Diffuse benign pulmonary disorders cover a broad range of primary lung diseases but may also be associated with systemic disorders. These range from chronic conditions such as idiopathic pulmonary fibrosis (IPF) associated with poor survival to acute disease of hypersensitivity pneumonitis (HP) with usually a good response to treatment. Some of these diseases have unique clinical characteristics while others share similar radiographic changes, symptoms, or pulmonary function abnormalities. Therapy differs for many of the diffuse benign pulmonary diseases, making accurate diagnosis paramount.

Each of these disorders may occur due to intrinsic or extrinsic injury. For instance, the pneumoconioses are due to the inhalation of damaging foreign material into the lung, while HP is due to an allergic response to foreign material or medications. On the other hand, interstitial lung diseases such as IPF, sarcoidosis, lymphangioleiomyomatosis (LAM), eosinophilic granulomatosis (EG), and the pulmonary disorders associated with collagen vascular disease are believed to be due to intrinsic lung inflammation and injury.

The benign diffuse lung diseases may also be categorized based on physiologic presentation, particularly the type of change seen by pulmonary function studies. Some of the disorders are associated with an obstructive ventilatory defect (LAM, EG) or restrictive ventilatory defect [IPF, nonspecific interstitial pneumonitis (NSIP), asbestosis], while others may present with combined obstruction and restriction [sarcoid, bronchiolitis obliterans with organizing pneumonia (BOOP)].

Finally, these diseases may be categorized based on radiographic findings (i.e., diffuse interstitial infiltrates, alveolar infiltrates, cystic lesions, or honeycombing). This chapter reviews the most common benign pulmonary diseases including clinical presentation, diagnosis, and treatment.

IPF is a progressive, fatal disease with no known cause. It is manifest by diffuse interstitial lung scarring with a predominance of fibrosis in the subpleural and lower lung zones.¹ This disease has several different names, including cryptogenic fibrosing alveolitis, usual interstitial pneumonitis, and IPF. IPF is progressive, refractory to therapy, and ultimately leads to respiratory compromise and death, usually within 5 years of diagnosis.^2–5 The typical patient presents in the seventh decade of life with gradual onset of shortness of breath and a dry, nonproductive cough. Young patients can be affected, however, particularly in familial forms of the disease. IPF is frequently misdiagnosed as “pneumonia” because common symptoms of cough and dyspnea are associated with pulmonary infiltrates; however, the protracted course and lack of fever and purulent sputum make pneumonia less likely. Physical examination typically demonstrates bilateral “Velcro-like” crackles, predominantly in the lung bases. Resting or exercise-induced hypoxemia is often present. Chest radiographs show small lung volumes with interstitial infiltrates predominantly in the lower and peripheral lung zones (Fig. 5-1). High-resolution computed tomography (HRCT) of the chest can help distinguish the diagnosis of IPF from other interstitial lung disorders. Typical findings include peripheral and lower lung zone interstitial thickening with honeycombing and traction bronchiectasis^6,7 (Fig. 5-2A and B). The fibrosis and honeycombing may be interspersed with relatively normal-appearing lung parenchyma. Pulmonary function studies show a restrictive ventilatory defect with a low diffusing capacity for carbon monoxide (DLCO).⁷ As the disease progresses, the total lung capacity, vital capacity, and DLCO fall, indicating worsening fibrosis. In the early stages of the disease, oxygen desaturation may occur only with exercise; but as the disease progresses, severe resting hypoxemia is a common finding.⁷

The diagnosis of IPF is established by open lung biopsy together with appropriate clinical and radiographic findings.^1,7 Transbronchial bronchoscopic biopsies are frequently performed by many practitioners for interstitial lung disease and may be useful to exclude other diagnoses such as sarcoidosis, BOOP, eosinophilic pneumonia, or extrinsic allergic alveolitis. However, transbronchial biopsies are inadequate to establish the diagnosis of IPF because a larger tissue sample is necessary to visualize the geographic changes seen in this condition. These include areas of fibrosis and honeycombing interposed between areas of normal-appearing lung^1,7 (Fig. 5-3). Thus, video-assisted thoracic surgical (VATS) biopsy has become the standard approach if a tissue diagnosis is warranted. It is important to note that there is controversy regarding the need to establish a tissue diagnosis when all clinical and radiographic findings suggest the diagnosis of IPF.⁸ This is particularly true for older patients and those with far advanced disease. For those patients who are younger with atypical findings, open biopsy should be considered.

