Respiratory bronchiolitis (RB) is a histopathologic lesion, seen in virtually all smokers, that was first recognized on autopsy series of young cigarette smokers who died of nonpulmonary causes. The histopathologic features are characterized by clusters of brown pigmented macrophages in the first-order and second- order respiratory bronchioles [13]. Clinically, RB is associated with asymptomatic or a minimally symptomatic disease state characterized by mild cough and/or dyspnea [13–15]. In rare cases, RB may present with significant pulmonary symptoms, abnormal imaging and pulmonary function testing. In this scenario it is described as RB associated interstitial lung disease (RB-ILD) [1].

RB-ILD lies on a spectrum of smoking-related lung diseases that ranges from minimally symptomatic RB to very severe but pathologically similar desquamative intertstitial pneumonia (DIP). RB-ILD was first introduced by Myers et al as pathologic explanation for a clinically described chronic ILD where RB was the only pathologic diagnosis seen on biopsy [16, 17]. RB-ILD has since been further characterized as a distinct clinical entity, albeit very rare.

The majority of patients present with nonspecific respiratory complaints including gradual onset of dyspnea and new or changing cough. Impairment in functional capacity is generally minimal and overlaps with early emphysema, making the diagnosis difficult. On exam, inspiratory crackles are the most prominent feature and are generally coarse in nature and occur throughout inspiration and occasionally into exhalation [15]. Rarely, do patients have any clubbing [1, 14, 15, 17]. RB-ILD is seen in patients in the fourth and fifth decades of life and the patients are usually heavy smokers (>30 pack years) with a 2:1 male predominance [1, 14, 17].

The pulmonary function testing (PFT) pattern most often seen in RB-ILD is obstructive, however, both restrictive and a mixed patterns are seen frequently as well. The fibrosis and inflammation of the respiratory bronchioles seen in RB-ILD are similar changes to those in COPD and along with coexisting emphysema are responsible for the obstruction [16]. However, a significant response to inhaled bronchodilators is not typically seen due to the fact that the pathologic process is not bronchospastic. Overall, the most common PFT abnormality is a decreased DL_CO and often times will correlate with disease severity [1, 18]. Approximately, 10 % of patients have normal lung function at diagnosis [19].

There are no specific laboratory tests that aid in the diagnosis of RB-ILD. Disease severity can also correlate with imaging findings.

Although there are no pathognomonic imaging findings associated with RB-ILD, common imaging patterns are seen. Chest radiography often appears normal but can have abnormalities such as thickening of the walls of the central or peripheral bronchi and fine reticulonodular opacities, typically diffuse or upper lung predominant [1, 14, 15]. HRCT is more clinically useful and frequently shows nonspecific changes such as centrilobular nodularity and patchy GGO with septal thickening (Fig. 23.4). The radiographic differential includes hypersensitivity pneumonitis and non-specific interstitial pneumonia (NSIP) [20]. Since all of these patients are smokers or former smokers, concomitant emphysema is common as well.

The next step in the work up of RB-ILD usually includes a bronchoscopy, as is the case with many ILDs. In the case of suspected RB-ILD bronchoscopy is not typically helpful. The vast majority of BAL samples are indistinguishable from lavage fluid from otherwise healthy smokers (increased cells with normal differential). One difference seen in RB-ILD is that there are a relatively higher amount of pigmented macrophages compared to healthy nonsmoking individuals [1, 18]. This finding is nonspecific and may be seen other smoking related lung diseases. A surgical lung biopsy is required to see definitive patterns of RB-ILD. Histopathologically RB-ILD differs from RB by demonstrating fibrous scarring that extends into the surrounding alveolar wall in addition to the aforementioned clusters of pigmented macrophages [16, 17]. These clusters are more frequently found near the bronchioles as compared to the rest of the lung parenchyma. Additionally, these clusters are more prominent than those seen in healthy cigarette smokers [15]. RB-ILD lacks features of usual interstitial pneumonia (UIP) such as honeycombing and fibroblastic foci. Concominant emphysema may be seen as well in RB and RB-ILD, owing to the strong association with smoking [16] (Fig. 23.5).

