9: Overview of diffuse parenchymal lung diseases
OUTLINE
Pathology, 125
Pathology of Idiopathic Interstitial Pneumonias, 126
End-Stage Diffuse Parenchymal Lung Disease, 129
Pathogenesis, 130
Pathophysiology, 131
Decreased Compliance, 131
Decrease in Lung Volumes, 132
Impairment of Diffusion, 132
Abnormalities in Small Airway Function, 133
Disturbances in Gas Exchange, 133
Pulmonary Hypertension, 133
Clinical Features, 133
Diagnostic Approach, 134
A large group of disorders affects the alveolar wall in a fashion that ultimately may lead to diffuse scarring or fibrosis. These disorders traditionally have been referred to as interstitial lung diseases, although the term is somewhat of a misnomer (see Chapter 8). The interstitium formally refers only to the region of the alveolar wall exclusive of and separating the alveolar epithelial and capillary endothelial cells. However, interstitial lung diseases affect all components of the alveolar wall: epithelial cells, endothelial cells, and cellular and noncellular components of the interstitium. In addition, the disease process often extends into the alveolar spaces and therefore is not limited to the alveolar wall. Many authors now prefer the expression diffuse parenchymal lung disease, which is the term generally used in this book. However, for practical purposes, the reader should recognize that the expressions diffuse parenchymal lung disease and interstitial lung disease typically refer to the same group of disorders causing inflammation and fibrosis of alveolar structures. Another label, the idiopathic interstitial
pneumonias, identifies a group of pathologic entities that represent a subcategory of diffuse parenchymal
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lung disease. The disorders included within that label will be discussed in more detail in the Pathology section of this chapter, as well as in Chapter 11, where we consider those diffuse parenchymal lung diseases that do not have a well-defined etiology.
The idiopathic interstitial pneumonias represent a subgroup of disorders within the broader category of diffuse parenchymal lung disease.
There are more than 150 diffuse parenchymal lung diseases. Table 9.1 lists the most common of these disorders, grouped by broad categories according to whether the underlying etiology of the disease is currently known or unknown. A third category of “mimicking disorders” is included in recognition of the fact that a number of additional well-defined clinical problems can produce diffuse parenchymal abnormalities on chest imaging. Even though these mimicking disorders often are not included in traditional lists of diffuse parenchymal lung diseases, the clinician must remember to consider them in the appropriate clinical settings.
TABLE 9.1
Classification of Selected Diffuse Parenchymal Lung Diseases
Known Etiology
Resulting from inhaled inorganic dusts (pneumoconiosis [e.g., asbestosis, silicosis]) Caused by organic antigens (hypersensitivity pneumonitis)
Iatrogenic (drugs, radiation pneumonitis)
Unknown Etiology
Idiopathic interstitial pneumonias
Associated with systemic rheumatic (connective tissue) disease
Sarcoidosis
Less common:
Pulmonary Langerhans cell histiocytosis
Lymphangioleiomyomatosis
Goodpasture syndrome
Granulomatosis with polyangiitisa
Chronic eosinophilic pneumonia
Pulmonary alveolar proteinosis
Mimicking Disorders
Heart failure
Disseminated carcinoma (lymphangitic carcinomatosis)
Pulmonary infection (e.g., Pneumocystis, viral pneumonia)
aTypically associated with focal or multifocal disease rather than diffuse disease.
Familiarity with this large number of specific diseases is difficult even for the pulmonary specialist, so the novice in pulmonary medicine cannot be expected to amass deep knowledge regarding each individual
entity. Rather, the reader is urged to first develop an understanding of the pathologic, pathogenetic, pathophysiologic, and clinical features common to these disorders. This chapter is an overview of general aspects of diffuse parenchymal lung disease and refers to individual diseases only when necessary. Chapter 10 discusses disorders associated with an identifiable etiologic agent; the minority of patients with diffuse parenchymal lung disease are in this category. Chapter 11 discusses diseases for which a specific etiologic agent has not been identified, representing the majority of patients with diffuse parenchymal lung disease. These chapters focus on only a small number of the described types of diffuse parenchymal disease. The goal throughout is to consider those disorders the reader most likely will encounter.
