Treatment options for RB-ILD are limited but must include smoking cessation at the forefront. Studies are mixed regarding the reversibility of the disease process with smoking cessation with some studies arguing that there are signi cant improvement in symptoms, pulmonary function, and imaging while others argue that there is merely stabilization [28, 29]. In some cases a trial of corticosteroids is used. Once again, results are mixed but studies suggest that there is no consistent improvement in symptoms or pulmonary function with corticosteroid treatment and therefore is not routinely recommended [29]. Empiric dosing of prednisone 0.5 mg/ kg/day has been tried with most tapers lasting 3–9 months depending on response. Steroids are usually reserved for patient with a documented decline in lung function despite abstinence from smoking. The data on steroid-sparing second line immunosuppressive treatments such as azathioprine is very limited and has been used in patients with response to steroids who are unable to taper off the steroids [29]. It is unclear whether or not any intervention alters the natural history of the disease. Lung transplantation for RB-ILD has not been reported.

Desquamative Interstitial Pneumonia (DIP)

History and Defnition

As mentioned above, DIP is another smoking-related idiopathic interstitial pneumonia that should be distinguished from RB-ILD. DIP was rst described in 1965 as a case series of 18 patients noted to have similar pathology on open lung biopsy. This study de ned a clinicopathologic syndrome characterized by a chest X-ray showing peripheral and basilar GGO and a clinical response to corticosteroid therapy with a combination of pathologic ndings. While the initial description and name was descriptively termed by extensive desquamation of pneumocytes on histopathology, it was later recognized that the intra-alveolar cells are macrophages and not desquamated pneumocytes yielding the title as a misnomer [36]. DIP is currently characterized by the alveolar accumulation of pigmented macrophages followed by interstitial infammation and brosis. Beyond the realization that DIP is a misnomer, there remains ongoing debate on the best nomenclature as some promote that smoking-related diseases should not be considered “idiopathic” [36]. RB-ILD and DIP remain related on a histologic spectrum but are considered separate as disease entities based on the clinical presentation, imaging ndings, and response to treatment [3, 37].

In contrast to RB-ILD which is invariably associated with smoking, approximately 90% of patients with DIP are smokers or former smokers. The remainder are seen with systemic disorders, infections, and environmental triggers [34, 35, 38, 39]. Due to its rarity and the inherent dif culties with disease recognition, it is dif cult to make an accurate estimate of the incidence and prevalence of DIP. There are more than 290 reported cases in the literature [40]. The discovery of new cases of DIP has decreased recently. This is likely due to new classi cation systems from which cases that were previously described as DIP are now classi ed into other entities such as RB-ILD, NSIP, PLCH, or other diagnoses [30].

Presentation

Clinically, DIP behaves similarly to other ILDs, meaning, an insidious onset of dyspnea and cough over weeks to months. Presentation is usually in the fourth or fth decades of life and has a male predominance, both similar to RB-ILD [1, 34]. On exam, most patients have inspiratory crackles and clubbing is common as well [1, 34, 35, 39]. The clinical distinctions between DIP and RB-ILD are subtle but notable as well with DIP causing generally more severe respiratory symptoms.

Diagnostic Evaluation

The work-up for DIP, as is common with the other ILDs, includes a detailed history and physical exam, pulmonary function testing (PFT), chest radiography/HRCT, and obtaining tissue specimens. On physical examination, clubbing is frequent in DIP but not seen in RB-ILD and pulmonary function testing can show obstruction in RB-ILD and this pattern is not seen in DIP [34, 35]. Pulmonary physiology may show normal lung volumes or varying amounts of restriction. This is consistent with the major pathology being a brotic process. The major and most consistent PFT abnormality is impairment in gas exchange signi ed by a low DLCO [35, 39].

Radiology

Chest radiography can be normal or show patchy abnormality including GGO or linear or reticulonodular in ltrates with a lower lung and peripheral predominance [1, 29, 34, 38]. HRCT typically shows patchy GGO with a lower and peripheral lung zone predominance as well (Fig. 34.6).

