IDIOPATHIC INTERSTITIAL PNEUMONIAS

IDIOPATHIC INTERSTITIAL PNEUMONIAS What are IIPs ? • The idiopathic interstitial pneumonias (IIPs) are a subgroup of diffuse parenchymal lung diseas...
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IDIOPATHIC INTERSTITIAL PNEUMONIAS

What are IIPs ? • The idiopathic interstitial pneumonias (IIPs) are a subgroup of diffuse parenchymal lung diseases, a group also described as ILDs.

• IIPs are a heterogeneous group of non-neoplastic disorders resulting from damage to the lung parenchyma by varying patterns of inflammation and fibrosis.

Why Idiopathic “Interstitial” Pneumonias ? • The interstitium includes the space between the epithelial and endothelial basement membranes and it is the primary site of injury in the IIPs.

• However, these disorders frequently affect not only the interstitium, but also the airspaces, peripheral airways, and vessels along with their respective epithelial and endothelial linings * * Cushley MJ et al. Thorax 1999;54:1-30

What are the different IIPs ? • IIPs include : (ATS / ERS consensus statement 2001)

– Idiopathic Pulmonary Fibrosis (IPF) – Nonspecific Interstitial Pneumonia (NSIP) – Cryptogenic Organizing pneumonia (COP) – Acute Interstitial Pneumonia (AIP) – Respiratory Bronchiolitis-Associated Interstitial Lung Disease (RB-ILD) – Desquamative Interstitial Pneumonia (DIP) – Lymphocytic Interstitial Pneumonia (LIP)

• As a subgroup they can be distinguished from other forms of diffuse parenchymal lung disease by clinical methods : – History – Physical Examination – Laboratory studies – Chest radiology – Pathology

Before describing the features of each IIPs, it is necessary to consider the principles that apply to the general assessment of patients with IIPs.

The new classification of IIP is based on clinical, radiological, and pathological criteria.

The Diagnostic Process… A. CLINICAL EVALUATION : 1. A careful history taking : • • • • • • •

First Symptoms (Breathlessness/Cough). Progression of symptoms. Clinical course. Presence of any co-morbid diseases (CTDs /HIV). Environmental exposures (Smoking/Drugs/Occupational). Past h/o malignancy. Family h/o lung diseases.

B. PHYSICAL EXAMINATION : •

General Physical Examination : i. Clubbing. ii. Pallor, Cyanosis, Oedema. iii. Skin Changes, Joint swellings.



Respiratory System Examination : i. Reduced Chest Movements. ii. Normal / Increased TVF. iii. Fine end inspiratory crepititions.

C. LAB FINDINGS : ¾ Hb, TLC, DLC, ESR, CRP, ANAs, Specific Abs, Rheumatoid Factor etc.

D. PULMONARY FUNCTION TESTING : ¾ ¾ ¾ ¾ ¾

FEV1, FVC = Decreased. FEV1/FVC = Normal. TLC, Lung Vol = Decreased. DLCO = Decreased. PAO2-PaO2 = Normal / Increased.

RADIOLOGY IN IIPs ¾ CHEST X-ray : Common features are -

:

Localized/Diffuse fibrosis. Ground glass opacities. Areas of consolidation. Honeycombing. Volume Loss. Bronchial wall thickening. Nodules.

¾ CT/HRCT : HRCT is indicated for all but a small proportion of patients for whom a specific diagnosis is strongly suggested by standard chest x-ray.* *Austin JH et al. Radiology 1996;23:374-379

• Common CT findings in IIPs are : – – – – – – –

Diffuse/ Sub-pleural reticular pattern. Sub-Pleural Cysts. Ground glass attenuation. Septal thickening. Areas of consolidation. Micro/Macro Nodular shadows. Honeycombing.

Broncho-alveolar Lavage in IIPs • BAL is a useful diagnostic adjunct but it is not a stand-alone diagnostic test. • It must be interpreted in the context of clinical presentation and radiologic, especially HRCT, findings. • When used in this fashion, BAL can be helpful in establishing a specific ILD diagnosis, and it may obviate the need for TBLB or surgical Lung biopsy.

BAL fluid cell counts in IIPs IIPs

Macrophages Neutrophils (cells/ml) (%)

Eosinophils (%)

Lymphocytes (%)

IPF



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NSIP





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AIP





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COP





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DIP



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RBILD LIP

Surgical Lung Biopsy in IIPs • A surgical lung biopsy is necessary for a confident clinico-pathologic diagnosis, except in cases with a typical clinical-radiological picture of UIP/IPF. • Pathology is least helpful when obtained late in the course of the illness or after commencement of treatment. • Helps clinician to make more informed decisions about therapy and saves patient from unnecessary adverse effects of current treatment modalities.