The entities covered in these three chapters are primarily chronic (although sometimes subacute and rarely acute) diseases affecting the alveolar structures. Another process associated with diffuse disease, the acute respiratory distress syndrome (ARDS), is due to acute injury to various components of the alveolus. ARDS, which is of clinical importance as a major cause of acute respiratory failure, is discussed in detail in Chapter 29.
Pathology
Typically, the diffuse parenchymal lung diseases, regardless of cause, have two major pathologic components: an inflammatory process in the alveolar wall and alveolar spaces (sometimes called an alveolitis) and a scarring or fibrotic process (Fig. 9.1). Both features frequently occur simultaneously, although the relative proportions of inflammation and fibrosis vary with the particular cause and phase of disease. The general presumption has been that active inflammation is the primary process and that fibrosis follows as a secondary feature. However, idiopathic pulmonary fibrosis (IPF) is a major exception to this generalization. As discussed in Chapter 11, the primary process in IPF appears to be epithelial cell injury and fibrosis (representing an abnormal repair of injury) rather than alveolar inflammation (see Pathogenesis).
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FIGURE 9.1 Photomicrograph of diffuse parenchymal lung disease showing
markedly thickened alveolar walls. Cellular inflammatory process and fibrosis are
present. Compare with appearance of normal alveolar walls in Fig. 8.1.
Diffuse parenchymal (interstitial) lung diseases are characterized pathologically by variable amounts of inflammation and fibrosis.
When active alveolitis is present, a variety of inflammatory cells (e.g., macrophages, lymphocytes, neutrophils, eosinophils, and plasma cells) infiltrate the alveolar wall. Individual types of diffuse parenchymal lung disease may be associated with a prominence of a specific inflammatory cell type, such as eosinophils in chronic eosinophilic pneumonia. In addition to the presence of inflammatory cells, other characteristic pathologic features that help to define a specific disorder may be associated with the alveolitis. These individual patterns are useful in, and in many cases critical to, the diagnosis of a specific pathologic entity.
One of the most important and distinctive pathologic features associated with several of the diffuse parenchymal lung diseases is the granuloma. A granuloma is a localized collection of cells called epithelioid histiocytes, which are tissue cells of monocyte/macrophage lineage (Fig. 9.2A). These cells are generally accompanied by T lymphocytes within the granuloma, often also forming a rim around it. When cellular necrosis is present in the center of a granuloma, the entity is termed a caseating or necrotizing granuloma, but diffuse parenchymal lung diseases are associated almost exclusively with noncaseating granulomas (i.e., granulomas in which the central area is not necrotic). In contrast, caseating granulomas are characteristically seen in infectious diseases, especially tuberculosis (see Chapter 25, Pathology). The granuloma typically also has multinucleated giant cells, which result from fusion of several phagocytic cells into a single large cell with abundant cytoplasm and many nuclei (see Fig. 9.2B). Examples of diffuse parenchymal lung disease in which granulomas are part of the pathologic process include sarcoidosis and hypersensitivity pneumonitis. Granulomas are often considered to reflect some underlying immune process, specifically an immune reaction to an exogenous agent. In the case of hypersensitivity pneumonitis, many agents have been identified. In contrast, in the case of sarcoidosis, no specific exogenous agent has been definitively identified. Granulomas in the lung have many other causes
(e.g., tuberculosis, certain fungal infections, and foreign bodies), but they are not covered here because the granulomas are generally not associated with diffuse parenchymal lung disease.
FIGURE 9.2 Granulomas. A, Low-power photomicrograph of transbronchial lung
biopsy showing characteristic non-necrotizing granulomas (arrows) from a patient
with sarcoidosis. B, High-power photomicrograph showing several multinucleated
giant cells within a granuloma.