Fig. 34.6  High-resolution computed tomography images from a patient with desquamative interstitial pneumonia showing patchy ground glass opaci cation in a lower and peripheral lung zone distribution

Irregular linear opacities are another common nding on HRCT. Honeycombing is uncommon but thin-walled cystic changes can be seen within the areas of GGO [1, 24, 31, 34]. As these patients are usually current or former smokers, simultaneous emphysema may be present. In RB-ILD imaging studies show upper lung predominant disease whereas DIP is characteristically a lower lung and peripheral process. The HRCT differential includes RB-ILD, hypersensitivity pneumonitis, sarcoidosis, NSIP or atypical infection such as pneumocystis jirovecii pneumonia [1, 24]. HRCT abnormalities are less severe in DIP compared to UIP and are not thought to have a progression to UIP which is a distinct and separate entity.

Histopathology

Bronchoalveolar lavage (BAL) is not particularly helpful in the diagnosis of DIP but is done to evaluate for other ILDs and to rule out infection. Regardless, BAL typically shows increased number of macrophages containing “smoker’s pigment.” Fluid differential may have increased percentages of PMNs, eosinophils, or lymphocytes; however, all of these BAL ndings are nonspeci c [38, 40]. The yield of transbronchial biopsies remains limited and generally the diagnosis is best made by surgical lung biopsy [40].

Histologically, DIP is similar to RB-ILD with respect to the fact that pigmented macrophages are the dominant cell type. DIP is characterized by pigmented macrophages accumulating in the distal airspaces in a diffuse pattern throughout the lung parenchyma. Lymphocyte follicles and giant

cells are also frequently seen in the distal airways indicating mild chronic infammation. The interstitium is thickened by a sparse infammatory in ltrate which is often composed of eosinophils and plasma cells and is lined by cuboidal pneumocytes [24, 34, 35, 41]. Additionally, there is brotic thickening of the alveolar septa. Underlying architecture is maintained and honeycombing is minimal or not present [1]. Pertinent characteristics that are not seen in DIP which differentiate it from other ILD, speci cally UIP, are extensivebrosis, smooth muscle proliferation, and organizing pneumonia [33, 35].

Pathologically, these distinctions, as discussed above, involve the amount of macrophage clusters and the presence of brous scarring that is seen in RB-ILD [22, 25]. DIP is characterized by higher levels of macrophages, diffuse rather than bronchocentric pattern of involvement and a greater amount of brosis compared to RB-ILD. DIP also demonstrates the presence of interstitial lymphoid follicles, eosinophils, Giant cells, and brous thickening of the alveolar septa which are not seen in RB-ILD [1, 24, 42] (Fig. 34.7).

Clinical Course

The natural history of untreated disease can range from mild to quite severe. Spontaneous remissions and acute exacerbations leading to fulminant respiratory failure have been reported [39, 42, 43]. There is an associated 5-year mortality of approximately 5% and 10-year mortality of approximately 30% [39]. If left untreated, an estimated two-thirds of patients will have clinical worsening [39, 40]. Lastly, DIP is generally considered a more severe disease with higher morbidity and mortality than RB-ILD and may progress despite smoking cessation and other treatments [44].

Treatment

Treatment consists primarily of smoking cessation although few studies have shown clear clinical bene t [34, 39]. Avoidance of any probable environmental or occupational exposures and treatment of underlying infection or systemic illness should also be considered as a general approach but research is lacking [38]. In a summary of studies dedicated to DIP a response rate of 71.2% was found when systemic corticosteroids were used [41]. The recommended dose of prednisone is around 0.5 mg/kg daily but varies widely among studies [40]. The duration of steroids also varies but is usually tapered over 3–9 months [30, 38]. Macrolides such as clarithromycin have shown to be helpful in patients with incomplete or refractory response to steroids in some studies

