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Idiopathic interstitial pneumonias: Classification and pathology

Idiopathic interstitial pneumonias: Classification and pathology
Literature review current through: Sep 2023.
This topic last updated: Mar 15, 2023.

INTRODUCTION — "Diffuse interstitial lung disease" (ILD) or diffuse parenchymal lung disease (DPLD) is a generic term encompassing a broad range of largely unrelated conditions that share the propensity to cause breathlessness and/or cough associated with bilateral abnormal opacities of various types on conventional chest radiographs or high-resolution computed tomographic (HRCT) scans (algorithm 1).

The idiopathic interstitial pneumonias (IIPs) are a subset of diffuse parenchymal lung diseases of unknown etiology characterized by expansion of the interstitial compartment (ie, that portion of the lung parenchyma sandwiched between the epithelial and endothelial basement membranes) with an infiltrate of inflammatory cells. The inflammatory infiltrate is sometimes accompanied by fibrosis, either in the form of abnormal collagen deposition or proliferation of fibroblasts capable of collagen synthesis.

The pathologic classification of idiopathic interstitial pneumonias is reviewed here. The clinical features of the individual IIPs and diagnostic approach to patients with ILD are presented separately. (See "Clinical manifestations and diagnosis of idiopathic pulmonary fibrosis" and "Causes, clinical manifestations, evaluation, and diagnosis of nonspecific interstitial pneumonia" and "Respiratory bronchiolitis-associated interstitial lung disease" and "Acute interstitial pneumonia (Hamman-Rich syndrome)" and "Cryptogenic organizing pneumonia" and "Lymphoid interstitial pneumonia" and "Approach to the adult with interstitial lung disease: Clinical evaluation" and "Approach to the adult with interstitial lung disease: Diagnostic testing".)

CLASSIFICATION — Averill Liebow pioneered the notion that morphologic characteristics are useful in separating idiopathic interstitial pneumonias (IIPs) into clinically and histologically distinct groups, and subsequent classifications have built on this foundation (table 1) [1-4]. The American Thoracic Society and European Respiratory Society (ATS/ERS) statement on the histopathologic classification of IIPs further refines this terminology (table 2) [3-5].

Over time, as the understanding of the clinical behavior and histologic features of the IIPs has evolved, the categories of IIP have changed: usual interstitial pneumonia (UIP) and desquamative interstitial pneumonia (DIP) have persisted as important histologic groups, nonspecific interstitial pneumonia (NSIP) has been added, and bronchiolitis obliterans with classical interstitial pneumonia (BIP) and giant cell interstitial pneumonia (GIP) have been removed (table 1 and table 2) [6]. Idiopathic lymphoid interstitial pneumonia (LIP) remains controversial in terms of its relationship to other IIPs. (See "Lymphoid interstitial pneumonia".)

Liebow was careful to say that these were histological patterns rather than free-standing diagnostic entities, and that each could occur in a variety of clinical contexts. Regardless of the clinical context, however, he maintained that precise histological classification of interstitial pneumonias provides clues to etiology, pathogenesis, natural history, and prognosis. In other words, although individual histological patterns are not free-standing diagnostic entities, each significantly limits the differential diagnosis in terms of potential etiologies or clinical associations, and each has specific implications concerning likely treatment response and outcome.

Role of lung biopsy – The role of lung biopsy in patients with diffuse parenchymal lung disease is to identify histologic patterns encompassed under the heading of IIP, and exclude IIP mimics, such as sarcoidosis, hypersensitivity pneumonitis, and pulmonary Langerhans cell histiocytosis (algorithm 2) [4]. As features of more than one IIP may be present, the biopsy sample must be of sufficient size to determine the predominant features. Histologic patterns of IIP require careful correlation with clinical and radiologic data before considering individual cases to be idiopathic. A multidisciplinary assessment is often useful to combine the clinical, radiologic, and histopathologic findings into a unified diagnosis (table 3) [4,5]. (See "Approach to the adult with interstitial lung disease: Clinical evaluation" and "Role of lung biopsy in the diagnosis of interstitial lung disease" and "Interpretation of lung biopsy results in interstitial lung disease".)

CHRONIC FIBROSING INTERSTITIAL PNEUMONIAS — The two IIPs categorized as chronic fibrosing interstitial pneumonias are usual interstitial pneumonia (UIP) and nonspecific interstitial pneumonia (NSIP) [5]. These IIPS are also the most common among the IIPs.

