial lung disease

(2) there is a long list of agents causing hypersensitivity pneumonitis; in our practice, we have found often overlooked culprits to include bird antigens (down conforters and feather pillows) and hot tubs (thermophilic actinomycetes and microorganisms)

g) rheumatologic diseases

(1) systemic lupus erythematosis

(2) rheumatoid arthritis

(3) scleroderma

(4) mixed connective tissue disease

(5) polymyositis

3. diseases of unknown cause, e.g.: sarcoidosis, Langerhan's cell granulomatosis (eosinophilic granuloma; histiocytosis X), lymphangioleiomyomatosis

4. idiopathic pulmonary fibrosis

II. Clinical Presentation Of Patients With Interstitial Lung Disease:

A. History:

1. symptoms: cough, dyspnea, arthralgias?

2. duration of symptoms

3. what makes symptoms worse?

4. what makes symptoms better?

5. occupational, travel & drug exposures?

B. Physical examination:

1. vital signs: respiratory rate, temperature

2. pulmonary exam: crackles present?

3. cardiac exam: cor pulmonale (pulmonary hypertension) present?

4. extremities: nail clubbing present? arthritis? skin rash? sclerodactaly? muscle weakness?

III. Diagnostic Testing Of Patients With Interstitial Lung Disease:

A. blood tests: useful to look for evidence of rheumatologic diseases:

1. rheumatoid factor (all patients)

2. ANA (all patients)

3. extractable nuclear antigens (select patients)

4. anti-JO-1, CK (select patients)

5. anti-phospholipid antibiody and antibodies to individual phospholipid components (phosphatidylcholine, phosphatidylserine, etc.) - select patients

B. Chest x-ray: nodules? interstitial markings? alveolar markings? pleural disease? hilar/mediastinal lymph node enlargement?

C. High resolution chest CT:

1. used for diagnosis:

a) some patterns relatively specific for certain diseases; eg.: bronchiectasis, emphysema, Langerhan's cell granulomatosus

b) location of abnormalities can guide site of bronchoscopy & lung biopsy

2. used for disease management:

a) ground glass infiltrates: correlate with inflammation and are potentially reversible

b) "honeycombing": correlate with fibrosis and are irreversible

C. Pulmonary function tests:

1. lung volumes - reduced

2. diffusing capacity - reduced

3. spirometry - generally normal

4. pulmonary exercise testing - typical findings include:

a) reduced maximum oxygen uptake

b) resting or exercise-induced hypoxemia

c) reduced ventilatory reserve

D. Bronchoalveolar lavage:

1. normal findings:

a) >90% alveolar macrophages

b) <10% lymphocytes most are T-cells with a usual T-helper:suppressor ratio is between 1:1 and 2:1

c) <2% neutrophils

d) <2% eosinophils

2. important abnormal findings:

a) increased lymphocyte percentage

(1) increased T-helper:suppressor ratio: sarcoidosis

(2) decreased T-helper:suppressor ratio: hypersensitivity pneumonitis

(3) rare cases of idiopathic pulmonary fibrosis can have a BAL pattern of predominately lymphocytes

(3) current immunologic theory recognizes 2 forms of T-helper cells: Th1 & Th2 cells.

(a) Th1 cells make interleukin-2 and gamma-interferon

(b) Th2 cells make interleukin-4, interleukin-5, & interleukin-10.

b) increased neutrophils: most cases of IPF, most other interstitial lung diseases

(1) diagnostically, the least specific when present in increased percentages

(2) contain a number of oxidants and enzymes with potential for lung tissue damage

c) increased eosinophils: chronic eosinophilic pneumonia, some cases of drug-induced lung disease

(1) eosinophils are largely controlled by interleukin-5 and other mediators produced by Th2 lymphocytes

(2) make a variety of high pH granule contents which are extremely toxic to parasites and normal lung tissue

(3) in cases of documented idiopathic pulmonary fibrosis, increased eosinophils indicates a worse prognosis

E. Lung Biopsy

1. transbronchial biopsy (via a flexible bronchoscope)

a) advantages

(1) minimally invasive

(2) outpatient procedure

b) disadvantages

(1) very small tissue samples

(2) pulmonary vessels usually not present in specimens

(3) usually too small to make a pathologic diagnosis except for sarcoidosis, some cancers, and some infections

2. thorascopic biopsy

a) advantages

(1) larger tissue pieces than transbronchial biopsy - typically larger pieces are required for diagnosis of IPF