Fig. 34.7  At low power (panel a), the main histologic nding of desquamitive interstitial pneumonia is increased numbers of intra-alveolar macrophages. At higher magni cation (panel b), the macrophages con-

tain the coarsely granular, golden brown smoker’s pigment. Mild alveolar septal brosis is also a common nding

[45]. Additional reports mention further immunosuppression with azathioprine and cyclophosphamide in refractory cases but the response rates to these therapies was not discussed [41]. With treatment, reversal of the GGO seen on CT may improve or disappear [1, 24]. In addition, patients who are treated may fully recover lung function [39]. Others may experience relapse even years after discontinuation of steroids and have shown some response to resumption of steroid treatment [41]. In extreme cases, those patients who continue to progress despite treatment may be referred for lung transplantation; however, there are reports of possible recurrence seen after lung transplantation as well [28, 46].

exchange. Chest X-ray is normal. Laboratory work drawn in the of ce shows normal cell counts, and a normal comprehensive metabolic panel. Antinuclear antibody (ANA) titer is positive to a dilution of 1:160, and rheumatoid factor is negative. Anti-Ro/SSA and anti-la/SSB antibodies are also noted to be positive. HRCT demonstrates diffuse intralobular septal thickening with a signi cant degree of GGO. The subpleural region is relatively spared throughout the chest. A surgical lung biopsy is planned for the patient given the ndings, and her progressive functional decline. The nal pathology report demonstrates diffuse brosis and infammation that was temporally homogeneous suggestive of a pattern of NSIP.

Nonspecifc Interstitial Pneumonia (NSIP)

Case

A 55-year-old non-smoking female presents to her primary care physician due to several months of progressive shortness of breath and diffuse joint pain. She denies any fevers, recent travel or any other illness. She also admits to worsening refux symptoms over the last several weeks. On further questioning, she describes predictable color changes to her hands when she puts foods in her freezer.

On physical exam, she is afebrile, normotensive, with normal respiratory and heart rates. Oximetry is noted be 92% on room air. Cardiac exam is normal. Posterior chest auscultation reveals faint crackles at the bilateral bases. She has mildly tender proximal interphalangeal joints, and knees bilaterally. There are no obvious changes to the skin. The remainder of the physical exam is normal.

Pulmonary function testing performed at the visit shows a mild restrictive ventilatory pattern with mildly impaired gas

History and Defnition

Nonspeci c interstitial pneumonia (NSIP) is a pathologic description of a chronic interstitial pneumonia that lacks the histopathologic features typical of other IIPs, despite many similarities in clinical and radiographic presentation. It originated as a histopathologic categorization reserved for surgical lung biopsies not demonstrating a clearly identi able pattern [47]. This de nition has been rede ned over time, given concern that it was a “wastebasket” diagnosis [48]. It is well known that the histologic pattern of NSIP can be seen in association with other disease states including connective tissue diseases, drug-induced, autoimmune disease, hypersensitivity pneumonitis, and other rare entities such as IgG4-­ related disease, familial interstitial pneumonia, and graft versus host disease [49]. Commonly associated connective tissue diseases include systemic sclerosis, polymyositis/dermatomyositis, rheumatoid arthritis, and Sjogren’s disease

[49]. Implicated drug-induced etiologies have been correlated­

with amiodarone, methotrexate, nitrofurantoin, statins, and chemotherapeutic agents [49].

Despite a correlation with NSIP and these various disease states, a causal relationship has not been demonstrated. Another category is idiopathic NSIP, which as the name implies, is disease without any known origin. Several studies, however, have reported that a substantial number of patients with idiopathic NSIP have positive autoantibodies [50]. This has led to the description of NSIP due to an undifferentiated connective tissue disease (UCTD), a clinical entity with symptoms and/or signs suggestive of connective tissue disease, but not ful lling the classi cation criteria for any speci c diagnostic entity [51]. NSIP with organizing pneumonia overlap is a controversial nding that has recently appeared in the criteria of interstitial pneumonia with autoimmune features (IPAF). However, details of this controversial entity are not well known [52].

