**4. Pulmonary histopathology in connective tissue disease**

**3.3. Laboratory tests and biomarkers**

152 Contemporary Topics of Pneumonia

drug-induced pneumonitis, etc. [24, 26].

nological characteristics will be explained later.

**autoimmune features (IPAF)**

Since the spectrum of ILD associated with CTD is broad, careful evaluation for autoantibodies or other serologic tests in conjunction with clinical features of autoimmune disease is crucial [19, 20]. Because of the variable incidence and outcome of ILD in CTD, biomarkers including autoantibodies are critical for diagnosis, prognosis, patient subtyping, and predicting response to treatment. Major autoantibodies and serologic tests commonly available for the evaluation of CTD-ILDs include antinuclear antibody (ANA), anti-double-stranded DNA, anti-ribonucleoprotein (anti-RNP) antibody, anti-Smith (anti-Sm) antibody, anti-scleroderma-70 (Scl-70) antibody, anti-Ro (SS A), anti-La (SS B), anti-Jo-1 antibody, rheumatoid fac-

Some of the established biomarkers include lung epithelium-specific proteins [20]. Evidence indicates that repetitive injuries to alveolar epithelial cells (AEC) and airway Club cells trigger an exaggerated wound healing response. During the process, while AEC type I cells undergo apoptosis, regenerated hyperplastic AEC type II cells produce a vast array of cytokines, growth factors, and release surfactant proteins and mucins [21]. Surfactant proteins (SP-A and SP-D) and KL-6 in the serum are useful biomarkers, which have been well established for various ILDs. SP-D and SP-A, secreted by AEC II and airway Club cells, are surfactant lipoproteins and phospholipids which stabilize alveolar surface tension, playing an important role in the lung host defense system [22]. SP-D serum levels are more sensitive than SP-A in detecting ILD as defined by CT but less specific [23]. KL-6 is a high-molecular-weight mucinlike glycoprotein, now classified as MUC1, which is highly expressed by AEC II and bronchiolar epithelial cells and increases following cellular injury and/or regeneration [24]. KL-6 has profibrotic and antiapoptotic effects on lung fibroblasts [25]. Serum KL-6 has been shown to be elevated not only in IIP but also in CTD-ILD, as well as hypersensitivity pneumonitis,

There are a number of principal autoantibodies which have been validated for the clinical use. Antinuclear antibody (ANA) determined by an immunofluorescence assay is most versatile, presenting with several major patterns; mainly homogeneous (associated with ANAs against double strand (ds) DNA in SLE and histones), speckled/peripheral (less specific), and nuclear (most often associated with limited scleroderma). ANA titer higher than 1–160 is regarded as significant in most laboratories [27]. When using enzyme immunoassay (EIA) and enzymelinked immunosorbent assay (ELISA) for ANAs, we can detect single autoantigens such as dsDNA, Smith antigen, scleroderma (Scl-70) (also termed topoisomerase-1), SSA/Ro, SSB/La, etc. [27]. Some of the recent, newly developed autoantibodies with distinct clinical and immu-

**3.4. Undifferentiated connective tissue disease (UCTD) and interstitial pneumonia with** 

Besides classical, well-established CTDs, increasing attention has been paid to pulmonary involvement in undifferentiated CTD (UCTD) [15, 17, 28–30]. UCTD has been generally defined as a condition that presents with signs and symptoms suggestive of CTDs along with

tor (RF), and anti-cyclic citrullinated peptide antibody (ACPA) [5].

