Interstitial Lung Diseases

Overview

Definition: broad category of respiratory disorders that produce functional "restrictive ventilatory defects"

Causes: infectious, inflammatory, neoplastic, allergic, metabolic, idiopathic

Characterization: localization within the alveolar septa, alveolitis: inflammation and consequent fibrosis of the alveolar wall

Pulmonary Interstitium

Definition: the compartment of the lung interposed between the airspace (airway and alveolar) epithelium, the capillary endothelium and pleural mesothelium. It constitutes the architectural framework of the lung.

Function: provides the scaffold upon which endothelial, mesothelial, and epithelial cells reside. Contributes to the mechanical behavior of the lung, modulates and serves as a barrier to the flow of plasma constituents from the capillaries to the alveolar spaces.

Characteristics: interstitium is continuous with peribronchial and perivascular connective tissue and with the connective tissue of the visceral pleura.

Cellular components: macrophages, lymphocytes, mesenchymal cells (fibroblasts, myofibroblasts, smooth muscle cells, undifferentiated mesenchymal cells). Neutrophils, eosinophils, mast cells – <1% of all cells

Matrix components: basement membrane, collagen (types I and III), elastin, proteoglycans, fibronectin (cell-adhesive molecule that plays a major role in cell-matrix interactions

Interstitial inflammatory disorders

Known etiologies:

Inhalation of environmental agents
organic dusts (hypersensitivity pneumonitis)
Inorganic dusts (pneumoconiosis)
gases, fumes, vapors
Adult Respiratory Distress Syndrome
Radiation
toxins
drugs
infections

Unknown etiologies:

Systemic:

Sarcoidosis
collagen vascular disease
histiocytosis X
autoimmune liver disease
inflammatory bowel disease
vasculitis

Affects lung exclusively:

idiopathic pulmonary fibrosis
chronic eosinophilic pneumonia
bronchiolitis obliterans organizing pneumonia

Inflammatory/Immune cells and mediators

Injury: results in recruitment of inflammatory cells into the lung. Cells distort the normal interstitial architecture and injure alveolar and capillary lining cells, and non-cellular structural components of the interstitium.

Mediated by: proteases (elastase, collagenase) and toxic oxidants (released by neutrophils and macs)

Chemotactic factors: leukotriene B4 and Il-8, monocyte chemotactic factor (epithelial derived), Ý E-selectin on endothelial cells (promote recruitment of leukocytes).

Immune reactants: B-cell derived immunoglobulins: immune complexes, activate complement; T-cell derived mediators: Il-2, IFN-g , (Ý T-cells + activate alveolar macs – important in sarcoidosis)

Histological patterns of lung inflammation

Patterns are NOT clinical entities but are reactions that can be seen in a variety of diseases

(1) Usual Interstitial Pneumonitis (UIP): cellular infiltrate of lymphocytes and plasma cells (associated with interstitial fibrosis).

Major patter of inflammation in idiopathic pulmonary fibrosis, collagen vascular disease (rheumatoid, dermatomyositis), viral infections, asbestosis, drug reactions.

(2) Desquamative Interstitial Pneumonitis (DIP): numerous alveolar macs in addition to mild chronic interstitial inflammation

Seen with: idiopathic pulmonary fibrosis, asbestosis, drug reactions

(3) Lymphocytic Interstitial Pneumonitis (LIP): lymphocytes and plasma cells densely infiltrate the interstitium and are much more numerous than in UIP. Considered by many to be a lymphoproliferative disorder rather than in inflammatory condition.

Associated with: Sjogren’s syndrome, AIDS

(4) Diffuse Alveolar Damage (DAD): form of acute injury to the alveolar wall. Early phase: edema, hemorrhage, acute inflammation, hyaline membranes. Proliferative (reparative) phase: resembles UIP

Seen in: adult respiratory distress syndrome, viral pneumonia, radiation pneumonitis

(5) Eosinophilic Pneumonia: domination of eosinophils, with fewer #’s of macs and lymphocytes in the interstitium and alveolar spaces

Assoc with: allergic rxn to inhaled antigen, parasites or fungi, drug toxicity, collagen vascular disease, vasculitic syndrome, idiopathic condition of chronic eosinophilic pneumonia

(6) Organizing Pneumonia: process of subacute interstitial inflammation associated with organizing fibrous tissue in alveolar ducts and respiratory bronchioles

Causes: partial treated bacterial pneumonia, toxic fume inhalation, viral, autoimmune

(7) Granulomatous interstitial inflammation: major component in several interstitial lung diseases in which a type IV (delayed) hypersensitivity reaction predominates.