There is no known effective medical treatment for IPF. High-dose corticosteroids (1 mg/kg methylprednisolone) given for several weeks and followed by a gradual taper has been the mainstay of therapy for many years, with few patients improving.⁷ One study showed minimal improvement with a combination of prednisone and azathioprine,⁹ but widespread success with this approach has not been reported. Other potent agents such as cyclophosphamide have been used, also with limited success.⁷ Gamma interferon has also been studied but has little clinical benefit.^10,11 For patients below 65 years of age who are otherwise healthy, lung transplantation remains the only viable treatment option for IPF.

After Liebow and Carrington proposed the first major classification scheme for the idiopathic interstitial pneumonias (IIP),¹² several investigators found that a significant number of biopsies did not fit into the described subtypes.^13,14 The term nonspecific interstitial pneumonitis (NSIP), first used by Katzenstein, represents a distinct histologic type of interstitial pneumonitis with clinical characteristics that differ from UIP/IPF.

Although NSIP and IPF may be clinically indistinguishable, there are some differences that may help to differentiate these two diagnoses. Patients with NSIP typically present with subacute symptoms rather than the insidious onset characteristic of IPF.¹⁵ Fever is also a common complaint among patients with NSIP and is rare in IPF.

Radiographically, NSIP typically has diffuse bilateral ground-glass opacities on HRCT.¹⁶ Honeycombing is a hallmark feature of IPF but is not present in NSIP. Alveolar infiltrates and occasionally nodules have been described in NSIP, but these are not common.

The diagnosis of NSIP is made by open or VATS lung biopsy (Fig. 5-4). Katzenstein originally divided biopsies among three groups based on the amount of fibrosis present.¹⁴ Group I consisted of interstitial infiltrates with predominant lymphocytes, occasional plasma cells, and minimal fibrosis. The infiltrates were noted to be temporally uniform, in contrast to the lesion of UIP, which is temporally heterogeneous. Group II contained the interstitial infiltrates but had marked amounts of associated fibrosis. Group III included marked distortion of the lung architecture from collagen deposition, scarring, and occasional honeycombing.

The prognosis for NSIP is much better than that for IPF. The majority of patients will improve or recover (74% in one series).¹⁵ However, the likelihood of improvement depends on the severity of fibrosis. Patients with Katzenstein Group III NSIP (severe fibrosis) have the least favorable prognosis. Corticosteroids with or without other immunosuppressive agents are the mainstay of therapy. However, it is important to note that there are no randomized controlled trials proving benefit for any form of therapy, and a number of patients have improved without specific treatment.

First described in 1983¹⁷ and then again in 1985¹⁸ under the name BOOP, cryptogenic organizing pneumonia (COP) is an increasingly recognized cause of pulmonary disease. Disagreement continues to exist regarding the name for this process; thus, both names are used interchangeably.¹⁹ Although the term BOOP is more commonly used in the United States, COP is preferred, as designated by the American Thoracic Society and European Respiratory Society. COP specifically refers to the idiopathic form of the disease. However, organizing pneumonia, the histologic correlate, has been identified in association with a variety of diseases as well as drug and inhalational exposures.

COP can present in a variety of forms.^20–23 The most common is a nonresolving pneumonia.^18,20–23 Patients typically complain of fevers, cough, and malaise. Myalgias have been described in a number of patients. Symptoms usually are present for several months, and patients may have been treated with one or multiple courses of antibiotics without significant improvement. Inspiratory squeaks are often present on physical examination.

Mild leukocytosis is common, as well as an elevated erythrocyte sedimentation rate, which may sometimes be over 100. Pulmonary function testing can show a combination of restriction and obstruction as well as a reduced diffusion capacity. Frank hypoxemia is rare.¹⁸

Chest radiography typically shows multiple areas of patchy alveolar infiltrates bilaterally.¹⁸ CT scans most commonly show areas of consolidation with air bronchograms; however, a variety of other patterns have also been described (Fig. 5-5).^18,21 These range from a diffuse nodular pattern to band-like areas of consolidation. Pleural effusions are uncommon.