Usual interstitial pneumonia

Clinical context — UIP is the typical histopathologic finding in patients with idiopathic pulmonary fibrosis (IPF), a specific form of chronic fibrosing interstitial pneumonia limited to the lung [7,8]. IPF/UIP is the most common of the IIPs and typically presents in the sixth and seventh decades of life. High-resolution computed tomography (HRCT), when typical, demonstrates a characteristic pattern of peripheral (subpleural), bibasilar reticular opacities associated with architectural distortion, including honeycomb changes and traction bronchiectasis (image 1 and table 4) [8-10]. The epidemiology, clinical manifestations, evaluation, and diagnosis of IPF are discussed separately. (See "Clinical manifestations and diagnosis of idiopathic pulmonary fibrosis".)

Pathology — UIP is a specific morphologic entity (picture 1 and table 5 and table 6) [5,8,11-13]. The histologic hallmark and chief diagnostic criterion is a heterogeneous appearance with alternating areas of normal lung, interstitial inflammation, fibroblast foci, and honeycomb change [14]. The histological changes correlate with findings on HRCT, in that the peripheral subpleural parenchyma is most severely affected.

The fibrotic zones are composed mainly of dense collagen, although scattered foci of fibroblast proliferation ("fibroblast foci") are a consistent finding. A morphometric analysis with three-dimensional reconstruction showed that in some cases of UIP, the fibroblast foci appear highly interconnected, forming a complex reticulum at the advancing edge of the fibrosis [15].

Interstitial inflammation is usually sparse and consists of an alveolar septal infiltrate of lymphocytes, plasma cells, and histiocytes associated with hyperplasia of type 2 pneumocytes.

Areas of honeycomb change are composed of cystic fibrotic air spaces, which are frequently lined by bronchiolar epithelium and filled with mucin. Smooth muscle hyperplasia is commonly seen in areas of fibrosis and honeycomb change.

Patients who are biopsied during an accelerated phase of their illness (eg, an acute exacerbation of IPF) may show a combination of UIP and a superimposed acute lung injury pattern such as diffuse alveolar damage [16,17].

Insights into the pathogenesis of UIP have helped correlate histology with survival and response to treatment [18-20]. In a carefully executed, prospective cohort study of 87 patients with biopsy-proven UIP, a greater degree of granulation/connective tissue deposition (characteristic of fibroblast foci) was correlated with shorter survival [21]. This finding is consistent with the view that UIP is predominantly a disease of abnormal lung fibroblast proliferation and dysregulated fibrogenesis, rather than active inflammation. (See "Pathogenesis of idiopathic pulmonary fibrosis".)

When a lung biopsy is performed, the results should be correlated with the features present on HRCT, preferably in the context of a multidisciplinary discussion to determine whether the patient has definite, probable, or indeterminate evidence of IPF or an alternate diagnosis (table 6) [8,13]. (See "Clinical manifestations and diagnosis of idiopathic pulmonary fibrosis", section on 'Diagnosis'.)

Differential diagnosis — The histopathologic features of UIP need to be differentiated from the other IIPs and pulmonary Langerhans cell histiocytosis (algorithm 1). (See "Approach to the adult with interstitial lung disease: Clinical evaluation" and "Approach to the adult with interstitial lung disease: Diagnostic testing" and "Pulmonary Langerhans cell histiocytosis".)

When evaluating patients with a lung biopsy demonstrating the histopathology of UIP, it is important to remember that a pattern of interstitial inflammation and fibrosis indistinguishable from UIP can occur in patients with rheumatic disease (eg, rheumatoid arthritis, systemic sclerosis), chronic hypersensitivity pneumonitis, familial pulmonary fibrosis, Hermansky-Pudlak syndrome, asbestosis, and certain drug-induced lung diseases (table 7) [22-25]. The finding of even rare poorly formed granulomas or giant cells in the interstitium should raise suspicion for chronic hypersensitivity pneumonia [25]. (See "Clinical manifestations and diagnosis of idiopathic pulmonary fibrosis", section on 'Differential diagnosis' and "Asbestos-related pleuropulmonary disease" and "Hypersensitivity pneumonitis (extrinsic allergic alveolitis): Clinical manifestations and diagnosis", section on 'Surgical lung biopsy'.)