Includes: mycobacterial and fungal infection, berylliosis, Wegener’s granulomatosis, hypersensitivity pneumonitis, sarcoidosis
Sarcoidosis: presence of non-necrotizing granulomas throughout the interstitium as well as in airway mucosa and blood vessel walls

Epithelial and Endothelial Cell Injury

Process: Inflammation within the alveolar wall invariably causes or is accompanied by injury to the capillary endothelial cells and the type I alveolar epithelial cells. Injury and necrosis Þ breakdown of the alveolar capillary barrier Þ passage of plasma proteins (fibrin) into the interstitium and alveolar space.

Hyperplasia of Type II pneumocytes: frequent accompaniment of interstitial inflammation. It is more resistant to injury and proliferates in an attempt to restore the alveolar epithelial surface following injury to the type I pneumocyte.

Pathogenesis of Interstitial Fibrosis

Idiopathic pulmonary fibrosis: mesenchymal cells within the interstitium respond to chemotactic factors (fibronectin, platelet derived growth factors, alveolar macrophage insulin-like growth factor)Þ Mesenchymal cells proliferate and produce excessive collagen (major component of fibrous tissue)

Hallmark of chronic interstitial lung disease: widening of the interstitium

Mechanisms of alveolar wall fibrosis: Intrinsic interstitial fibrosis and Fibrosis by accretion

Typically, both processes occur concomitantly

(1) Intrinsic interstitial fibrosis: collagen deposited beneath alveolar basement membrane, within framework of alveolar wall

(2) Fibrosis by accretion: fibrous tissue within the alveolar space is incorporated into the alveolar wall.

Sequence: initial injury to alveolar epithelium and capillary endothelium Þ leakage of fibrin into alveolar space and fibroblast migration from the interstitium though breaks in the alveolar basement membrane Þ type II pneumocytes proliferate over the intra-alveolar fibrous tissue incorporating the fibrous tissue into the alveolar wall. Eventually the interstitial fibrous tissue becomes less cellular and more collagenous

End Stage lung: all processes of interstitial fibrotic destruction result in the same non-specific pattern of fibrosis

Fibrous remodeling of the lung can either be diffuse or honeycombed

Usually both are present but one or the other may predominate:

Honeycomb: porous network of enlarged airspaces separated by fibrous tissue. Airspaces are lined by respiratory or squamous epithelium and are ineffectual for gas exchange.

Abnormal airspaces: result of alveolar destruction, bronchiolectasis, and the formation of fibrous septa between widely separated spaces.

Clearance of intrapulmonary secretion is impaired in these dilated airspaces: Ý susceptibility to mucus stasis and secondary infection

Vascular change in interstitial Lung Disease

Changes: capillary endothelial injury and a dramatic loss of pulmonary capillary bed

Muscular arteries: severe intimal sclerosis and medial hypertrophy (from inflammation and hypoxia)

associated with increased vascular resistance and pulmonary HTN Þ atherosclerotic plaque formation in initima of large pulmonary arteries Þ Right ventricular hypertrophy and cor pulmonale: from prolonged pulmonary HTN

Necrotizing vasculitis: NOT a feature of most interstitial inflammatory processes.

Structure function relationships

Process: Replacement of normal, delicate, alveolar architecture by stiff, non-compliant fibrous tissue results in contraction of the lung and reduction of lung volumes.

Residual Volume and Functional Residual Capacity are reduced

Vital Capacity (VC) and Total Lung Capacity (TLC) are reduced

Forced Expiratory Volume (1 sec) (FEV1) ß in proportion to the overall reduction in vital capacity and FEV1/FVC ratio is normal

Ý elastic recoil causes reduced compliance Þ Ý transpulmonary pressure @ TLC

Ý work of breathing, patients ventilate at reduced tidal volumes and increased rate of respiration

Mechanical changes worsen as disease progresses from cellular Þ fibrotic

Arterial hypoxemia: result of V/Q mismatch and perfusion of non-ventilated fibrotic lung (like blue bloaters in COPD)

Pulmonary HTN: results in right ventricular hypertrophy and cor pulmonale.

Interstitial lung disease (ILD)

diverse group of pulmonary disorders characterized by diffuse infiltrate on CXR, physiologic abnormalities of gas exchange and histologic distortion of lung parencyhma

Differential Diagnosis: over 160 clinical entities identified with ILD; 80% are pneumoconiosis, drug induced disease, hypersensitivity pneumonitis

Less frequent: sarcoidosis, idiopathic pulmonary fibrosis, collagen vascular disease, granulomatous vasculitis, Goodpasture’s syndrome, histiocytosis X, chronic eosinophilic pneumonia, pulmonary alveolar proteinosis

Pathophysiology

Normal anatomy: Lung interstitium is formed by connective tissue and mesenchymal cells bounded by alveolar epithelium and capillary endothelium. The alveolus (gas exchange unit of lung) and corresponding capillary network is supported by interstitium (which is only 1-2 cells thick) to facilitate gas exchange. The alveolus is lined by type I and type II cells; inflammatory and immune effector cells reside within the surfactant which coats the alveolar wall.