Histologic and Clinical Classification of IIPs Histologic Patterns

Clinical-Radio-Pathologic Dx

Usual Interstitial Pneumonia

IPF / CFA

Nonspecific Interstitial Pneumonia

NSIP

Organizing Pneumonia

COP

Diffuse Alveolar Damage

AIP

Respiratory Bronchiolitis

RB-ILD

Desquamative Interstitial Pneumonia

DIP

Lymphoid Interstitial Pneumonia

LIP

IDIOPATHIC PULMONARY FIBROSIS

What is IPF ? • According to the current definition, IPF is a distinctive type of chronic fibrosing interstitial pneumonia of unknown cause limited to the lungs and associated with a histological pattern of UIP.* • Definitive histologic diagnosis of IPF requires a surgical lung biopsy. *King TE et al. Am J Respir Crit Care Med 2000;161:646-664



In the presence of a surgical biopsy showing a UIP pattern, the diagnosis of IPF requires: 1. Exclusion of other known causes of ILD (drug toxicities, environmental exposures and CTDs). 2. Characteristic abnormalities on chest X-rays and HRCT. 3. PFT showing restriction, reduced vital capacity, impaired gas exchange and decreased PaO2 with rest or exercise.

What if surgical biopsy is not available ? • In the absence of a surgical lung biopsy, the diagnosis of IPF remains uncertain. • However, in the immunocompetent adult, the presence of all the major criteria as well as at least three minor criteria increases the likelihood of correct clinical diagnosis of IPF.*

*Talmadge E et al. Am J Respir Crit Care Med 2000;161:646-664

IPF MAJOR CRITERIA 1.

Exclusion of other causes of ILD.

2.

Abnormal PFTs.

3.

Bibasilar reticular abnormalities with minimal ground glass opacities on HRCT scans. TBLB or BAL showing no features to support an alternative diagnosis.

4.

IPF MINOR CRITERIA 1.

Age > 50 years

2. 3.

Insidious onset of otherwise unexplained dyspnoea on exertion. Duration of illness > 3 mths

4.

Bibasilar, inspiratory crackles (dry or “Velcro”)

CLINICAL FEATURES • Gradual onset of symptoms. • Dyspnoea is the most prominent and disabling symptom. • A non productive, paroxysmal cough which is refractory to anti-tussive agents. • IPF is more common in males more than 50 yrs of age.

• Constitutional symptoms are unusual. • In most patients, symptoms have been present for more than 6 months before presentation. • The clinical course is invariably one of gradual deterioration. Median length of survival from time of diagnosis varies between 2.5 and 3.5 yrs.* *Talmadge E et al. Am J Respir Crit Care Med 2000;161:646-664

EXAMINATION AND LAB FINDINGS • Digital clubbing in 25-50% of patients. • Velcro type fine end-inspiratory crackles that are initially confined to the basal areas are found on chest auscultation. • Features of Rt. Heart failure and peripheral edema develop only in the late stages.

• Most patients exhibit a restrictive pattern of ventilatory defect with a decrease in DLCO and low resting PaO2, which falls on exercise. • BAL fluid contains an excess of neutrophils, the proportions of which correspond to the reticular change on HRCT. • BAL cell counts, although correlating with severity of disease, do not predict prognosis.

RADIOLOGY OF IPF A. Chest X-ray: ¾ Peripheral reticular opacity most marked at the bases. ¾ Honeycombing. ¾ Lower lobe volume loss.

IPF

B. CT: ¾ Reticular opacities with traction bronchiectasis. ¾ Honeycombing. ¾ Ground glass attenuation. ¾ Architectural distortion due to lung fibrosis. ¾ Lobar volume loss with more advanced fibrosis. * The distribution of UIP on CT is characteristically basal and peripheral, although often patchy.

IPF

1. 2.

Ground-glass attenuation in a peripheral distribution. There is interlobular septal thickening, irregularity of the fissures (arrowheads) and bronchiectasis (arrows) consistent with early UIP. Progression of UIP, manifested as diffuse ground-glass attenuation, interlobular septal thickening (arrows), and a honeycomb pattern (arrowhead).

IPF

HISTOLOGY OF IPF • The key histologic features of UIP pattern are: – Architectural destruction – Fibrosis (often with honeycombing) – Scattered fibroblastic foci. – Patchy distribution and involvement of the periphery of the acinus or lobule. * The histological changes affect the peripheral sub-pleural parenchyma most severely.

IPF

1.

2.

Cystically dilated air spaces that constitute a honeycomb pattern (a) within dense fibrosis (b) beneath the pleura (c). Scar obliterates normal alveolar architecture. d = fibroblastic foci, e = smooth muscle hyperplasia. Active fibroblastic foci of myxoid connective tissue (d), which form nodules projecting into alveolar-sized air space. Pneumocytes are hyperplastic.