Nonspecific interstitial pneumonia

Clinical context — Idiopathic NSIP can occur across a broad age range, but most commonly presents in patients 40 to 50 years of age. The most important clinical characteristics that distinguish NSIP from UIP are a subacute rather than insidious onset of symptoms, associated fever in about one-third of patients, lack of a strong male predominance, relative absence of clubbing in NSIP, and increased frequency of features suggestive of rheumatic disease. The most compelling distinction between idiopathic NSIP and IPF is related to outcome: NSIP has a significantly better prognosis [26-29]. Nearly 75 percent of patients with NSIP improve or recover, versus none of the patients with IPF. When NSIP follows a more aggressive clinical course, a predominance of fibrosis is noted on biopsy. Of note, around 20 percent of patients diagnosed with idiopathic NSIP develop an associated connective tissue disorder during follow-up [30].

A more detailed discussion of the clinical manifestations (image 2A-B), risk factors, prognosis, evaluation, and treatment of NSIP is provided separately. (See "Causes, clinical manifestations, evaluation, and diagnosis of nonspecific interstitial pneumonia" and "Treatment and prognosis of nonspecific interstitial pneumonia".)

Pathology — NSIP is a pathologic description of a chronic “nonspecific” interstitial pneumonia that lacks the histopathologic features typical of UIP, desquamative interstitial pneumonia (DIP), respiratory bronchiolitis-associated interstitial lung disease (RB-ILD), or acute interstitial pneumonia (AIP) (table 8). Examples of NSIP have undoubtedly been included in studies of IPF as "early" or "cellular" UIP. In a retrospective review of patients suspected of having IPF, 14 percent had NSIP, making it the second most common histological category [18].

While NSIP has a relatively uniform appearance at low magnification, the histological findings are variable between patients (table 9) [31-33]. The main abnormality is an interstitial pneumonia characterized by expansion of alveolar septa by a variably dense infiltrate of predominantly mononuclear inflammatory cells with or without associated fibrosis. As with any interstitial pneumonia, there is the usual range of associated nonspecific secondary changes, including epithelial hyperplasia and some airspace organization.

NSIP was initially divided into three groups based upon the presence and degree of interstitial fibrosis [34]. In a series of 64 patients, the majority had a prominent inflammatory component either without (Group I) or with (Group II) concomitant fibrosis (picture 2). Biopsies showing predominantly fibrosis (Group III) were the least common (9 of 64 patients) but accounted for a disproportionate number of patients (2 of 5) who died of their disease (picture 3). Later studies show no prognostic difference between Groups II and III [27], so the American Thoracic Society/European Respiratory Society (ATS/ERS) consensus was to merge NSIP into cellular and fibrotic subgroups [4,5].

The fibrotic changes noted in patients with fibrotic NSIP have the same peripheral subpleural distribution as that typically seen in UIP, but differ in that they are more temporally homogeneous in contrast to the variegated pattern typical of UIP [27,28]. These observations raise the possibility that some patients with fibrotic NSIP may in fact have UIP that is not fully appreciated in the lung biopsies.

Focal areas of organizing pneumonia resembling the histopathologic changes seen in the syndrome of cryptogenic organizing pneumonia (COP) are a common finding. NSIP differs from classical organizing pneumonia, however, in that "COP-like" areas represent less than 10 percent of the cross-sectional area of the lesional tissue and are overshadowed by the interstitial pneumonia. (See "Cryptogenic organizing pneumonia".)

The potential difficulty in separating fibrotic forms of NSIP from UIP was highlighted in a study of explanted specimens from transplant recipients who had undergone previous surgical lung biopsy [35]. Areas resembling NSIP are common as a nonspecific finding in cases of otherwise typical UIP. The key features important in accurately separating NSIP and UIP include:

Patchy involvement and fibrosis characterized by abrupt transitions resulting in a patchwork pattern

Architectural distortion that included honeycomb change and/or interstitial scarring

Fibroblast foci

None of these features taken on its own is diagnostic, but the three together excludes a diagnosis of NSIP.

SMOKING-RELATED INTERSTITIAL PNEUMONIAS — The category of smoking-related IIPs includes most cases of desquamative interstitial pneumonia (DIP) and nearly all cases of respiratory bronchiolitis-associated interstitial lung disease (RB-ILD). Neither RB-ILD nor DIP should be viewed as free standing histopathologic entities, since areas resembling both patterns are common as incidental findings in cigarette smokers. DIP and RB-ILD share several overlapping clinicopathologic features, and both have a better prognosis than usual interstitial pneumonia (UIP).

