Smoking-Related Idiopathic Interstitial Pneumonias
Allen P. Burke, M.D.
Fabio R. Tavora, M.D., Ph.D.
Seth Kligerman, M.D.
Marie-Christine Aubry, M.D.
Respiratory Bronchiolitis—Interstitial Lung Disease
Terminology
Respiratory bronchiolitis (RB) and desquamative interstitial pneumonia (DIP) form a spectrum of smoking-related lung disease that is characterized by inflammation of the small airways, aggregates of cohesive finely pigmented macrophages within alveolar spaces, and variable degrees of interstitial fibrosis (Table 18.1). The term “respiratory bronchiolitis” is considered a pathologic pattern by the ATS/ERS and “respiratory bronchiolitis-associated interstitial lung disease” a clinicopathologic designation.
It was first appreciated in 1974 that “clusters of pigmented alveolar macrophages [are] present in the lungs of all smokers …”1 The term RBILD was introduced by Myers and Katzenstein2 and subsequently used by Yousem et al.3 The initial report involved 6 heavy cigarette smokers with lung infiltrates, cough, dyspnea, and histologic features on open lung biopsy of inflammation with macrophage infiltrates of the terminal airways and airspaces.2 Another entity related to smoking is pulmonary Langerhans cell histiocytosis (PLCH), which is discussed separately in Chapter 24.
Whether or not RBILD and DIP are considered a single entity or two different ones is debated. In some classifications, they are considered the same entity4,5; in the latest ATS-ERS (American Thoracic Society-European Respiratory Society) nomenclature, they are separated into two entities under “smoking-related interstitial pneumonia” since the clinical and radiologic presentations differ.6 A DIP pattern may be present in pediatric interstitial lung disease related to surfactant deficiency, but this entity is unrelated to smoking-related DIP. Rarely, other agents have been reported as causing a DIP-like reaction, which include dust inhalation, drug reactions, and other inborn error of metabolism other than surfactant deficiency.7,8,9,10 An even small number of patients have no identifiable cause and are never smokers.11
TABLE 18.1 Fibrosing Lung Diseases Associated with Smoking, Various Terms Used by Radiologists, Clinicians, and Pathologists | ||||||||||||||||||
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Clinical Findings
Pathologists most commonly see respiratory bronchiolitis in resection specimens for lung cancers as an incidental finding. In rare cases, the condition presents as a form of interstitial lung disease with pulmonary symptoms, abnormal pulmonary function tests, and imaging abnormalities, especially reticular densities and ground-glass opacities. It is then described as respiratory bronchiolitis-associated interstitial lung disease (RBILD). RBILD presents with nonspecific complaints such as dyspnea and new or changed cough. It usually affects current smokers in the fourth and fifth decades of life with average exposures of more than 30 pack-years of cigarette smoking. Men are more often affected than women; in contrast to DIP, finger clubbing is usually absent.2,6,12 In Fraig et al.’s study, RB was found in some patients many years after cessation of smoking, including 42% after 3 years and 33% after 5 years.13
Radiologic Findings
The HRCT findings of RBILD include centrilobular nodules, patchy ground-glass attenuation, and airway thickening. Upper lobe centrilobular emphysema is common.12 Upper lobe predominant centrilobular nodules can have an appearance similar to nonfibrotic hypersensitivity pneumonia (Fig. 18.1).
 FIGURE 18.1 ▲ Respiratory bronchiolitis, CT findings. Coronal 50-mm-thick minimum intensity projection image shows upper lobe predominant ground-glass opacity (asterisks), centrilobular nodules (arrows), and emphysema (arrowhead). The lung attenuation is diffusely heterogeneous. Although similar imaging findings can be seen in nonfibrotic hypersensitivity pneumonia, the smoking history confirms the diagnosis of respiratory bronchiolitis. There are large collections of cohesive brown macrophages adjacent to airways. |
 FIGURE 18.2 ▲ Respiratory bronchiolitis. A. At low power, RB is characterized by airspace accumulation of pigmented macrophages, which are more prominent within the lumen of the small airway and decrease in density in the alveolar spaces away from the airway. B. The pigment of smoking is brown-black and finely granular. |
Tissue Sampling
Smoking-related lung disease is often diagnosed by computed tomography and only occasionally will be the major finding at wedge biopsy. Bronchoalveolar lavage fluid contains alveolar macrophages with golden-, brown-, or black-pigmented inclusions typical of those seen in smokers. A modest increase in neutrophils may also be present.12
Microscopic Findings
The pathologic lesion of RBILD is RB. At low power, RB displays a patchy bronchiolocentric distribution characterized by airspace accumulation of pigmented (smoker’s) macrophages within distal bronchioles and adjacent alveolar spaces (Fig. 18.2). The macrophages contain a finely granular brown pigment. Peribronchiolar chronic inflammation and fibrosis may be present in the areas of RB and extend into adjacent alveolar septa with bronchiolar metaplasia of the pneumocytes.3
Prognosis and Treatment
The reported 5-year mortality is <5% and presumably related to other conditions.14 A follow-up study of biopsied patients with RBILD showed that although mortality is low, improvement (either symptomatic or on pulmonary function testing) occurs in a minority of patients. Furthermore, some patients who stopped smoking or received immunosuppressive treatment had progressive disease.15
Desquamative Interstitial Pneumonia
Terminology
DIP is usually considered to be a more extensive form of RBILD in which the pigmented macrophages fill alveolar spaces diffusely throughout larger areas of the lung. Although it is considered a smokingrelated disease, along with RBILD,6 there are a slightly higher proportion of cases in which there appears to be no relationship with smoking, as compared to RBILD.
DIP was first included in the classification of idiopathic interstitial pneumonias in 1969.16 DIP was described as an interstitial pneumonia morphologically distinct from usual interstitial pneumonia (UIP) and later shown to have significantly better survival than UIP.17 Initially, the intra-alveolar cells were thought to be desquamated reactive pneumocytes; thus the terminology of “desquamative” in the diagnosis of DIP.
Clinical Findings
Although considered one of the rarest of interstitial pneumonias,18 the true incidence depends on its distinction from the much more common smoking-related lung disease, RBILD. DIP affects cigarette smokers at a mean age of about 40 to 50 years.3,19 Sex predilection reflects smoking trends, and most studies show a male predominance.3,17,20,21,22 Although in most series about 90% of patients are smokers,3,22 one study reported a rate of only 60%.20 Similar to RBILD, there is an insidious onset of dry cough and dyspnea that may progress to respiratory failure. Digital clubbing develops in about 50% of patients.17 Lung physiology confirms normal lung volumes or a mild restrictive abnormality, and the carbon monoxide diffusing capacity is moderately decreased.12
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