The underlying pathology in CTD-associated ILD can be dominated by inflammation or fibrosis or by a combination of both with distinct radiologic and histopathologic patterns [12]. Classification of histological and radiological patterns developed for IIPs is applied to CTD-ILD [1, 5, 11]. The radiological and corresponding histological patterns defining each entity of CTD-associated IP are summarized in **Table 2** [11]. Although there is substantial histological overlap among the pulmonary manifestations of different CTDs and with other etiologies, certain histologic patterns may favor one CTD over another, and occasionally distinctive histologic clues may be present [35, 36]. It is possible in many cases to confirm CTD-ILD and guide patient management using histologic features. Pulmonary histopathology is thus helpful, and surgical lung biopsy remains the gold standard for evaluation of CTD-associated ILD [35]. ILD can present acutely or chronically, with acute presentations being more common in SLE and PM/DM. Histological patterns of CTD-associated IP include, most frequently, nonspecific interstitial pneumonia (NSIP), usual interstitial pneumonia (UIP), organizing pneumonia (OP), diffuse alveolar damage (DAD), and lymphocytic interstitial pneumonia (LIP). By contrast, desquamative interstitial pneumonia (DIP) and respiratory bronchiolitisassociated interstitial pneumonia (RB-ILD) are uncommon forms of IP in CTD. Both, typically affecting cigarette smokers, share overlapping clinicopathological features and have a relatively better prognosis than UIP.

## **4.1. Nonspecific interstitial pneumonia (NSIP)**

In the history of classification, the recognition that the cases of ILD exist from which lung biopsy samples do not fit into any well-defined histologic patterns of idiopathic IP led to proposals of the terms "unclassified interstitial pneumonia" by Kitaichi in 1990 [37] and "nonspecific interstitial pneumonia/fibrosis (NSIP)" by Katzenstein and Fiorelli in 1994 [38]. This novel concept has helped to identify a group of ILDs with a more favorable prognosis and which needs to be distinguished from IPF/UIP, while also having different characteristics from DIP, AIP, and COP [1]. Katzenstein, in her large study of 64 such cases, utilized the descriptive term "nonspecific interstitial pneumonia/fibrosis (NSIP)," which was characterized by varying proportions of interstitial inflammation and fibrosis that appeared to be occurring over a single time span (i.e., a temporally uniform process). NSIP may have varying etiologies, including underlying CTD as well as organic dust or other exposures [38]. Subsequent intensive studies in collaboration with pathologists and radiologists have endorsed its differentiation from other types of IP, gaining the term NSIP, a broad acceptance [39, 40]. NSIP pattern of lung injury, itself further subdivided into cellular and fibrotic NSIP, is the most common pattern of IP in all CTDs except for RA, in which UIP pattern pathology may be more common [41, 42]. NSIP lung injury is characterized by diffuse, although often variable, alveolar septal thickening due to collagen deposition. The amount of associated interstitial inflammation varies, but in most cases, it consists of mild patchy lymphoplasmacytic infiltrate. Although NSIP is not a pattern specific to CTD-IP, there are several histologic clues which support CTD, and when found, make the diagnosis of CTD-IP more likely [35].

In SSc-ILD, UIP pattern was found in 15% in one study and 26% in another. UIP pattern has also been reported in 17% of Sjögren's syndrome cases in a study. Whereas idiopathic pulmonary fibrosis (IPF) is a progressively deteriorating ILD, in which the characteristic histological pattern of IPF is UIP; interestingly, a UIP pattern is associated with a significantly better survival in CTD compared to the IPF [43]. Histologically, CTD-associated UIP biopsies had fewer fibroblastic foci, smaller honeycombing spaces, higher numbers of germinal centers,

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Since 1935, when Louis Hamman and Arnold Rich described four patients with acute respiratory failure of unknown etiology, the existence of cases which manifest acute respiratory failure with bilateral lung infiltrates has been recognized [45]. All four patients died and were revealed at autopsy to have a distinctive pathology that in modern times is recognized as the organizing stage of diffuse alveolar damage (DAD). This acute idiopathic respiratory condition was subsequently given the eponym Hamman-Rich syndrome. Although the histology of DAD was described even earlier, the term of "diffuse alveolar damage" (DAD) was presented by Katzenstein, et al. in their comprehensive review with their own data [46]. They concluded that endothelial and alveolar cell injury leads to fluid and cellular exudation, with hyaline