Diffuse parenchymal lung diseases with granulomas include sarcoidosis and hypersensitivity pneumonitis.
Pathology of idiopathic interstitial pneumonias
The idiopathic interstitial pneumonias represent a subgroup that includes several types of diffuse parenchymal lung disease. Although the term “idiopathic” in this subgroup label indicates that a specific etiologic agent has not been identified for these disorders, there is now recognition that smoking plays a significant contributory role or adds to the risk of developing several of the idiopathic interstitial pneumonias. The individual idiopathic interstitial pneumonias were initially defined by their histopathologic appearance; however, the terms used to describe the pathology and the associated clinical disorder may be different. A good example is the pathologic description of usual interstitial pneumonia (UIP) being associated with the clinical label of IPF. As we have gained experience with radiographic imaging studies, we also have recognized that specific pathologic descriptions are often associated with characteristic patterns on high-resolution computed tomography (HRCT) scanning. Table 9.2 summarizes the pathologic–clinical–radiographic correlations for the idiopathic interstitial pneumonias, which will also be discussed further in Chapter 11.
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TABLE 9.2
Pathologic, Clinical, and Radiographic Correlations for the Idiopathic Interstitial Pneumonias
|
|
|
Common |
Subcategory |
Clinical Diagnosis |
Pathologic Pattern |
Radiographic |
|
|
|
Description |
Chronic fibrosing |
Idiopathic pulmonary |
Usual interstitial pneumonia |
Reticular (fibrosis), |
interstitial |
fibrosis (IPF) |
(UIP) |
honeycombing |
pneumonias |
|
|
|
|
|
|
|
|
Idiopathic |
Nonspecific interstitial |
Ground glass |
|
nonspecific |
pneumonia (NSIP) |
|
|
interstitial |
|
|
|
pneumonia |
|
|
|
|
|
|
Smoking-related |
Respiratory |
Respiratory bronchiolitis |
Bronchial wall |
interstitial |
bronchiolitis– |
|
thickening, |
pneumonias |
interstitial lung |
|
centrilobular |
|
disease (RB- |
|
nodules, ground |
|
ILD) |
|
glass |
|
|
|
|
|
Desquamative |
Desquamative interstitial |
Ground glass |
|
interstitial |
pneumonia (DIP) |
|
|
pneumonia (DIP) |
|
|
|
|
|
|
Acute/subacute |
Cryptogenic |
Organizing pneumonia (formerly |
Patchy consolidation, |
interstitial |
organizing |
bronchiolitis obliterans with |
often peripheral |
pneumonias |
pneumonia |
organizing pneumonia, |
(subpleural) |
|
(COP) |
BOOP) |
|
|
|
|
|
|
Acute interstitial |
Diffuse alveolar damage (DAD) |
Diffuse alveolar |
|
pneumonia (AIP) |
|
filling |
|
|
|
|
Copyright © 2022 American Thoracic Society. All rights reserved. Modified and expanded from Travis WD, Costabel U, Hansell DM, et al. An official American Thoracic Society/European Respiratory Society statement: update of the International Multidisciplinary Classification of the Idiopathic Interstitial Pneumonias. Am J Respir Crit Care Med. 2013;188:733–748. The American Journal of Respiratory and Critical Care Medicine is an official journal of the American Thoracic Society. Readers are encouraged to read the entire article for the correct context at https://www.atsjournals.org/doi/10.1164/rccm.2013081483ST. The authors, editors, and The American Thoracic Society are not responsible for errors or omissions in adaptations.
Pathologists and clinicians have spent considerable time and effort refining and intermittently updating the description and categorization of the idiopathic interstitial pneumonias. These disorders display variable amounts of nonspecific inflammation and fibrosis, and they lack granulomas or specific pathologic features characteristic of other previously well-defined diseases. Classification of the idiopathic interstitial pneumonias and determination of whether the various pathologic appearances represent different diseases or, in some cases, different stages or parts of the spectrum of a single disease have been subject to uncertainty and confusion, particularly when a biopsy specimen may contain more
than one of these pathologic appearances. Although the field is still evolving, this chapter attempts to present a simplified framework based on current pathologic and clinical concepts about these disorders.