• Interstitial inflammation is usually mild to moderate and patchy. • It consists of an alveolar septal infiltrate of lymphocytes, plasma cells and histiocytes associated with hyperplasia of type II pneumocytes.

What is the treatment of IPF ? • IPF progresses in a relentless and often insidious manner that may be difficult to detect using parameters such as clinical features, CXR or spirometry alone. • Spontaneous remissions do not occur. • The treatment has been based on the concept that inflammation leads to injury and fibrosis.

• The practical treatment armentarium has been largely restricted to anti-inflammatory medications and, most recently, lung transplantation. • Treatment options include* : – Corticosteroids. – Immunosuppressive agents. – Anti-fibrotic agents. *Rudd R et al. Am Rev Repir Dis 1991;124:1-8

Corticosteroids for IPF • Initiate therapy with high dose steroids (40-100mg daily of prednisone) x 2-4 mths. • After 3 mths of steroid therapy, objective clinical parameters are required to gauge response. • Steroid responsive patients are maintained on prednisone chronically, but in a gradually tapering doses.

• The dose of steroid and rate of taper should be guided by clinical and physiological parameters. • Since its unlikely that steroids completely eradicate the disease, prolonged treatment of 12 years is reasonable for steroid responsive patients. • Relapses or deterioration warrant escalation of dose or addition of an immunosuppressive agent.

Immunosuppressive agents for IPF • Azathioprine or Cyclophosphamide are used in : – Steroid nonresponders. – Patients experiencing serious adverse effects from steroids. – Patients at high risk for steroid complications.

Favorable responses have been noted in a few small treatment trials with these agents in 15-50% cases.

Other novel alternative treatments for IPF

1. Anti-fibrotic agents : Colchicine, D-penicillamine. 2. Novel anti-fibrotic agents : INF-γ, INF-β, relaxin, pirfenidone, suramin and PGE2. 3. Anti-oxidants : Glutathione, taurine.

Lung Transplantation for IPF • Transplantation should be considered for those patients who experience progressive physiologic deterioration despite optimal medical management. • Single lung transplantation is currently the preferred surgical operation. • After successful transplantation, arterial O2 tension is improved, lung volumes and DLco are increased and PAH and right ventricular dysfunction are reversed.

NON-SPECIFIC INTERSTITIAL PNEUMONIA

What is NSIP ? • The term was introduced by Katzenstein and Fiorelli in 1994. • It was due to the fact that lung biopsy samples from some patients with ILDs did not fit into any well defined histologic pattern of IIP. • The concept of NSIP has helped to identify a group of ILDs with a more favorable prognosis that need to be distinguished from other IIPs.

• Katzenstein and Fiorelli divided NSIP into 3 major subgroups based on the amount of inflammation and fibrosis in lung biopsies: – Group I: Primarily with interstitial inflammation – Group II: With both inflammation and fibrosis – Group III: Primarily with fibrosis

What is the importance of NSIP ? • The finding of a NSIP pattern on biopsy should prompt the clinician to redouble the efforts to find potentially causative exposures. • Specific occupational exposures may give rise to this pattern. • NSIP maybe the presenting manifestation preceding the Dx of CTDs by several months or years.

• Conditions associated with NSIP pattern : – Collagen vascular diseases. – Hypersensitivity pneumonitis. – Drug induced pneumonitis. – Immunodeficiency disorders (HIV). – Infections.

Is NSIP an early lesion of UIP ? • There is no definite answer about whether histologic NSIP pattern evolves into a more mature fibrotic lesion, especially UIP. • The following concepts could support that NSIP pattern is not an early lesion of UIP pattern : – Typical UIP pattern can be found even in early stages of IPF/UIP on HRCT. – BAL fluid lymphocytosis can be found in patients with NSIP,whereas it cannot be found in patients with early stages of IPF/UIP.

CLINICAL FEATURES • Mean age of onset = 40-50 years. • No sexual predominance. • No association with cigarette smoking. • Onset usually gradual or sub-acute (6 mths to 3 yrs).* *Cottin V et al.Am J Respir Crit Care Med 1998;158:1286-1293

• Breathlessness, cough and fatigue are usual symptoms. • Most patients present with a h/o weight loss (6 kgs). • The prognosis of NSIP is more variable than in IPF and appears to depend on the extent of fibrosis. • Some patients experience almost complete recovery, the remainder stabilize or improve on treatment. A minority of patients progress and die.

RADIOLOGY OF NSIP A. CHEST X-ray: ¾ B/L pulmonary infiltrates in the lower lung zones. ¾ Patchy parenchymal opacities. B. CT: ¾ B/L and symmetrical ground glass attenuation with sub-pleural predominance.

• Other CT findings are : – Irregular linear/reticular opacities. – Traction bronchiectasis. ™In general, honey combing and consolidation are relatively infrequent.

NSIP

NSIP

1.