(2) shorter hospital stay and less post-operative discomfort than open lung biopsy

b) disadvantages

(1) inpatient procedure requiring general anesthesia

(2) inability to palpate lung during procedure may lead to sampling error

(3) difficult to obtain deep samples

3. open lung biopsy

a) advantages

(1) provides large samples

(2) surgeon can better identify involved portions of lung

b) disadvantages

(1) inpatient procedure requiring general anesthesia

(2) longest recovery time

IV. Diagnosis & Treatment of Idiopathic Pulmonary Fibrosis (for this handout considered eqivilent to usual interstitial pneumonitis):

1. epidemiology

a) prevalence = 20/100,000 men & 13/100,000 women

b) incidence = 10.7/100,000/year men & 7.4/100,000/year women

c) no geographical or racial variation

d) 2/3 patients over 60; mean age of diagnosis = 66

e) mean survival from diagnosis = 3-5 years

2. risk factors

a) cigarette smoking (2-fold risk)

b) chronic aspiration

c) environmental factors (steel, brass, lead, pine wood dusts)

d) infectious agents (EBV, CMV, parvovirus)

e) genetic

3. diagnosis

a) clinical presentation:

(1) usual age = 50-70

(2) subacute onset dyspnea on exertion

(3) non-productive cough

(4) dry inspiratory crackles (90%)

(5) nail clubbing in 25 - 50%

b) laboratory

(1) elevated ESR & LDH common

(2) low levels of ANA & RF in 10-20%

c) chest x-ray:

(1) basilar or diffuse interstitial changes

(2) no hilar lymph node enlargement

(3) no pleural disease

(4) may be normal

(5) notoriously inaccurate

d) high resolution chest CT is moderately specific

(1) peripheral/subpleural interstitial densities

(2) patchy "ground-glass" infiltrates

(3) small cystic areas

(4) "traction" bronchiectasis

e) pulmonary function tests

(1) reduced lung volumes

(2) reduced diffusing capacity

(3) low pO2

(4) low MVO2 during exercise testing (more sensitive than plain PFTs and resting oxygenation)

(5) nocturnal oxygen frequently low and patients may require nocturnal supplemental oxygen before needing daytime supplemental

f) BAL

(1) primarily useful to exclude other diseases

(2) cellular patterns may imply prognosis

(a) increased lymphocytes may predicts favorable response to treatment

(b) increased neutrophils (the more frequent finding) usually indicates a less favorable response to treatment

(c) increased eosinophils may correlate with a more rapid progression

g) biopsy

(1) surgical biopsy recommended for most patients unless the procedure is relatively contraindicated (transbronchial biopsy gives insufficient sized pieces of lung)

h) histology

(1) usual interstitial pneumonitis (UIP)

(a) temporal heterogeniety (areas of normal lung, areas of interstitial expansion, areas of dense fibrosis)

(b) fibroblast foci

(c) honeycombed areas of cystic air spaces

i) differential diagnosis

(1) desquamative interstitial pneumonitis (DIP)

(a) most patients are smokers

(b) CXR and CT less severely abnormal and show ground glass infiltrates

(c) pathology = uniform, diffuse intraalveolar macrophage accumulation with abundant intracellular hemosiderin

(d) much better prognosis with more than 70% of patients alive in 5 years; smoking cessation is essential and steroids are generally required

(2) respiratory bronchiolitis-associated interstitial lung disease

(a) almost all patients smokers or former smokers

(b) CXR and CT show diffuse fine reticular or nodular opacities

(c) PFTs show mixed obstructive and restrictive defects

(d) pathology = pigmented macrophages within lumens of respiratory bronchioles with patchy submucosal and peribronchial infiltrate of lymphocytes and histiocytes

(e) smoking cessation essential; prognosis better than UIP

(f) in reality, most smokers have some degree of RBILD and the decision to treat (steroids with or without cyclophosphamide) requires clinical judgement regarding the severity of the disease and the degree to which RBILD contributes to their symptoms

(3) non-specific interstitial pneumonitis

(a) often associated with rheumatologic diseases but can occur idiopathically

(b) many patients have auto antibodies to individual phospholipid components suggesting endothelial injury as a part of the pathogenesis

(c) CXR and CT may show more ground glass infiltrates than in UIP

(d) pathology = temporal homogeniety to the abnormalities showing mostly diffuse expansion of the alveolar walls and interstitium with inflammatory cells; we have found many patients have evidence of capillary injury adn destruction leading to a "microangiopathic" form of pulmonary fibrosis