The natural history of RB-ILD is difficult to ascertain as it is very rare. Previous studies are conflicted as to whether patients worsen, improve or stabilize regardless of smoking status. Initial studies suggested it was a benign disease process however, more recent studies suggest that RB-ILD has a more sinister course [18, 21–23]. Additionally, there are reports of a disconnect between the patient’s described sense of stable or improved dyspnea and objective measurements of validated dyspnea scores which clearly worsened over the same time [18]. There have been no deaths reported due to RB-ILD.

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 significant improvement in symptoms, pulmonary function and imaging while others argue that there is merely stabilization [15, 18]. In some cases a trial of corticosteroids is used. Once again, results are mixed but recent studies suggest that there is no consistent improvement in symptoms or pulmonary function with corticosteroid treatment and therefore is not routinely recommended [18]. Empiric dosing of prednisone 0.5 mg/kg/day has been tried. The overall course is short (~4–6 weeks) and is usually reserved for patient with a documented decline in lung function despite abstinence from smoking [24]. It is unclear whether or not any intervention alters the natural history of the disease.

As mentioned above, DIP is another smoking related ILD thought to be on the severe end of the spectrum with RB-ILD. DIP was first described in 1965 as a case series of 18 patients noted to have similar pathology on open lung biopsy. This study defined 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 findings. These include extensive desquamation and proliferation of large alveolar cells within the alveolar space which contain PAS positive brown colored granules, accumulation of lymphoid follicles in the periphery of the lung, slight thickening of the alveoli without any evidence of necrosis, hyaline membranes or fibrinous exudates and uniform lesions throughout the lungs [25]. DIP was further expanded upon in 1978 by differentiating it from UIP [26]. In 1987, Myers et al. were the first to consider that RB-ILD may evolve into DIP [17]. The true relationship between DIP and RB-ILD is not well understood due to the rarity of both diseases. Since RB, RB-ILD and DIP are generally considered on the same spectrum of disease it is important to be able to differentiate between them. This distinction is especially important because each process has a different natural history. Specifically, there is increased morbidity and mortality associated with DIP as compared to RB and RB-ILD [27].

Approximately 90 % of patients with DIP are smokers or former smokers although it can be seen with systemic disorders, infections and environmental triggers [22, 23, 26]. Due to its rarity and the inherent difficulties with disease recognition, it is difficult to make an accurate estimate of the incidence and prevalence of DIP. There are more than 150 reported cases in the literature [28]. The discovery of new cases of DIP has decreased recently. This is likely due to new classification systems from which cases that were previously described as DIP are now classified into other entities such as RB-ILD, NSIP or other diagnoses [24].

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 fifth decades of life and has a male predominance, both similar to RB-ILD [1, 22]. On exam, most patients have inspiratory crackles and clubbing is common as well [1, 22, 23, 26]. The clinical distinctions between DIP and RB-ILD are subtle but notable as well with DIP causing generally more severe respiratory symptoms.

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 exam, 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 [22, 23]. Pulmonary physiology may show normal lung volumes or varying amounts of restriction. This is consistent with the major pathology being a fibrotic process. The major and most consistent PFT abnormality is impairment in gas exchange signified by a low DL_CO [23, 26].

Chest radiography can be normal or show patchy abnormality including GGO or linear or reticulonodular infiltrates with a lower lung and peripheral predominance [1, 22, 26]. HRCT typically shows patchy GGO with a lower and peripheral lung zone predominance as well (Fig. 23.6). Irregular linear opacities are another common finding on HRCT. Honeycombing is uncommon but thin walled cystic changes can be seen within the areas of GGO [1, 14, 20, 22]. As these patients are 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 jiroveci pneumonia [1, 14].