Bilateral, subpleural ground-glass attenuation. There are irregular linear areas of high attenuation (arrowhead) and evidence of architectural lung distortion with distortion of the left fissure (arrow).

HISTOLOGY OF NSIP • Lung biopsies may show predominantly interstitial inflammation or fibrosis or a combination of inflammation and fibrosis. • The lung typically is uniformly involved but the distribution of the lesions is often patchy. • The interstitium around airways, blood vessels, interlobular septa and pleura is sometimes involved.

NSIP

1. 2.

Alveolar architecture that is altered by interstitial fibrosis (a), all of which is approximately the same age. Alveolar walls that are thickened by chronic inflammation (b) and fibrillar collagen (c).

• At the cellular end of the spectrum, the NSIP pattern consists primarily of mild to moderate interstitial chronic inflammation, usually with lymphocytes and a few plasma cells. • At the fibrosing end of the spectrum, the NSIP pattern consists of dense or loose interstitial fibrosis in varying degrees and the connective tissue is temporarily homogenous.

NSIP

NSIP

How to treat NSIP ? • Corticosteroids are considered effective therapeutic drugs for idiopathic NSIP and NSIP associated with CTDs. • Immunosuppressant drugs, such as cyclophosphamide, azathioprine and methotrexate have been administered to patients with NSIP. • Initial response to steroids therapy is good. Relapses are common on tapering the dose of steroids.

CRYPTOGENIC ORGANIZING PNEUMONIA

What is COP ? • COP was described by Davidson in 1983. • In 1985 Epler described the same entity under the term BOOP. • Organizing pneumonia pattern is organization within alveolar ducts and alveoli with or without organization within bronchioles.

Why COP is an IIP ? • COP is included in classification of IIP because of : – Its idiopathic nature. – The tendency to be confused with other forms of IIPs. – Histologic features of alveolar septal infiltration by lymphoid cells with Type II pneumocytes hyperplasia in the involved areas.

CLINICAL FEATURES • Equal sex distribution. • Mean age of onset = 55 yrs. • Patients typically present with an illness of relatively short duration (< 3 mths). • There is variable degree of cough and dyspnoea.

• Cough may be productive of clear or discolored sputum. • Symptoms usually follow a suspected lower respiratory tract infection. • Continuing weight loss, sweats, chills, intermittent fever and myalgia are common. • Majority of cases recover completely on administration of steroids, but a significant number relapse within 1-3 mths after steroids are reduced or stopped.

EXAMINATION AND LAB FEATURES • Clubbing is absent. • Localized/ Widespread crackles are present. • Features of consolidation can be found. • Raised ESR, CRP levels and Neutrophils level in blood is present commonly.

• PFT shows a restrictive pattern with a moderately reduced DLCO. • Mild resting hypoxemia may be present and reflects marked disturbance of gas exchange. • BAL fluid contains increased total number of lymphocytes. • The ratio of CD4+ to CD8+ cells is decreased. Neutrophils and eosinophils are increased.

RADIOLOGY OF COP A. CHEST X-ray : ¾ B/L or U/L migratory areas of consolidation. ¾ Small nodular opacities are seen in 10-50% of cases. ¾ Large nodular opacities (>1cm)are seen in 15% of cases. ¾ A minority of patients presents with a reticulonodular pattern.* *Cordier JF et al. Chest 1989;96:999-1004

COP

B. CT : ¾ Areas of airspace consolidation (90%). ¾ Lower lung zones more commonly involved. ¾ Small nodules (75% of cases.* • BAL fluid shows many lymphocytes. *DeCoteau WE et al. Arch Intern Med 1974;134:519-522

RADIOLOGY OF LIP A. CHEST X-ray : ¾ 2 patterns described : - Basilar with an alveolar component - Diffuse with associated honeycombing.

B. CT : ¾ Ground glass opacity is the dominant finding. ¾ Perivascular cysts/honeycombing can be seen. ¾ Lung nodules and widespread consolidation may occur.

LIP

1. 2.

Peripheral ground-glass attenuation and interlobular septal thickening (arrows). Bilateral subpleural ground-glass (black arrows) and denser nodular attenuation.

LIP

HISTOLOGY OF LIP • Dense interstitial lymphoid infiltrate. Including lymphocytes, plasma cells and histiocytes. • The alveolar septa is extensively infiltrated. • Lymphoid follicles with germinal centers are often present ,in the distribution of pulmonary lymphatics.

LIP

1. 2.

Alveolar septa that are widened by a lymphoid infiltrate (a). No scarring is present. Interstitial infiltrate that consists of mature lymphocytes (b), plasma cells (c), and macrophages (d). Epithelium lining of the bronchiole (e) is unremarkable.

Treatment of LIP • Not a common entity. • Treatment modalities have not been well elucidated in current literature. • A trial of corticosteroids in high doses initially, can be tried in these patients.

All the best..

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