The diagnosis of COP is made by lung biopsy, which shows the histologic features of organizing pneumonia (Fig. 5-6).^18,20–24 Although transbronchial biopsies are mostly sufficient, the small biopsies obtained by this procedure may be insufficient to completely distinguish the process from other underlying pathology.^19,23,24 It is important to exclude other processes, since organizing pneumonia can sometimes be found in association with other entities, such as fibrotic disease. VATS or open lung biopsy may be necessary in some circumstances to establish a firm diagnosis.

Treatment consists of glucocorticoids for 6 to 12 months.^18,20–24 Patients typically have a good response, with close to two-thirds having clinical remission within a short time. However, relapses while tapering steroids are common. Relapses typically respond to reinstitution of higher doses of glucocorticoids and do not appear to affect the long-term course of the disease.

COP has had other notable presentations.^18,20–24 Focal lesions resembling solitary lung nodules have been described by a number of authors. The diagnosis was typically found after surgical resection, which stemmed from the concern that the nodules were a malignant process. The patients tended to do well without any further treatment. A rapidly progressive form of COP has also been described.²⁵ This form advances much more rapidly, with a fulminant course and high mortality.

IPF, NSIP, and COP make up the majority of the IIP encountered in clinical practice. There are other forms of IIP that are less common and are dealt with briefly below.

Acute Interstitial Pneumonia (AIP)

AIP is a rapidly progressive interstitial disease with typically a fulminant course.¹⁹ It typically presents with a viral-like prodrome of myalgias, fever, chills, and malaise. Patients usually present within 3 weeks of onset of the illness and most require mechanical ventilation. CT reveals diffuse ground-glass opacification and, to a lesser extent, basilar airspace consolidation. The histologic lesion is that of diffuse alveolar damage. Mortality is high, well over 50 percent, and there is no effective therapy.

Respiratory Bronchiolitis-Associated Interstitial Lung Disease (RB-ILD) and Desquamative Interstitial Pneumonia (DIP)

Respiratory bronchiolitis is a pathologic lesion found in cigarette smokers; it is characterized by pigmented macrophages in the lumens of the first- and second-order respiratory bronchioles.¹⁹ These lesions are most often seen incidentally on biopsies done for unrelated reasons and rarely cause symptoms. However, a small percentage of patients do present with clinically significant interstitial disease with this lesion on biopsy; the clinical condition is then termed RB-ILD.

The clinical spectrum ranges from minimal complaints to severe dyspnea.¹⁹ The most common symptoms are gradually progressive dyspnea and new or worsening cough. Males are more likely to be affected than females. CT typically reveals centrilobular nodules, thickened airways, and sometimes ground-glass opacification. Patients almost universally improve with cessation of smoking.

The pathologic lesion of DIP is an accumulation of macrophages in the alveolar spaces.¹⁹ Because of its similar male predominance, association with cigarette smoking, and the presence of macrophages, DIP is thought to represent one end of a spectrum of disease, where the other end would be RB-ILD. However, there are some differences, such as the uniform presence of ground-glass opacification seen in DIP. Honeycombing can be seen in DIP, but only in a minority of patients, and it tends to be very limited in extent. As with RB-ILD, the prognosis is good, with smoking cessation thought to be important. Patients with DIP are commonly treated with corticosteroids, but there have been no treatment trials proving benefit.

Lymphoid Interstitial Pneumonia (LIP)

LIP is the last of the IIP included in the recent consensus classification.¹⁹ This disease is most often seen in combination with other diseases such as Sjögren syndrome, acquired immunodeficiency syndrome, various autoimmune diseases, and Castleman disease.^19,26,27 The disease tends to affect women more than men. Initial presentations include slowly progressive shortness of breath, cough, and weight loss. CT typically reveals a pattern of bilateral diffuse or patchy ground-glass opacification, with poorly defined centrilobular nodules.²⁷ Thickening of the peribronchiovascular bundles and irregular septal thickening are also common.²⁷ Cystic changes are noted in a majority of patients, but honeycombing is less common.

