Chronic Interstitial Lungs disease

CHRONIC INTERSTITIAL (RESTRICTIVE, INFILTRATIVE) LUNG DISEASES

Table 12–3 Major Categories of Chronic Interstitial Lung Disease

Chronic interstitial diseases are a heterogeneous group of disorders characterized predominantly by bilateral, often patchy, and usually chronic involvement of the pulmonary connective tissue, principally the most peripheral and delicate interstitium in the alveolar walls. The pulmonary interstitium is composed of the basement membrane of the endothelial and epithelial cells (fused in the thinnest portions), collagen fibers, elastic tissue, fibroblasts, a few mast cells, and occasional mononuclear cells (Fig. 12–1). Many of the entities in this group are of unknown cause and pathogenesis; some have an intra-alveolar as well as an interstitial component, and there is frequent overlap in histologic features among the different conditions. Nevertheless, the similarity in clinical signs, symptoms, radiographic alterations, and pathophysiologic changes justifies their consideration as a group. The hallmark feature of these disorders is reduced compliance (i.e., more pressure is required to expand the lungs because they are stiff), which in turn necessitates increased effort of breathing (dyspnea). Furthermore, damage to the alveolar epithelium and interstitial vasculature produces abnormalities in the ventilation–perfusion ratio, leading to hypoxia. Chest radiographs show diffuse infiltration by small nodules, irregular lines, or “ground-glass shadows.” With progression, patients can develop respiratory failure, often in association with pulmonary hypertension and cor pulmonale (Chapter 10). Advanced forms of these diseases may be difficult to differentiate because they result in scarring and gross destruction of the lung, referred to as end-stage or “honeycomb” lung. Chronic interstitial lung diseases are categorized based on clinicopathologic features and characteristic histology (Table 12–3).

Fibrosing Diseases

Idiopathic Pulmonary Fibrosis

Idiopathic pulmonary fibrosis (IPF), also known as cryptogenic fibrosing alveolitis, refers to a pulmonary disorder of unknown etiology. It is characterized by patchy but progressive bilateral interstitial fibrosis, which in advanced cases results in severe hypoxemia and cyanosis. Males are affected more often than females, and approximately two thirds of patients are older than 60 years of age at presentation. The radiologic and histologic pattern of fibrosis is referred to as usual interstitial pneumonia (UIP), which is required for the diagnosis of IPF. Of note, however, similar pathologic changes in the lung may be present in well-defined entities such as asbestosis, the collagen vascular diseases, and a number of other conditions. Therefore, known causes must be ruled out before the appellation of idiopathic is used.

PATHOGENESIS

Figure 12–14 Schematic representation of current understanding of the pathogenesis of idiopathic…

The current concept is that IPF is caused by “repeated cycles” of epithelial activation/injury by some unidentified agent (Fig. 12–14). Histopathologic features include inflammation and induction of T_H2 type T cell response with eosinophils, mast cells, IL-4, and IL-13 in the lesions. There has been considerable interest in the idea that “alternatively activated macrophages” are dominant in patients with lung fibrosis and may be important in its pathogenesis (Chapter 2). Abnormal epithelial repair at the sites of damage and inflammation gives rise to exuberant fibroblastic or myofibroblastic proliferation, leading to the characteristic fibroblastic foci. Although the mechanisms of abnormal repair are incompletely understood, recent data point to TGF-β1, which is released from injured type I pneumocytes and induces transformation of fibroblasts into myofibroblasts leading to excessive and continuing deposition of collagen and ECM. Some patients with familial IPF have mutations that shorten telomeres (Chapter 1) leading to rapid senescence and apoptosis of pneumocytes. TGF-β1 also downregulates fibroblast caveolin-1, which acts as an endogenous inhibitor of pulmonary fibrosis.

MORPHOLOGY

Figure 12–15 Usual interstitial pneumonia. The fibrosis, which varies in intensity, is more pronounced in the…

Figure 12–16 Usual interstitial pneumonia. Fibroblastic focus with…

Grossly, the pleural surfaces of the lung have the appearance of cobblestones because of the retraction of scars along the interlobular septa. The cut surface shows fibrosis (firm, rubbery white areas), with lower lobe predominance and a distinctive distribution in the subpleural regions and along the interlobular septa. The pattern of fibrosis in IPF is referred to as usual interstitial pneumonia (UIP). The histologic hallmark of UIP is patchy interstitial fibrosis, which varies in intensity (Fig. 12–15) and worsens with time. The earliest lesions demonstrate exuberant fibroblastic proliferation and appear as fibroblastic foci (Fig. 12–16). Over time these areas become more collagenous and less cellular. Quite typical is the existence of both early and late lesions(temporal heterogeneity). The dense fibrosis causes collapse of alveolar walls and formation of cystic spaces lined by hyperplastic type II pneumocytes or bronchiolar epithelium(honeycomb fibrosis). The interstitial inflammation usually is patchy and consists of an alveolar septal infiltrate of mostly lymphocytes and occasional plasma cells, mast cells, and eosinophils. Secondary pulmonary hypertensive changes (intimal fibrosis and medial thickening of pulmonary arteries) are often present.