The pathologic categories subsumed under the idiopathic interstitial pneumonias include:
1.Usual interstitial pneumonia (UIP)
2.Nonspecific interstitial pneumonia (NSIP)
3.Respiratory bronchiolitis–interstitial lung disease (RB-ILD)
4.Desquamative interstitial pneumonia (DIP)
5.Cryptogenic organizing pneumonia (COP)
6.Acute interstitial pneumonia (AIP)
Confusion also sometimes arises from the fact that several of the same pathologic appearances associated with the idiopathic interstitial pneumonias can be seen in lung disease associated with some of the systemic rheumatic (also called connective tissue or collagen vascular) diseases. A good example is the pathologic appearance of NSIP, which can be idiopathic but is also a common pathologic expression of pulmonary involvement with diseases such as systemic lupus erythematosus, rheumatoid arthritis, and systemic sclerosis (scleroderma).
This chapter discusses six pathologic entities subsumed under the broad term idiopathic interstitial pneumonias: (1) UIP, (2) NSIP, (3) RB-ILD, (4) DIP, (5) COP, and (6) AIP. This section briefly describes the pathologic characteristics defining these six entities, whereas Chapter 11 expands upon their clinical and radiographic features. Table 9.2 also groups these six disorders into three categories—chronic fibrosing interstitial pneumonias, smoking-related interstitial pneumonias, and acute/subacute interstitial pneumonias—and correlates their pathologic, clinical, and radiographic features.
UIP is characterized by patchy areas of parenchymal fibrosis and interstitial inflammation interspersed between areas of relatively preserved lung tissue (Fig. 9.3). Fibrosis is the most prominent component of the pathology, with focal collections of proliferating fibroblasts called fibroblastic foci. The fibrosis often is associated with honeycombing, which represents cystic air spaces that result from retraction of surrounding fibrotic lung tissue. The inflammatory process in the alveolar walls is nonspecific, not prominent, and typically composed of a variety of cell types, including lymphocytes, macrophages, and plasma cells. Hyperplasia of type II pneumocytes (alveolar epithelial cells) presumably reflects an attempt to replenish damaged type I cells. Importantly, the pathology of UIP is characterized by the simultaneous presence of all stages of fibrosis: from early fibrosis with actively proliferating fibroblasts to end-stage acellular collagenous scarring. It is thought the fibrotic process in UIP is ongoing and not related to a single event. By far the most important of the clinical disorders associated with the histopathologic pattern of UIP is IPF, and the terms are often used synonymously. However, the pathologic appearance of UIP can also result from exposure to certain inhaled dusts (especially asbestos), from a number of drug-induced lung diseases, and as a form of parenchymal lung disease associated with some systemic rheumatic diseases. It is important to remember that the term UIP refers to the histologic pattern seen under the microscope, whereas IPF refers to the clinical disease associated with idiopathic UIP.
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FIGURE 9.3 Low-power photomicrograph of usual interstitial pneumonia shows
prominent fibrosis accompanied by honeycombing. Source: (Courtesy Dr. Olivier
Kocher.)
NSIP is characterized by a prominent histopathologic component of mononuclear cell infiltration within the alveolar walls (Fig. 9.4). Despite the designation “nonspecific,” NSIP is a distinct pathologic entity that presents either in an idiopathic form or in association with a number of systemic rheumatic diseases. In contrast to UIP, the pathologic process in NSIP appears relatively uniform, fibrosis is variable but generally less apparent, and the prognosis is better. In the past, this pattern was often not recognized as separate from UIP. As a result, its inclusion in many clinical studies of IPF served to confound our understanding of the natural history and treatment of IPF.