The term "acute interstitial pneumonia" (AIP) was introduced in 1986 by Katzenstein et al. for cases identical to the Hamman-Rich syndrome to lay emphasis on the fact that the condition is an acute form of idiopathic interstitial lung disease, clinically and histologically distinct from chronic forms, the prototype of which is IPF [47]. The prognosis of AIP is dismal and the mortality high. Today, AIP is defined by the following key elements: acute onset of respiratory symptoms typically resulting in acute respiratory failure; bilateral lung infiltrates on radiographs; the absence of identifiable etiology; and histological documentation of DAD [1, 47, 48]. Whereas the term AIP is applied when DAD is of unknown etiology, similar injury due to a known cause is generally referred to as DAD (stating the cause or the underlying disease). DAD is thus a histologic pattern of injury usually associated with a life-threatening acute or subacute presentation which often correlates with the clinical entity of acute respiratory distress syndrome (ARDS) [49]. In earliest phase, the histology of DAD comprises alveolar septal edema and fibrin deposition in airspace. Over hours to days, these changes are accompanied by fibroplasia in alveolar septa, accumulation of alveolar macrophages (including foam cells), and formation of hyaline membranes [50]. Organizing thrombi are often found in small to medium-sized arteries. Within days to weeks after injury, airspace plugs of organizing pneumonia and type II pneumocytes hyperplasia on alveolar surfaces become prominent, repre-

Besides AIP, infection is the most important etiology to exclude in patients in whom a diagnosis of AIP is clinically considered. Infectious etiology includes fungi, pneumocystis organisms, and viruses such as cytomegalovirus (CMV), etc. Despite prominent neutrophilia observed in bronchoalveolar lavage (BAL) fluid samples, there is usually a paucity of inflammatory cells on histologic sections in case of AIP. If prominent acute inflammation is seen, particularly in

and higher inflammation scores than IPF/UIP biopsies [44].

membranes and edema being well-known features.

senting a histologic pattern described as "organizing DAD."

**4.3. Diffuse alveolar damage (DAD)**


#### **4.2. Usual interstitial pneumonia (UIP)**

UIP is the prototype of histopathology which characterizes IPF, a chronic form of idiopathic interstitial lung disease [1, 2]. UIP pattern is often encountered in CTD-IP, with more prevalence in advanced cases. This pattern is classically identified by its patchy nature (spatial heterogeneity) and chronic active appearance (temporal heterogeneity). Fibrosis is accentuated in the subpleural regions with microscopic honeycombing observed as irregular airspaces surrounded by dense fibrosis. Fibroblast foci (regions of new fibrosis) are found at the interface between central and peripheral regions [35]. While primary UIP pattern is found in 13–56% of RA-ILD cases, some studies have reported that the most frequent histologic pattern of ILD among RA patients is NSIP, followed closely by UIP, accounting for 30–67% and 13–57% of RA-ILD, respectively [36]. Studies of PM/DM-ILD identified an UIP pattern in 5–33% of cases. In SSc-ILD, UIP pattern was found in 15% in one study and 26% in another. UIP pattern has also been reported in 17% of Sjögren's syndrome cases in a study. Whereas idiopathic pulmonary fibrosis (IPF) is a progressively deteriorating ILD, in which the characteristic histological pattern of IPF is UIP; interestingly, a UIP pattern is associated with a significantly better survival in CTD compared to the IPF [43]. Histologically, CTD-associated UIP biopsies had fewer fibroblastic foci, smaller honeycombing spaces, higher numbers of germinal centers, and higher inflammation scores than IPF/UIP biopsies [44].

#### **4.3. Diffuse alveolar damage (DAD)**

**4.1. Nonspecific interstitial pneumonia (NSIP)**

154 Contemporary Topics of Pneumonia

when found, make the diagnosis of CTD-IP more likely [35].

can be helpful in differentiation of it from IPF.

ants of chronic hypersensitivity pneumonia, etc.