Clinical Features

IPF usually manifests insidiously, with the gradual onset of a nonproductive cough and progressive dyspnea. On physical examination, most patients with IPF have characteristic “dry” or “Velcro”-like crackles during inspiration. Cyanosis, cor pulmonale, and peripheral edema may develop in later stages of the disease. The clinical and radiologic findings often are diagnostic; surgical lung biopsy is needed for diagnosis in selected cases. Unfortunately, progression of IPF is relentless despite medical therapy, and the mean survival is 3 years or less. Lung transplantation is the only definitive therapy available.

Nonspecific Interstitial Pneumonia

Nonspecific interstitial pneumonia (NSIP) is a chronic bilateral interstitial lung disease of unknown etiology, which despite its nonspecific name, has distinct clinical, radiologic, and histologic features. It is important to recognize this disease, since it carries a much better prognosis than that for IPF. On the basis of the histologic appearance, NSIP is divided into cellular and fibrosing patterns. The cellular patternfeatures mild-to-moderate chronic interstitial inflammation (lymphocytes and a few plasma cells) in a uniform or patchy distribution. The fibrosing pattern consists of diffuse or patchy interstitial fibrosis,without the temporal heterogeneity characteristic of UIP. Fibroblastic foci and honeycombing are typically absent in both variants. Patients present with dyspnea and cough of several months’ duration. Patients with the cellular pattern have a better outcome than those with the fibrosing pattern and UIP.

Cryptogenic Organizing Pneumonia

Figure 12–17 Cryptogenic organizing pneumonia. Some alveolar spaces are filled with balls of…

Cryptogenic organizing pneumonia is synonymous with the previously popular designation bronchiolitis obliterans organizing pneumonia (“BOOP”); the former term is now preferred, however, because it emphasizes the unknown etiology of this clinicopathologic entity. Patients present with cough and dyspnea, and chest radiographs demonstrate subpleural or peribronchial patchy areas of air space consolidation. On histologic examination, cryptogenic organizing pneumonia is characterized by the presence of polypoid plugs of loose organizing connective tissue within alveolar ducts, alveoli, and often bronchioles (Fig. 12–17). The connective tissue is all of the same age, and the underlying lung architecture is normal. Some patients recover spontaneously, but most require treatment with oral steroids for 6 months or longer. Of note, organizing pneumonia with intra-alveolar fibrosis also can be seen as a response to infection (e.g., pneumonia) or inflammatory injury (e.g., collagen vascular disease, transplantation injury) to the lung; in such cases, the etiology obviously is not “cryptogenic,” and the outcome is determined by the underlying disease.

Pulmonary Involvement in Collagen Vascular Diseases

Many collagen vascular diseases (e.g., systemic lupus erythematosus, rheumatoid arthritis, systemic sclerosis, dermatomyositis-polymyositis) are associated with pulmonary manifestations. Several histologic variants can be seen, depending on the underlying disorder, with NSIP, UIP pattern (similar to that seen in IPF), vascular sclerosis, organizing pneumonia, and bronchiolitis (small airway disease, with or without fibrosis) being the most common. Pleural involvement (pleuritis, pleural nodules, and pleural effusion) may also be present. Pulmonary involvement in these diseases is usually associated with a poor prognosis, although it is still better than that with IPF.

SUMMARY

Chronic Interstitial Lung Diseases

• Diffuse interstitial fibrosis of the lung gives rise to restrictive lung diseases characterized by reduced lung compliance and reduced forced vital capacity (FVC). The ratio of FEV to FVC is normal.
• The diseases that cause diffuse interstitial fibrosis are heterogeneous. The unifying pathogenetic factor is injury to the alveoli with activation of macrophages and release of fibrogenic cytokines such as TGF-β.
• Idiopathic pulmonary fibrosis is prototypic of restrictive lung diseases. It is characterized by patchy interstitial fibrosis, fibroblastic foci, and formation of cystic spaces (honeycomb lung). This histologic pattern is known as usual interstitial pneumonia (UIP).