Given the dangers of sampling bias, RB-ILD and DIP should be diagnosed only when other forms of interstitial lung disease have been vigorously excluded, a process that requires correlation of biopsy findings with clinical and radiographic features. A review identified respiratory bronchiolitis in 109 of 156 consecutive surgical specimens; "DIP-like" areas were identified in six. Only two (1.8 percent) patients were thought to have either RB-ILD (1) or DIP (1) after careful correlation with clinical, radiologic, and pathologic findings [36].

Desquamative interstitial pneumonia

Clinical features — DIP is a distinct clinicopathologic entity that differs substantially from UIP (table 10). It is relatively uncommon, comprising 8 percent of biopsied Mayo Clinic patients suspected of having idiopathic pulmonary fibrosis (IPF), less than 3 percent of interstitial lung disease biopsies at National Jewish Health in Denver, Colorado, and 16 percent of patients in a series from the Pulmonary Branch of the United States National Heart, Lung, and Blood Institute [37].

DIP typically affects cigarette smokers in their fourth or fifth decades of life. While the vast majority (>90 percent) of patients with DIP are smokers, a small percentage of cases are associated with rheumatic diseases [38], drugs such as sirolimus [39], and marijuana smokers [40]. In children, a DIP pattern can be seen in patients with mutations in surfactant protein genes [5,41]. Physiologic testing usually shows mild reduction in lung volumes associated with a moderate decrease in diffusing capacity [42].

The radiographic abnormalities tend to be less severe than those seen in UIP; indeed, chest radiographs are normal in as many as one-fifth of patients. High-resolution computed tomography (HRCT) shows ground glass opacities without the peripheral reticular opacities characteristic of UIP (image 3) [43]. One review of HRCT findings found no evidence of progression from DIP to UIP, further supporting the concept that DIP and UIP are separate and distinct entities, with important differences in prognosis [44].

Pathology — The most striking feature of DIP is the presence of numerous mononuclear cells filling most of the distal air spaces (picture 4). The alveolar septa are lined by plump cuboidal pneumocytes and thickened by a sparse inflammatory infiltrate that often includes plasma cells and occasional eosinophils. There is usually minimal or mild associated fibrosis without honeycomb changes. The mononuclear cells represent smokers' macrophages rather than desquamated pneumocytes, as had been originally proposed. The smokers' macrophage contains light brown pigment flecked with tiny black particles; heavy tobacco use can lead to darker pigment [45]. Occasional alveolar giant cells may be noted [41].

Differentiating DIP from UIP DIP differs histologically from UIP in that the histopathologic changes of DIP tend to be much more uniform at low magnification and lack the variegated appearance typical of UIP (table 11 and picture 4) [5,41,45]. While smokers’ macrophages may be present in biopsies of UIP, the predominant features are temporal heterogeneity, areas of dense collagen deposition, and scattered fibroblast foci. (See 'Pathology' above.)

Differentiating DIP from RB-ILD The histopathologic changes of DIP (eg, intraluminal macrophages containing dusty light brown pigment) overlap with those of respiratory bronchiolitis and RB-ILD, as described below [46,47], although RB-ILD is bronchocentric and DIP is diffuse. DIP also shows a greater extent of eosinophilia, fibrosis, and germinal center formation [48]. (See 'Respiratory bronchiolitis-associated ILD' below.)

Differentiating DIP from alveolar hemorrhage – It is important to differentiate the dusty light brown pigment of smokers’ macrophages (on hematoxylin and eosin staining) from patients with DIP and the darker and coarser hemosiderin in macrophages from patients with alveolar hemorrhage [41]. Hemosiderin granules tend to be larger and refractile. Prussian blue staining (for iron) often reveals a faint blue blush in the macrophages from patients with DIP, compared with an intense dark blue in macrophages from alveolar hemorrhage.