Process – injury to lung parenchyma Þ inflammatory response within interstitium, adjacent alveolar airspaces and vasculature

inflammation causes interstitial edema and exudation of serum proteins along with an influx of inflammatory and immune effector cells into tissue; as inflammation continues, fibroblasts proliferate and collagen is synthesized within interstitium

if fibrosis continues, obliteration of the alveolar-capillary units occurs Þ formation of "honeycomb lung"

Features – Lung compliance decreases Þ reduced lung volumes and increased work of breathing

V/Q mismatch: destruction of alveolar capillary interface

Elevation in minute ventilation to maintain a normal PCO₂; Ý respiratory rate (not tidal volume)

Hyperventilation: 1/3 of patients, stimulation of pulmonary stretch receptors and/or vagal afferent by inflam. mediators

Hypoxemia: V/Q mismatch; can be normal resting PO₂ if patient is hyperventilating

Clinical features

Presentation: insidious onset of exertional dyspnea and a reticulonodular pattern on CXR

Symptoms: vary depending on the specific disease entity and severity of pulmonary impairment. Include: cough, hemoptysis, wheezing, chest pain. Generalized symptoms: fever, chills, weight loss

Diagnosis

Comprehensive history and exam: time course, exposure to agents (organic/inorganic dusts, chemicals or drugs),

Associated pulmonary symptoms: hemoptysis chest pain, dyspnea, etc

Extrathoracic symptoms: joints, skin, renal etc.; Constitutional symptoms: fever, chills, weight loss

Physical exam: diagnostically nonspecific; abnormalities may include: tachypnea, basilar rales, wheezing and digital clubbing

Lab evaluation: complete blood count with a differential, urinalysis, serum creatinine, collagen vascular screen (WESR, ANA, RF) PPD, and control skin tests

CXR: pulmonary infiltrates; Gallium lung scanning: assess degree of inflammation in the lung tissue

Pulmonary function tests: restrictive pattern: ß FVC, FEV₁, normal FEV₁ /FVC. TLC and RV are also ß . Reduced DLCO, ß PaO₂, widened A-a oxygen gradient

Definitive diagnosis: transbronchial or open lung biopsy. Fiberoptic bronchoscopy with bronchoalveolar lavage (BAL): exclude infectious and neoplastic causes of diffuse infiltrates

Treatment: therapeutic objectives:

(1) elimination of etiologic agent
(2) preservation of lung structure and function
(3) palliation of symptoms
(4) management of complications

Therapies: Corticosteroids (mainstay of treatment), supplemental O2 (with a PaO₂ < 55mmHg), appropriate immunizations, treatment of cor pulmonale and RV failure, lung transplantation

Idiopathic Pulmonary Fibrosis (IPF) – Prototype Interstitial lung Disease

Epidemiology: Second most frequent cause of diffuse pulmonary infiltrates

Synonyms for IPF: Cryptogenic Fibrosing Alveolitis, Hamman-Rich syndrome and Interstitial pneumonia.

5 pathological subtypes:

(1) usual interstitial pneumonitis (UIP)
(2) UIP with bronchiolitis obliterans
(3) desquamative interstitial pneumonitis (DIP)
(4) lymphocytic interstitial pneumonitis (LIP)
(5) giant cell interstitial pneumonitis (GIP)
Subtypes describe histopathological features found in a variety of lung disorders, NOT specific for IPF

Immunopathogenesis

Etiology: unknown; one hypothesis is that unknown antigen initiates an exaggerated inflammatory reaction that ultimately leads to destruction of alveolus. Alveolar Macs orchestrate the events that eventually results in parenchymal fibrosis.

Sequence: immune complexes Þ stimulate alveolar macs Þ mac chemotactic factors attract inflammatory cells (PMNs, eosinophils) Þ products of PMN’s (collagenase) injure structural tissue.

Macrophages also elaborate fibrogenic factors and fibronectin: alter secretion of collagen products by interstitial fibroblasts. Ý production of type III collagen at the expense of type I collagen

Clinical aspects

Clinical presentation:

usually appears in men after age 60
insidious onset of dyspnea and a non-productive cough
pts symptomatic for 24 mo prior to diagnosis
arthralgias
½ of patients complain of constitutional symptoms (malaise, weight loss)

Physical exam:

tachypnea
basilar rales
digital clubbing
exercise cyanosis
Pulmonary HTN (late in disease)

CXR: diffuse reticular or reticulonodular infiltrate that is most apparent in the lung bases. May have normal x-ray though.

In general, radiographic abnormalities do NOT correlate with histology

Pulmonary function tests: restrictive pattern with gas exchange abnormalities

Treatment: high dose corticosteroids (only 10-20% show improvement in PFT’s), cytotoxic drugs (effectiveness is controversial)

Prognosis: insidious progression; 50% mortality (80% respiratory, 20% cardiovascular)

Mean survival: 5 yrs (10% develop bronchogenic carcinoma)