The histology of LIP is marked by a dense infiltration with lymphocytes and plasma cells.^19,26 The infiltration is especially marked in the alveolar septum. Lymphoid follicles and germinal centers are commonly seen.

The prognosis is highly variable, with the majority of patients remaining stable or improving; however, over one-third of patients may have progressive disease.^19,26,27 Treatment usually consists of corticosteroids with or without other immunosuppressive agents.

The collagen vascular diseases present with a wide range of symptoms and findings, and they have variable courses. Given the systemic nature of the diseases, it is not unexpected to find that patients commonly develop pulmonary pathology. The full range of known complications is beyond the scope of this chapter and have been described in detail elsewhere.²⁸ The complications are not limited to the lung parenchyma but rather include all aspects of the respiratory system as well as the respiratory muscles, pleural space, upper airway, and pulmonary vasculature. The complications also do not always represent a direct injury caused by the underlying collagen vascular disease. Some of the therapies for these diseases have pulmonary side effects, such as methotrexate-induced lung injury in patients being treated for rheumatoid arthritis or pulmonary infections from immunosuppression. Bibasilar fibrosis from repeated aspirations due to esophageal dysmotility from scleroderma has been well described.

Histologically, the types of interstitial disease found include those that have been previously mentioned. These comprise nonspecific interstitial pneumonia, UIP, and BOOP.^28,29 Other forms of interstitial disease have also been described, including lymphocytic interstitial pneumonia and diffuse alveolar damage.^28,29 Prognosis depends on the histologic type of interstitial disease and is largely similar to that seen in patients without underlying collagen vascular disease.

Sarcoidosis is a multiorgan disease with almost all cases having pulmonary manifestations at some point during its course.³⁰ Pulmonary manifestations range from asymptomatic hilar adenopathy, to endobronchial involvement with airflow limitation to diffuse nodules to end-stage lung fibrosis.

Sarcoidosis has a worldwide distribution and affects different racial and ethnic groups variably. In the United States, annual incidence estimates are 10.9 cases per 100,000 Whites and 35.5 cases per 100,000 Blacks.³¹ The etiology remains unknown, but some epidemiologic research supports an infectious etiology whereas other evidence suggests an environmental exposure.³⁰

The clinical presentation of pulmonary sarcoidosis is highly variable. Probably the most common is asymptomatic hilar adenopathy found on chest radiography done for an unrelated reason.^30,32 Common pulmonary symptoms include cough, dyspnea, and retrosternal chest pain. Systemic symptoms include fatigue, weight loss, and malaise.^30,32 Löfgren syndrome is a notable acute presentation of sarcoidosis characterized by the triad of hilar lymphadenopathy, polyarthralgias, and erythema nodosum.

Sarcoidosis is staged by chest radiograph.³³ Stage I disease is defined as the presence of hilar lymphadenopathy without other parenchymal infiltrates (Fig. 5-7), whereas stage II includes hilar lymphadenopathy with infiltrates. In stage III disease, there are infiltrates without hilar lymphadenopathy, and stage IV disease is defined by the presence of end-stage fibrosis (Fig. 5-8). Classically, sarcoidosis affects the upper and midlung zones. Small nodules ranging in size from 2 mm to 1 cm in diameter are the most common finding.³³ The nodules are typically found around the bronchovascular bundles. Patchy areas of airspace consolidation can also be seen, leading to the term alveolar sarcoidosis.³³ Mediastinal adenopathy is very common on CT, with calcification present in approximately 50 percent of patients, typically in a focal or “eggshell” pattern.³³

Histologically, the lesion of sarcoidosis is the noncaseating granuloma. Granulomas are tightly packed and composed of epithelioid cells, including multinucleated giant cells and lymphocytes^30–32,34 (Fig. 5-9). These lesions can be found in lymph nodes, the lung parenchyma, and airway mucosa. However, noncaseating granulomas are not unique to sarcoidosis and other etiologies must be excluded clinically and pathologically, including fungal and mycobacterial disease, HP, pneumoconiosis such as beryllium-induced lung disease, and drug reactions.³⁴