Management — Smoking cessation is considered an essential component of the management of DIP in smokers, although the exact impact is unclear [49]. Some patients have improved with smoking cessation alone, but others have progressed despite cessation of smoking. Glucocorticoids have been reported to be beneficial in case series, although improvement may be temporary [38,43]. In a systematic review of reported cases of DIP, approximately 50 percent improved with smoking cessation and systemic glucocorticoid therapy [50]. A few patients have been treated with additional immunosuppressive agents including azathioprine and cyclophosphamide, although the response to these agents is not described [50]. The overall survival is 70 to 88 percent after 10 years [38,49,50]. Several studies have demonstrated 100 percent survival rates for DIP, but to some extent this reflects a trend toward excluding patients with associated fibrosis.

Respiratory bronchiolitis-associated ILD

Clinical context — Like DIP, RB-ILD is an uncommon form of interstitial pneumonia, accounting for only 2 percent of Mayo Clinic patients who underwent lung biopsy for suspicion of IPF. DIP and RB-ILD show significant clinical, radiologic, and histologic overlap, and in some patients the distinction is arbitrary and of uncertain clinical significance [46].

RB-ILD typically occurs during the fourth or fifth decades of life and almost always affects current smokers with average exposures of more than 30 pack-years of cigarette smoking (table 12) [36]. The clinical features of RB-ILD are nonspecific; symptoms include the subacute onset of dyspnea and new or changed cough. Characteristic HRCT findings are ground glass opacities and centrilobular nodules (image 4A-B) [4]. The epidemiology, clinical manifestations, evaluation, diagnosis, and management of RB-ILD are described separately. (See "Respiratory bronchiolitis-associated interstitial lung disease".)

Pathology — Respiratory bronchiolitis is defined by the presence of dusty light brown pigmented macrophages within the lumen of respiratory bronchioles (table 13 and picture 5). The changes are patchy at low magnification and have a bronchiolocentric distribution. Respiratory bronchioles, alveolar ducts, and peribronchiolar alveolar spaces contain clusters of macrophages. The lightly pigmented cells have abundant cytoplasm that contains finely granular, dusty brown particles. The cytoplasmic particles are periodic acid Schiff (PAS)-positive and also often stain faintly with Prussian blue. Positive staining with Prussian blue, an iron stain, correlates with observations of increased iron content in alveolar macrophages from cigarette smokers.

Intraluminal macrophages are accompanied by a patchy submucosal and peribronchiolar infiltrate of lymphocytes and histiocytes. The interstitial histiocytes may contain dusty light brown cytoplasmic pigment identical to that seen within the intraluminal macrophages, or they may contain coarse black anthracotic pigment. Peribronchiolar fibrosis is also seen and expands contiguous alveolar septa, which are lined by hyperplastic type 2 cells and cuboidal bronchiolar-type epithelium. The combination of alveolar septal thickening, epithelial hyperplasia, and pigmented intraluminal macrophages mimics the appearance of DIP.

Differential diagnosis — The histopathologic features of RB-ILD need to be differentiated from a number of interstitial lung diseases:

Desquamative interstitial pneumonia – The intraluminal macrophages in DIP usually contain dusty light brown pigment identical to that seen in RB-ILD and show the same positive staining reactions with PAS (pink) and Prussian blue (faintly blue). The main feature that distinguishes DIP from RB-ILD is that DIP affects the lung in a more uniform and diffuse manner, lacking the bronchiolocentric distribution seen in RB-ILD, but there is considerable clinical, radiologic, and histologic overlap between these entities. It is likely that DIP and RB-ILD are highly related if not identical lesions, differing only in the severity and extent of the abnormality (ie, RB-ILD = mild/early DIP). For that reason it has been suggested that all cases be grouped under the heading of RB-ILD, avoiding the historically entrenched but descriptively inaccurate term of "desquamative" interstitial pneumonia [46].

Usual interstitial pneumonia – Peribronchiolar fibrosis coupled with hyperplasia of peribronchiolar epithelium in RB-ILD may mimic the appearance of UIP. However, UIP differs from RB-ILD in that the interstitial changes are more peripherally situated and include alternating areas of inflammation, fibrosis, and honeycomb change, imparting a variegated appearance to the tissue at low magnification. In contrast, fibrosis is mild in RB-ILD, and honeycomb change does not occur. (See 'Usual interstitial pneumonia' above.)