**4.2. Usual interstitial pneumonia (UIP)**

In the history of classification, the recognition that the cases of ILD exist from which lung biopsy samples do not fit into any well-defined histologic patterns of idiopathic IP led to proposals of the terms "unclassified interstitial pneumonia" by Kitaichi in 1990 [37] and "nonspecific interstitial pneumonia/fibrosis (NSIP)" by Katzenstein and Fiorelli in 1994 [38]. This novel concept has helped to identify a group of ILDs with a more favorable prognosis and which needs to be distinguished from IPF/UIP, while also having different characteristics from DIP, AIP, and COP [1]. Katzenstein, in her large study of 64 such cases, utilized the descriptive term "nonspecific interstitial pneumonia/fibrosis (NSIP)," which was characterized by varying proportions of interstitial inflammation and fibrosis that appeared to be occurring over a single time span (i.e., a temporally uniform process). NSIP may have varying etiologies, including underlying CTD as well as organic dust or other exposures [38]. Subsequent intensive studies in collaboration with pathologists and radiologists have endorsed its differentiation from other types of IP, gaining the term NSIP, a broad acceptance [39, 40]. NSIP pattern of lung injury, itself further subdivided into cellular and fibrotic NSIP, is the most common pattern of IP in all CTDs except for RA, in which UIP pattern pathology may be more common [41, 42]. NSIP lung injury is characterized by diffuse, although often variable, alveolar septal thickening due to collagen deposition. The amount of associated interstitial inflammation varies, but in most cases, it consists of mild patchy lymphoplasmacytic infiltrate. Although NSIP is not a pattern specific to CTD-IP, there are several histologic clues which support CTD, and

• Involvement of multiple lung components: concurrent involvement of alveolar septal interstitium, airways, vessels, and pleura is an important clue to the diagnosis of CTD-IP and

• Interstitial fibrosis with overlapping NSIP and UIP: a histologic overlap of UIP and NSIP patterns is frequently shown in CTD, although similar findings may be seen in some vari-

• Lymphoid aggregates: formation of prominent lymphoid aggregates, often with germinal centers, is a characteristic feature of CTD-IP, classically seen in RA and Sjögren's syndrome.

UIP is the prototype of histopathology which characterizes IPF, a chronic form of idiopathic interstitial lung disease [1, 2]. UIP pattern is often encountered in CTD-IP, with more prevalence in advanced cases. This pattern is classically identified by its patchy nature (spatial heterogeneity) and chronic active appearance (temporal heterogeneity). Fibrosis is accentuated in the subpleural regions with microscopic honeycombing observed as irregular airspaces surrounded by dense fibrosis. Fibroblast foci (regions of new fibrosis) are found at the interface between central and peripheral regions [35]. While primary UIP pattern is found in 13–56% of RA-ILD cases, some studies have reported that the most frequent histologic pattern of ILD among RA patients is NSIP, followed closely by UIP, accounting for 30–67% and 13–57% of RA-ILD, respectively [36]. Studies of PM/DM-ILD identified an UIP pattern in 5–33% of cases. Since 1935, when Louis Hamman and Arnold Rich described four patients with acute respiratory failure of unknown etiology, the existence of cases which manifest acute respiratory failure with bilateral lung infiltrates has been recognized [45]. All four patients died and were revealed at autopsy to have a distinctive pathology that in modern times is recognized as the organizing stage of diffuse alveolar damage (DAD). This acute idiopathic respiratory condition was subsequently given the eponym Hamman-Rich syndrome. Although the histology of DAD was described even earlier, the term of "diffuse alveolar damage" (DAD) was presented by Katzenstein, et al. in their comprehensive review with their own data [46]. They concluded that endothelial and alveolar cell injury leads to fluid and cellular exudation, with hyaline membranes and edema being well-known features.

The term "acute interstitial pneumonia" (AIP) was introduced in 1986 by Katzenstein et al. for cases identical to the Hamman-Rich syndrome to lay emphasis on the fact that the condition is an acute form of idiopathic interstitial lung disease, clinically and histologically distinct from chronic forms, the prototype of which is IPF [47]. The prognosis of AIP is dismal and the mortality high. Today, AIP is defined by the following key elements: acute onset of respiratory symptoms typically resulting in acute respiratory failure; bilateral lung infiltrates on radiographs; the absence of identifiable etiology; and histological documentation of DAD [1, 47, 48]. Whereas the term AIP is applied when DAD is of unknown etiology, similar injury due to a known cause is generally referred to as DAD (stating the cause or the underlying disease).