FIGURE 9.4 High-power photomicrograph of nonspecific interstitial pneumonitis
showing characteristic mononuclear cell infiltrate in alveolar walls without
significant fibrosis.
RB-ILD and DIP are thought to be related, in that both are typically associated with tobacco smoking. RB-ILD is characterized by pigmented macrophages within the lumen of respiratory bronchioles, accompanied by an infiltrate of lymphocytes and macrophages. However, in contrast to DIP, alveolar inflammation is not present. RB-ILD is nearly always associated with smoking. The most important clinical intervention is assisting patients to successfully quit smoking. At times, the distinction between RB-ILD and DIP is difficult and somewhat arbitrary, and both pathologic appearances may be present in the same individual.
DIP is characterized by large numbers of intra-alveolar mononuclear cells (Fig. 9.5). Although originally thought to represent desquamated alveolar epithelial cells (hence the name), these cells are now known to be intra-alveolar macrophages. A less prominent component of the histology is inflammation within alveolar walls, and there is little associated fibrosis. In contrast to UIP, the process is temporally uniform, and architectural distortion is minimal. Based on a strong (although not universal) association of this histologic pattern with a history of smoking, as well as an apparent overlap in some patients with smoking-induced inflammation of respiratory bronchioles with pigmented macrophages, smoking is believed to be an important underlying etiology for this pathologic pattern.
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FIGURE 9.5 High-power photomicrograph showing macrophages within
respiratory bronchioles and alveolar spaces (arrows), characteristic of the spectrum
that includes respiratory bronchiolitis-interstitial lung disease (RB-ILD) and
desquamative interstitial pneumonia (DIP).
COP is characterized by organizing fibrosis (also referred to as “granulation tissue”) in small airways, associated with a mild degree of chronic interstitial inflammation (Fig. 9.6). Intraluminal small airway involvement is a key feature and distinguishes COP from the other idiopathic interstitial pneumonias. This histologic pattern has also been called bronchiolitis obliterans organizing pneumonia (BOOP). The histologic findings in BOOP are either idiopathic or associated with specific known causes (e.g., infections, toxic inhalants, systemic rheumatic disease). Although the terms have sometimes been used interchangeably, the term COP generally refers to the idiopathic form of BOOP.
FIGURE 9.6 Low-power photomicrograph of organizing pneumonia pattern, as
seen in cryptogenic organizing pneumonia (COP). In addition to an inflammatory
interstitial infiltrate, there is a branching tongue of fibroblastic tissue occupying a
small airway. Source: (From Leslie, K. O., & Wick, M. R. (2018). Practical
pulmonary pathology. A diagnostic approach (3rd ed.). Philadelphia, PA:
Elsevier.)
AIP is believed to represent the organizing or fibrotic stage of diffuse alveolar damage, which is the histologic pattern seen in ARDS (see Chapter 29). In most cases of ARDS an inciting cause is apparent, whereas in AIP no initiating trigger for ARDS can be identified. The histology is similar to the later phases of ARDS, and shows fibroblast proliferation and type II pneumocyte hyperplasia in the setting of what appears to be organizing diffuse alveolar damage.
End-stage diffuse parenchymal lung disease
When diffuse parenchymal lung disease has been present for an extended time and is associated with significant fibrosis, distinctive features of prior interstitial inflammation or alveolitis are often lost. For example, after sufficient time has elapsed and a substantial degree of fibrosis has developed, granulomas may no longer be identifiable in the granulomatous lung diseases. Therefore, at a certain point, many of the diffuse parenchymal lung diseases, if sufficiently severe and chronic, can follow a final common pathway toward end-stage diffuse parenchymal lung disease. At end-stage, severe fibrosis leads to significant architectural distortion of the lung that can be seen both grossly and microscopically, with areas of contraction and other areas showing formation of cystic spaces. In many cases, the result is “honeycomb lung,” in which the dense scarring and intervening cystic regions make areas of the lung resemble a honeycomb (Fig. 9.7).
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