Pulmonary Langerhans cell histiocytosis (PLCH) – PLCH (eosinophilic granuloma, Langerhans' granulomatosis) is frequently associated with a "DIP-like" reaction and also can resemble RB-ILD. At low magnification, however, PLCH is a predominantly interstitial lesion characterized by the presence of centrally scarred stellate nodules containing a polymorphic inflammatory infiltrate. Diagnosis of PLCH is predicated on recognition of characteristic Langerhans cells within the inflammatory infiltrate in the appropriate histological context. (See "Clinical manifestations, pathologic features, and diagnosis of Langerhans cell histiocytosis".)

Alveolar hemorrhage - Alveolar hemorrhage is also characterized by the presence of pigment-laden macrophages and can be confused with RB-ILD. Low magnification examination is helpful in distinguishing these conditions because the pigmented macrophages have a bronchiolocentric distribution in RB-ILD, as opposed to a more diffuse and random distribution in pulmonary hemorrhage. Other histological clues are often present in alveolar hemorrhage syndromes, including the presence of intra-alveolar erythrocytes with associated fibrin, and areas of organization resembling organizing pneumonia. The pigment in RB-ILD, like the pigment in DIP and "DIP-like" reactions, is finely dispersed and indistinct, imparting a dusty appearance to the cells. In contrast, hemosiderin pigment in pulmonary hemorrhage forms large, coarse, refractile granules that often have a yellow/gold hue. Both pigments stain positively with Prussian blue, but hemosiderin stains more brightly. (See "The diffuse alveolar hemorrhage syndromes".)

Smoking-related interstitial abnormalities — Subclinical interstitial lung abnormalities (ILA) appear common in smokers and these findings do not meet criteria for UIP, DIP, RB-ILD, or PLCH [51].

On HRCT, subclinical ILA are associated with parenchymal nodules with relatively low attenuation, ground-glass opacities, subpleural micronodules, and dependent areas of increased attenuation [52-57]. These radiographic findings have not been closely examined histopathologically. However, studies of lobectomy specimens from smokers without clinically defined interstitial lung disease have shown varying degrees of airspace enlargement and alveolar septal widening with collagen deposition, but without the temporal heterogeneity or fibroblast foci typical of UIP [58,59].

The histopathologic findings of smoking-related ILA appear to be distinct from combined pulmonary fibrosis (UIP) and emphysema (known as CPFE) [53,54,60-62], but may overlap with those of emphysematous airspace enlargement with associated interstitial fibrosis sometimes seen in smokers [63,64]. Other authors have described similar smoking related interstitial abnormalities that they termed RB-ILD with fibrosis [65].

ACUTE OR SUBACUTE IDIOPATHIC INTERSTITIAL PNEUMONIAS — Most of the IIPs are chronic processes characterized by an insidious onset and a progressive course.

Acute interstitial pneumonia

Clinical context — Acute interstitial pneumonia (AIP) presents with the explosive onset of respiratory symptoms and is characterized by rapidly progressive respiratory failure associated with diffuse opacities on chest radiographs. This acute form of IIP is analogous to the acute respiratory distress syndrome (ARDS), differing only in that it is not preceded by a catastrophic event (ie, the condition is idiopathic). (See "Acute respiratory distress syndrome: Clinical features, diagnosis, and complications in adults".)

Other terms have been proposed for this clinicopathological syndrome, including Hamman-Rich syndrome and accelerated interstitial pneumonia. Regardless of the terminology, the important point is that AIP should be distinguished from the group of chronic interstitial pneumonias because of marked differences in natural history. AIP has the same poor prognosis as ARDS, and the majority of patients die of respiratory failure [66]. (See "Acute interstitial pneumonia (Hamman-Rich syndrome)".)

Pathology — Histologically, AIP is identical to the organizing or proliferative stage of diffuse alveolar damage (DAD) (table 14). The main finding is extensive interstitial fibroblast proliferation within an edematous-appearing stroma (picture 6). Alveolar septa are dramatically thickened and are lined by hyperplastic type II pneumocytes that are often cytologically atypical. Hyaline membrane remnants are inconspicuous but may be present within occasional air spaces or within alveolar walls [67].

The main differential diagnosis in the setting of idiopathic interstitial lung disease in a non-immunocompromised patient is so-called accelerated idiopathic pulmonary fibrosis (IPF). The distinction depends not only on recognizing underlying usual interstitial pneumonia (UIP), but also on correlation with the clinical and radiographic findings. In a comparison of patients with AIP and patients suffering acute exacerbation of IPF reported only in abstract form, patients with accelerated IPF were older, more likely to have digital clubbing, and had radiographic features of UIP on high-resolution computed tomography (HRCT) scans. (See "Acute exacerbations of idiopathic pulmonary fibrosis".)