(e) fairly good prognosis with treatment - 80% of patients alive in 5 years; treatment = steroids with or without either cyclophosphamide or azathioprine

(4) acute interstitial pneumonitis

(a) acute onset of ARDS-like illness

(b) very high mortality rate - most patients die in first 6 months

(c) pathology = diffuse alveolar damage (similar to ARDS)

(5) bronchiolitis obliterans organizing pneunonia

(a) often heralded by flu-like illness

(b) CXR and CT show bilateral diffuse alveolar opacities

(c) pathology = intralumenal buds of granulation tissue in small airways

(d) most patients recover with prolonged corticosteroid therapy

(6) lymphocytic interstitial pneumonitis

(a) often associated with monoclonal gammopathy, Sjogren's syndrome, or HIV infection

(b) may be a sign of low grade lymphoma in some patients

(c) CXR and CT show bilateral basilar mixed interstitial and alveolar infiltrates

(d) may respond to corticosteroids with or without azathioprine

(7) Langerhan's cell granulomatosis (histiocytosis X, eosinophilic granuloma)

(a) primarily adults age 20-40; most are smokers

(b) CXR and CT show characteristic numerous nodules and thin walled cysts

(c) pathology = large stellate nodules staining positive for Langerhan's cells

(d) smoking cessation mandatory and may result in improvement in many patients; chemotherapy (2-CDa) is effective in some patients

4. treatment of usual interstitial pneumonitis (UIP)

a) general principles:

(1) the decision to start treatment should be individualized; in general, response rates for UIP to aggressive pharmacologic therapy are poor:

(a) 10% improve

(b) 30% stabilize

(c) 60% deteriorate

(2) probably the best time to treat is in the earliest phase of IPF/UIP, however, many patients are asymptomatic at this phase and thus reluctant to start potentially harmful medications

(3) for patients with advanced disease, treatment probably confers little benefit and often in this situation, the side effects of prednisone and cyclophosphamide can be worse the the symptoms of the underlying IPF

b) pharmacologic therapy

(1) daily prednisone (0.5 mg/kg/day x 4 weeks then 0.25 mg/kg/day x 8 weeks then 0.125 mg/kg/day); monitor glucose, blood pressure

(2) daily cyclophosphamide (100-150 mg/day); monitor CBC and urinalysis every 2 weeks

(3) daily azathioprine (100-150 mg/day); monitor CBC, LFTs

(4) interferon gamma 1b (200 mcg SQ 3 times/week); monitor CBC, chemistry profile, and LFTs

(a) gamma interferon had great promise based on initial (phase II) studies; however, the phase III study reported in the fall of 2002 showed no significant improvement in the primary endpoint of death/deterioration in the first year. It did appear that patients with more preserved lung function (FVC greater than 60% of predicted) who took gamma interferon for more than a year did better than placebo controls, however.

(5) single lung transplantation

(a) last resort in patients failing other treatment

(b) must be < 60 or 65 at most transplant centers

(c) because of the long waiting list for transplant (about 2 years), patients should generally be referred early due to the often rapid deterioration they generally have once they become hypoxemic

c) monitoring efficacy

(1) only continue medications if disease regresses or at least remains stable for 3 months

(2) may need one of more objective parameters to monitor efficacy

(a) pulmonary function studies (generally preferred for routine monitoring)

i) total lung capacity measurement

ii) diffusing capacity measurement

(b) presence of parenchymal abnormalities by CT

(c) dyspnea scores

(d) oxygen saturation OR maximum oxygen uptake during pulmonary exercise test

d) other management/interventions

(1) pulmonary rehabilitation

(2) supplemental oxygen if hypoxemic at rest, exercise, or when asleep

(3) watch for and treat depression

(4) cough can be difficult and often fails to respond to anything

(5) avoid/monitor osteoporosis in patients receiving chronic steroids or cyclophosphamide

(6) prevent pneumocystis carinii pneumonia in patients receiving steroids and/or cyclophosphamide by use of prophylactic trimethoprim-sulfamethoxazole (1 double strength tablet every Monday, Wednesday, and Friday)

e) prognosis is poor

(1) most patients with UIP will die without treatment (mean survival after diagnosis = 3-5 years)

(2) most patients with UIP will die even with treatment using either steroids or cyclophosphamide/azathioprine (although death may be delayed)

(3) factors associated with a better prognosis:

(a) younger age (less than 50)

(b) female gender

(c) ground glass infiltrates on CT

(d) increased lymphocytes on BAL

 

 last updated 1/22/03