DAD is thus a histologic pattern of injury usually associated with a life-threatening acute or subacute presentation which often correlates with the clinical entity of acute respiratory distress syndrome (ARDS) [49]. In earliest phase, the histology of DAD comprises alveolar septal edema and fibrin deposition in airspace. Over hours to days, these changes are accompanied by fibroplasia in alveolar septa, accumulation of alveolar macrophages (including foam cells), and formation of hyaline membranes [50]. Organizing thrombi are often found in small to medium-sized arteries. Within days to weeks after injury, airspace plugs of organizing pneumonia and type II pneumocytes hyperplasia on alveolar surfaces become prominent, representing a histologic pattern described as "organizing DAD."

Besides AIP, infection is the most important etiology to exclude in patients in whom a diagnosis of AIP is clinically considered. Infectious etiology includes fungi, pneumocystis organisms, and viruses such as cytomegalovirus (CMV), etc. Despite prominent neutrophilia observed in bronchoalveolar lavage (BAL) fluid samples, there is usually a paucity of inflammatory cells on histologic sections in case of AIP. If prominent acute inflammation is seen, particularly in the airspaces, it raises suspicion of infection. Other clues to specific etiologies include viral cytopathic changes observed in some viral pneumonias (e.g., cytomegalovirus, respiratory syncytial virus, adenovirus); food or other foreign material (with or without giant cell reaction) suggesting aspiration; and prominent eosinophilia suggesting a primary eosinophilic disorder such as eosinophilic granulomatosis with polyangiitis (EGPA/Churg–Strauss syndrome) or acute eosinophilic pneumonia [35].

note, OP can occasionally be the inaugural manifestation of RA [58]. In PM/DM-ILD, OP is common; OP as the primary pattern was present in 6 of 15 cases (40%) in one series, 5 of 13 (38%) in another [53, 59]. In a study of cases with Sjögren's syndrome reported, OP was found in 4 of 18 biopsies (22%) in the series [51]. By contrast, OP is a very rare manifestation in SSc;

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The term "lymphocytic interstitial pneumonia" (LIP) refers to a pattern of IP in cases with diffuse and marked thickening of alveolar septal interstitium predominantly by dense lymphocytic infiltrate [61]. The infiltrate is polyclonal and may be admixed with variable numbers of plasma cells and macrophages. Germinal centers are frequently present. Histologically, LIP overlaps with follicular bronchiolitis and nodular lymphoid hyperplasia. When present, LIP pattern may raise concern for a possible lymphoproliferative process, which should be ruled out using appropriate immunohistochemical studies and flow cytometric analyses [35]. It should be noted that LIP has been associated with some viral infections, particularly human immunodeficiency virus. Classically, LIP was well-recognized in Sjögren's-associated ILD, where it was initially reported in at least 25% of cases based on a series of 12 biopsies [62]. A more recent study identified LIP primary pattern in 3 of 18 cases of Sjögren's-ILD (17%) [51].

**5. Characteristic of interstitial lung disease in major connective tissue** 

SSc is recognized as the CTD with the highest prevalence of ILD, ranging from 40 to 80%, depending on the modalities used for ascertainment [63]. The frequency of ILD varies according to patient selection, subsets of skin disease extent and ethnicity. In a large autopsy study, ILD was the most common pulmonary lesion in SSc, being found in >70% of the cases, and arteriolar thickening, described as medial hypertrophy or concentric intimal proliferation, was the most specific lesion in the lungs suggestive of pulmonary hypertension, being noted in 29% of the patients [64]. SSc, classically "scleroderma," is defined by the presence of major criteria; i.e., skin thickening proximal to metacarpo-phalangeal joints and minor criteria; i.e., sclerodactyly, esophageal involvement, and lung fibrosis [65]. It is subdivided into a limited cutaneous form, including CREST (Calcinosis, Raynaud's syndrome, Esophageal dysmotility, Sclerodactyly, Telangiectasia) syndrome and a diffuse cutaneous form (diffuse SSc has skin sclerosis proximal to elbows and knees), with varying degrees of skin, esophageal, lung, car-

As mentioned above, pulmonary manifestations in SSc include ILD and vascular disorder manifesting as pulmonary arterial hypertension (PAH). Today, both pulmonary complications are the leading cause of morbidity and mortality in patients with SSc. In line with SSc as the vasculature disorder, ranging from Raynaud' s phenomenon to PAH and renal crisis,

diac, and vascular involvement. Both forms can be progressive in nature.

detected only in 1 of 80 cases in a large series [60].