Pneumoconioses

Pneumoconiosis is a term originally coined to describe the non-neoplastic lung reaction to inhalation of mineral dusts. The term has been broadened to include diseases induced by organic as well as inorganic particulates, and some experts also regard chemical fume- and vapor-induced non-neoplastic lung diseases as pneumoconioses. The mineral dust pneumoconioses—the three most common of which result from exposure to coal dust, silica, and asbestos—nearly always result from exposure in the workplace. However, the increased risk of cancer as a result of asbestos exposure extends to family members of asbestos workers and to other persons exposed to asbestos outside of the workplace. Table 12–4indicates the pathologic conditions associated with each mineral dust and the major industries in which the dust exposure is sufficient to produce disease.

Table 12–4 Mineral Dust–Induced Lung Disease

PATHOGENESIS

The reaction of the lung to mineral dusts depends on many variables, including size, shape, solubility, and reactivity of the particles. For example, particles greater than 5 to 10 µm are unlikely to reach distal airways, whereas particles smaller than 0.5 µm move into and out of alveoli, often without substantial deposition and injury. Particles that are 1 to 5 µm in diameter are the most dangerous, because they get lodged at the bifurcation of the distal airways. Coal dust is relatively inert, and large amounts must be deposited in the lungs before lung disease is clinically detectable. Silica, asbestos, and beryllium are more reactive than coal dust, resulting in fibrotic reactions at lower concentrations. Most inhaled dust is entrapped in the mucus blanket and rapidly removed from the lung by ciliary movement. However, some of the particles become impacted at alveolar duct bifurcations, where macrophages accumulate and engulf the trapped particulates. The pulmonary alveolar macrophage is a key cellular element in the initiation and perpetuation of lung injury and fibrosis. Many particles activate the inflammasome and induce IL-1 production. The more reactive particles trigger the macrophages to release a number of products that mediate an inflammatory response and initiate fibroblast proliferation and collagen deposition. Some of the inhaled particles may reach the lymphatics either by direct drainage or within migrating macrophages and thereby initiate an immune response to components of the particulates and/or to self-proteins that are modified by the particles. This then leads to an amplification and extension of the local reaction. Tobacco smoking worsens the effects of all inhaled mineral dusts, more so with asbestos than with any other particle.

Coal Worker’s Pneumoconiosis

Worldwide dust reduction in coal mines has greatly reduced the incidence of coal dust–induced disease. The spectrum of lung findings in coal workers is wide, ranging from asymptomatic anthracosis, in which pigment accumulates without a perceptible cellular reaction, to simple coal worker’s pneumoconiosis(CWP), in which accumulations of macrophages occur with little to no pulmonary dysfunction, tocomplicated CWP or progressive massive fibrosis (PMF), in which fibrosis is extensive and lung function is compromised (Table 12–4). Although statistics vary, it seems that less than 10% of cases of simple CWP progress to PMF. Of note PMF is a generic term that applies to a confluent fibrosing reaction in the lung; this can be a complication of any one of the pneumoconioses discussed here.

Although coal is mainly carbon, coal mine dust contains a variety of trace metals, inorganic minerals, and crystalline silica. The ratio of carbon to contaminating chemicals and minerals (“coal rank”) increases from bituminous to anthracite coal; in general, anthracite mining has been associated with a higher risk of CWP.

MORPHOLOGY

Pulmonary anthracosis is the most innocuous coal-induced pulmonary lesion in coal miners and also is commonly seen in all urban dwellers and tobacco smokers. Inhaled carbon pigment is engulfed by alveolar or interstitial macrophages, which then accumulate in the connective tissue along the lymphatics, including the pleural lymphatics, or in lymph nodes.

Figure 12–18 Progressive massive fibrosis in a coal worker. Large…

Simple CWP is characterized by coal macules and the somewhat larger coal nodule. The coal macule consists of dust-laden macrophages; in addition, the nodule contains small amounts of collagen fibers arrayed in a delicate network. Although these lesions are scattered throughout the lung, the upper lobes and upper zones of the lower lobes are more heavily involved. In due course, centrilobular emphysema can occur. Functionally significant emphysema is more common in the United Kingdom and Europe, probably because the coal rank is higher than in the United States.

Complicated CWP (PMF) occurs on a background of simple CWP by coalescence of coal nodules and generally requires many years to develop. It is characterized by usually multiple, intensely blackened scars larger than 2 cm, sometimes up to 10 cm in greatest diameter. On microscopic examination the lesions are seen to consist of dense collagen and pigment (Fig. 12–18).