Epidemiology

The incidence and prevalence of idiopathic NSIP are unknown. Since Katzenstein and Fiorelli’s description of NSIP in 1994 [47], several cases that were previously classi-ed as IPF were reclassi ed as NSIP in 11–43% of cases [52]. It constitutes 14–36% of cases of idiopathic interstitial pneumonia which is less common than usual interstitial pneumonia (UIP) (50–60%) but more common than desquamative interstitial pneumonia, respiratory bronchiolitis-­ associated interstitial lung disease (DIP/RB-ILD) (10–17%) and acute interstitial pneumonia (AIP) (0–2%) [49].

Idiopathic NSIP occurs mostly in middle-aged women who are non-smokers, while NSIP due to connective tissue disease is equal in men and women. Given the known prevalence of IPF, the extrapolated prevalence of idiopathic NSIP could range from 1 to 9/100,000 [52]. As radiographic and pathologic patterns of NSIP and UIP can be seen in the same patient (see below) the relationship between these entities is often questioned. At this time data are lacking to make concrete statements regarding the possibility that NSIP may evolve into UIP in some patients over time and the authors believe that they should be treated as separate entities.

Presentation

The typical patient with NSIP is a middle-aged adult presenting with cough and dyspnea developing over weeks to months prior to diagnosis [47, 48]. Two-thirds of the patients are women, and unlike patients with IPF, 70% are never smokers [48]. Patients may have nonspeci c symptoms such as fever [48] and serologic abnormalities (antinuclear anti-

bodies and rheumatoid factor) are common [53]. Many patients with NSIP meet the case de nition of undifferentiated connective tissue disease, suggesting an autoimmune process [53]. Complaints of xerostomia, arthralgia, myalgia, rash, or Raynaud’s phenomenon should raise clinical suspicion that a collagen vascular disease is the underlying cause of the disease. Additionally, a complete review of the patient’s medications, HIV risk factors, and exposures to airborne antigens should be conducted, given their individual associations with NSIP [53].

Diagnostic Evaluation

The diagnostic evaluation of suspected NSIP, like most ILDs, includes a detailed history and physical exam, pulmonary function testing (PFT), chest radiography/HRCT, and obtaining tissue specimens. Due to the strong association of many systemic diseases and exposures with NSIP an ongoing search for potential causes is warranted as in some cases the lung disease may manifest prior to other signs of a systemic disorder. Similarly, prior or ongoing drug or hobby/occupational exposures may not be revealed at the time of the initial evaluation and only come to light through the course of patient follow-up. The majority of patients with NSIP have bibasilar crackles, but only 10–35% have clubbing [54]. Pulmonary function testing demonstrates a restrictive ventilatory defect, often times with impaired gas exchange, however, this is in no way speci c to NSIP.

Radiology

Early in the course of NSIP, patients may present with normal chest imaging. Conversely, general imaging in late stage NSIP commonly demonstrates bilateral reticular or hazy opacities (Fig. 34.8). Though the lower lobes are involved, there is not as much of a clearly de ned apical-basal gradient as seen in UIP [47, 48].

The most frequently seen HRCT ndings are increased reticular markings with subpleural sparing, traction bronchiectasis, lobar volume loss, and GGO [48, 52] (Fig. 34.9). Other ndings in late stage NSIP are subpleural cysts, or honeycombing, which are smaller and less extensive compared to those found in UIP [55]. If honeycombing is the predominant nding, UIP should be favored as the diagnosis [55–57]. Additionally, areas of GGO do not progress to honeycombing on serial HRCTs in NSIP, whereas this progression can be seen in UIP [51].

Despite typical HRCT ndings, the ability to make a de nitive diagnosis of NSIP via HRCT is limited [48]. Unlike UIP, the accuracy of HRCT for diagnosing NSIP can range from 66% to 68% [56, 58] Given the signi cant differ-