Cryptogenic organizing pneumonia — Cryptogenic organizing pneumonia (COP), the name applied to the idiopathic form of organizing pneumonia, is a distinct clinical entity with features of an inflammatory pneumonia rather than a primary airway disorder, thus the omission of the term “bronchiolitis obliterans” from the name. The histopathologic findings characteristic of COP include excessive proliferation of granulation tissue within small airways (proliferative bronchiolitis) and alveolar ducts, associated with chronic inflammation in the surrounding alveoli. COP is discussed separately. (See "Cryptogenic organizing pneumonia".)

RARE TYPES AND PATTERNS OF IIP — Idiopathic presentations of lymphoid interstitial pneumonia (LIP) and pleuroparenchymal fibroelastosis (PPFE) are rare [5,68,69]. The patterns of acute fibrinous and organizing pneumonia (AFOP) and bronchiolocentric interstitial pneumonia are considered histologic patterns rather than distinct IIPs and are also rare, especially idiopathic cases when subjected to thorough clinical review [5].

Idiopathic lymphoid interstitial pneumonia — LIP (also known as lymphocytic interstitial pneumonia) is one entity within a spectrum of lymphoproliferative disorders that can involve the lung. LIP is an uncommon histopathologic entity characterized by infiltration of the interstitium and alveolar spaces of the lung by lymphocytes, plasma cells, and other lymphoreticular elements. Many cases diagnosed as idiopathic LIP prior to 2002 would now be considered to be cellular nonspecific interstitial pneumonia. LIP is discussed in detail elsewhere. (See "Lymphoid interstitial pneumonia".)

Idiopathic pleuroparenchymal fibroelastosis — Idiopathic PPFE is a rare condition that is characterized by fibrosis of the pleura and subpleural lung parenchyma, predominantly affecting the upper lobes [69]. High-resolution computed tomography (HRCT) shows pleural thickening, dense subpleural consolidation with traction bronchiectasis, architectural distortion, and upper lobe volume loss. On histopathology, the lung parenchyma shows changes of intra-alveolar fibrosis and elastosis, with overlying thickening of the visceral pleura. Some patients will show coexistent other patterns such as usual interstitial pneumonia (UIP) or features of hypersensitivity pneumonitis [70]. (See 'Pathology' above.)

Acute fibrinous and organizing pneumonia pattern — AFOP is a histologic pattern characterized by intraalveolar fibrin deposition (fibrin "balls") and associated organizing pneumonia (OP), but without the hyaline membranes found in diffuse alveolar damage (DAD). The distribution of AFOP is patchy, typically involving the alveoli and terminal bronchioles, DAD is usually more diffuse and affects all aspects of the lung parenchyma [71]. (See "Interpretation of lung biopsy results in interstitial lung disease", section on 'Rare histopathologic interstitial pneumonia patterns'.)

It is unclear whether AFOP is a distinct entity or a part of the spectrum of DAD and OP. It is associated with a clinical picture of acute lung injury and can be idiopathic but is more commonly associated with other processes such as hypersensitivity pneumonitis, infection (including coronavirus disease 2019 [COVID-19]), drug toxicity, eosinophilic pneumonia, and rheumatic disease [5,72-74].

Bronchiolocentric interstitial pattern — A pattern of bronchiolocentric fibroinflammatory changes has been described in case reports [5,75-77]. Affected patients tend to be 40 to 50 years of age, but may be older or younger; approximately 80 percent are women [77]. The most common complaints are dyspnea and nonproductive cough, but wheezing and chest pain are also reported. Most patients describe an insidious onset of symptoms. HRCT is normal or shows air trapping. On histopathology, the centrilobular inflammatory process radiates into the interstitium. The distribution is similar to hypersensitivity pneumonitis, but granulomas are not seen. This pattern is more commonly seen in patients with an occupational or environmental exposure, but idiopathic occurrences have been described.