**5.1. Interstitial lung disease in systemic sclerosis**

**4.5. Lymphocytic interstitial pneumonia (LIP)**

**disease**

CTDs are another major group of diseases that may manifest pathologically as DAD. To identify CTD as an etiology of DAD in patients, exclusion of other possible cause must be established. Of note, DAD usually occurs in patients with established CTD-ILD but also can occasionally be the presenting manifestation of the disease [51]. In CTD patients who initially present with DAD, rheumatologic manifestations and serological tests should help to establish the correct diagnosis. In patients with CTD on immunosuppressive therapy, infectious etiology and drug toxicity should be considered as a potential cause of DAD. In SLE, cases of diffuse alveolar hemorrhage commonly show histological features of DAD [52]. In PM/DM, an older case series found DAD pattern in 4 of 15 cases (27%); a more recent series identified DAD in 2 of 70 cases (3%), possibly reflecting improvements in diagnosis and treatment of this disease [53, 54]. A study suggests that DAD is more common in DM-ILD than in PM-ILD [55]. In RA, one study reported primary DAD pattern found in 2 of 33 cases (6%) [56]. In a more recent study of CTDassociated DAD, RA accounted for five of nine cases; in four cases, DAD occurred in patients with established, pre-existing RA-ILD, whereas one manifested as a de novo presentation [51].

#### **4.4. Organizing pneumonia (OP)**

While OP is characterized by fibrosis and chronic inflammation like IP, it differs in that the reaction affects predominantly the airspaces rather than the interstitium; this disorder is not an interstitial process [57]. However, many include OP in the classification of IP [40]. OP is histologically characterized by consolidation of airspaces by rounded branching polypoid plugs of granulation tissue [35]. This airspace organization is usually found in the alveoli as well as terminal airways. Pure involvement of airways is rare, and thus, it should raise suspicion of a primary small airway disease. Alveolar macrophages with foamy cytoplasm are often found; however, this nonspecific finding may also be observed in cases of aspiration or drug toxicity. Usually, there are not abundant neutrophils in the histology of OP. If prominent inflammation, particularly involving the airspaces, is found, it should raise suspicion of infection as a cause. Also, when eosinophils are prominent in the airspace, suspicion of a primary eosinophilic disorder, e.g., EGPA/Churg-Strauss syndrome, eosinophilic pneumonia, etc., or a drug adverse reaction must be raised. Overall, a predominant OP pattern, if encountered, accounts for a broad range of differential diagnosis to be considered, which include CTD, infectious pneumonia (particularly viral or atypical bacterial), aspiration, and drug toxicity. Thus, after all diagnostic exclusion is made, cryptogenic organizing pneumonia (COP) is determined as the diagnosis.

In many cases of CTD, the associated ILD may demonstrate focal lesions of OP pattern superimposed on a background of the other patterns of IP, frequently seen in NSIP. Therefore, true OP is less common in CTD-ILD. Among the RA-ILD, one study reported a primary OP pattern in 2 of 18 cases of RA-ILD (11%), and another stated 6 of 40 cases (15%) [42, 56]. Of note, OP can occasionally be the inaugural manifestation of RA [58]. In PM/DM-ILD, OP is common; OP as the primary pattern was present in 6 of 15 cases (40%) in one series, 5 of 13 (38%) in another [53, 59]. In a study of cases with Sjögren's syndrome reported, OP was found in 4 of 18 biopsies (22%) in the series [51]. By contrast, OP is a very rare manifestation in SSc; detected only in 1 of 80 cases in a large series [60].