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Interstitial lung disease".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

Basics topic (see "Patient education: Idiopathic pulmonary fibrosis (The Basics)")

SUMMARY AND RECOMMENDATIONS

Definitions and terms – The idiopathic interstitial pneumonias (IIPs) are a subset of diffuse interstitial lung diseases with unknown etiology. The IIPs are classified based on their histopathologic appearance, and include usual interstitial pneumonia (UIP), nonspecific interstitial pneumonia (NSIP), desquamative interstitial pneumonia (DIP), respiratory bronchiolitis-associated interstitial lung disease (RB-ILD), acute interstitial pneumonia (AIP), and cryptogenic organizing pneumonia (COP), as outlined in a joint American Thoracic Society and European Respiratory Society (ATS/ERS) statement (table 2 and table 15). (See 'Classification' above.)

Chronic fibrosing interstitial pneumonias – Among IIPs, UIP and NSIP, are categorized as chronic fibrosing interstitial pneumonias and are the most common. (See 'Chronic fibrosing interstitial pneumonias' above.)

Usual interstitial pneumonia – UIP is the most specific form of the IIPs and can be defined based on its morphologic features alone. The histologic hallmark and chief diagnostic criterion for UIP is a heterogeneous appearance with alternating areas of normal lung, interstitial inflammation, fibroblast foci, and honeycomb change. The clinical counterpart of UIP is idiopathic pulmonary fibrosis (IPF). (See 'Usual interstitial pneumonia' above.)

Nonspecific interstitial pneumonia – The histological findings of NSIP are variable, but features of UIP, DIP, RB-ILD, and AIP are absent (table 9). The main feature in all cases is an interstitial pneumonia characterized by expansion of alveolar septa by a variably dense infiltrate of predominantly mononuclear inflammatory cells with or without associated fibrosis. NSIP can be considered "cellular" in the absence of fibrosis (picture 2) or "fibrotic" when fibrosis is present (picture 3). (See 'Nonspecific interstitial pneumonia' above.)

Smoking-related idiopathic interstitial pneumonias – The category of smoking-related IIPs includes most cases of DIP and nearly all cases of RB-ILD. (See 'Smoking-related interstitial pneumonias' above.)

Desquamative interstitial pneumonia – The most striking histopathologic feature of DIP is the presence of numerous macrophages (smokers' macrophages) within most of the distal air spaces. DIP differs histologically from UIP in that the changes tend to be much more uniform at low magnification and lack the variegated appearance typical of UIP (table 11 and picture 4). (See 'Desquamative interstitial pneumonia' above.)

Respiratory bronchiolitis-associated interstitial lung disease – The key histopathologic feature of RB-ILD is the presence of pigmented macrophages within the lumen of respiratory bronchioles, similar to those seen in DIP (table 13 and picture 5). The main feature that distinguishes DIP from RB-ILD is that DIP affects the lung in a more uniform and diffuse manner and lacks the bronchiolocentric distribution seen in RB-ILD. However, considerable clinical, radiologic, and histologic overlap exists between these entities. (See 'Respiratory bronchiolitis-associated ILD' above.)

Acute or subacute presentations – The IIPs with acute or subacute presentations are AIP and COP. AIP presents with the explosive onset of respiratory symptoms and rapidly progressive respiratory failure, while COP usually has a subacute onset.

Acute interstitial pneumonia – Histologically, AIP is identical to the organizing or proliferative stage of diffuse alveolar damage (DAD) (table 14). The main finding is extensive interstitial fibroblast proliferation within an edematous-appearing stroma (picture 6). When AIP complicates underlying UIP, the process is called an acute exacerbation (or accelerated) IPF. (See 'Acute interstitial pneumonia' above and "Acute interstitial pneumonia (Hamman-Rich syndrome)".)

Cryptogenic organizing pneumonia – The histopathologic lesions characteristic of COP include excessive proliferation of granulation tissue within small airways (proliferative bronchiolitis) and alveolar ducts, associated with chronic inflammation in the surrounding alveoli. (See 'Cryptogenic organizing pneumonia' above and "Cryptogenic organizing pneumonia".)

Rare idiopathic interstitial pneumonias – Idiopathic presentations of lymphoid interstitial pneumonia (LIP) and pleuroparenchymal fibroelastosis (PPFE) are rare forms of IIP. Acute fibrinous and organizing pneumonia (AFOP) and bronchiolocentric interstitial pneumonia are considered histologic patterns rather than distinct IIPs and are also rare. (See 'Rare types and patterns of IIP' above.)

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Topic 4302 Version 29.0

References

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