#### **4.5. Lymphocytic interstitial pneumonia (LIP)**

the airspaces, it raises suspicion of infection. Other clues to specific etiologies include viral cytopathic changes observed in some viral pneumonias (e.g., cytomegalovirus, respiratory syncytial virus, adenovirus); food or other foreign material (with or without giant cell reaction) suggesting aspiration; and prominent eosinophilia suggesting a primary eosinophilic disorder such as eosinophilic granulomatosis with polyangiitis (EGPA/Churg–Strauss syn-

CTDs are another major group of diseases that may manifest pathologically as DAD. To identify CTD as an etiology of DAD in patients, exclusion of other possible cause must be established. Of note, DAD usually occurs in patients with established CTD-ILD but also can occasionally be the presenting manifestation of the disease [51]. In CTD patients who initially present with DAD, rheumatologic manifestations and serological tests should help to establish the correct diagnosis. In patients with CTD on immunosuppressive therapy, infectious etiology and drug toxicity should be considered as a potential cause of DAD. In SLE, cases of diffuse alveolar hemorrhage commonly show histological features of DAD [52]. In PM/DM, an older case series found DAD pattern in 4 of 15 cases (27%); a more recent series identified DAD in 2 of 70 cases (3%), possibly reflecting improvements in diagnosis and treatment of this disease [53, 54]. A study suggests that DAD is more common in DM-ILD than in PM-ILD [55]. In RA, one study reported primary DAD pattern found in 2 of 33 cases (6%) [56]. In a more recent study of CTDassociated DAD, RA accounted for five of nine cases; in four cases, DAD occurred in patients with established, pre-existing RA-ILD, whereas one manifested as a de novo presentation [51].

While OP is characterized by fibrosis and chronic inflammation like IP, it differs in that the reaction affects predominantly the airspaces rather than the interstitium; this disorder is not an interstitial process [57]. However, many include OP in the classification of IP [40]. OP is histologically characterized by consolidation of airspaces by rounded branching polypoid plugs of granulation tissue [35]. This airspace organization is usually found in the alveoli as well as terminal airways. Pure involvement of airways is rare, and thus, it should raise suspicion of a primary small airway disease. Alveolar macrophages with foamy cytoplasm are often found; however, this nonspecific finding may also be observed in cases of aspiration or drug toxicity. Usually, there are not abundant neutrophils in the histology of OP. If prominent inflammation, particularly involving the airspaces, is found, it should raise suspicion of infection as a cause. Also, when eosinophils are prominent in the airspace, suspicion of a primary eosinophilic disorder, e.g., EGPA/Churg-Strauss syndrome, eosinophilic pneumonia, etc., or a drug adverse reaction must be raised. Overall, a predominant OP pattern, if encountered, accounts for a broad range of differential diagnosis to be considered, which include CTD, infectious pneumonia (particularly viral or atypical bacterial), aspiration, and drug toxicity. Thus, after all diagnostic exclusion is made, cryptogenic organizing pneumonia (COP) is determined as the diagnosis.

In many cases of CTD, the associated ILD may demonstrate focal lesions of OP pattern superimposed on a background of the other patterns of IP, frequently seen in NSIP. Therefore, true OP is less common in CTD-ILD. Among the RA-ILD, one study reported a primary OP pattern in 2 of 18 cases of RA-ILD (11%), and another stated 6 of 40 cases (15%) [42, 56]. Of

drome) or acute eosinophilic pneumonia [35].

156 Contemporary Topics of Pneumonia

**4.4. Organizing pneumonia (OP)**

The term "lymphocytic interstitial pneumonia" (LIP) refers to a pattern of IP in cases with diffuse and marked thickening of alveolar septal interstitium predominantly by dense lymphocytic infiltrate [61]. The infiltrate is polyclonal and may be admixed with variable numbers of plasma cells and macrophages. Germinal centers are frequently present. Histologically, LIP overlaps with follicular bronchiolitis and nodular lymphoid hyperplasia. When present, LIP pattern may raise concern for a possible lymphoproliferative process, which should be ruled out using appropriate immunohistochemical studies and flow cytometric analyses [35]. It should be noted that LIP has been associated with some viral infections, particularly human immunodeficiency virus. Classically, LIP was well-recognized in Sjögren's-associated ILD, where it was initially reported in at least 25% of cases based on a series of 12 biopsies [62]. A more recent study identified LIP primary pattern in 3 of 18 cases of Sjögren's-ILD (17%) [51].
