Introduction
Previous chapters focused on the major diseases affecting primarily the intrathoracic airways. These diseases include asthma, bronchitis, cystic fibrosis, and bronchiectasis. Less common entities also primarily affect airways. Unlike the diseases discussed earlier, these entities, when diffuse, demonstrate a predilection for the peripheral airways. Their early diagnosis remains difficult, however. The large cross-sectional area of peripheral airways protects patients from symptoms of dyspnea and limits detection of flow abnormalities on functional testing until late in the disease course. Diseases affecting the peripheral airways, however, may have profound effects on lung function. Because pathologic narrowing of peripheral airways is difficult to detect, these airways may be considered a “silent zone” of the lung. Despite efforts to design tests to identify peripheral airway obstruction, none have been entirely successful. More recently, heightened recognition of the entities affecting peripheral airways and diagnostic advances have increased the frequency of diagnosis. Nevertheless, the epidemiology of disorders of the peripheral airways remains largely unknown. This chapter takes into account the heightened clinical recognition and evolving efforts at classification as our understanding of these entities advances. This is most evident for bronchiolitis obliterans (BO). In this chapter we will first review the anatomy of the peripheral airways. Next, we will present a classification for bronchiolitis and BO that reflects a contemporary hybrid understanding of bronchiolitis based on both clinical and histologic features. Lastly, we will review focal processes involving intrathoracic airways, including a review of tracheobronchial stents.
Disorders with Diffuse Involvement
Anatomic and Physiologic Features
Among other roles, the intrathoracic airways serve as a conduit between the outside environment and alveolar units. Moving distally from the trachea, bronchi transition to membranous bronchioles and ultimately to the terminal respiratory units. These transitions are defined by changes in the constellation of cell types and by architectural features. Bronchi are characterized by incomplete cartilaginous rings, ciliated epithelium, goblet cells, submucosal glands, and smooth muscle innervated by muscarinic output via the vagus nerve. Bronchioles feature sparsely ciliated simple columnar epithelium and secretory club cells (Clara) but lack cartilage, goblet cells, and glands. Bronchiolar smooth muscle is not innervated by the vagus nerve; the diameter of bronchioles ranges from 0.5 mm to 1 mm.
Because of their relatively small total cross-sectional area, bronchi are responsible for most airflow resistance in the lung. In contrast, bronchioles contribute little to total airflow resistance at high and normal lung volumes. This limited contribution is attributable to dichotomous branching that arranges vast numbers of bronchioles in parallel. This translates into a much larger total cross-sectional area for bronchioles relative to bronchi. At low lung volumes, bronchioles increase their relative contribution to total airflow resistance. As residual volume is approached, the flexible, thin-walled bronchioles, supported only by connective tissue, may collapse. Despite significant disease of the bronchioles, however, pulmonary function test (PFT) results may be normal. More commonly they may demonstrate upward concavity (“curvilinearity”) of the flow-volume curve, especially at low lung volumes, an increased slope of phase III (the alveolar plateau) of the single-breath nitrogen washout test, and air trapping. Computed tomography (CT) scans or magnetic resonance imaging with hyperpolarized gases, similarly, may demonstrate inhomogeneity of ventilation and air trapping ( Fig. 50-1 and see Videos 106-1 to 106-3 
).
Defining Bronchiolitis
Bronchiolitis refers to a nonspecific cellular and mesenchymal reaction of the bronchioles. Developing a straightforward classification, however, is difficult. Perhaps most importantly, bronchiolitis is a catchall term subsuming several unique clinical syndromes as well as a histopathologically diverse set of lesions identifiable in many diseases. Next, there are many diseases that, in addition to causing bronchiolitis, also cause disease proximal (e.g., bronchiectasis) or distal (e.g., organizing pneumonia) to the bronchioles. As a result, some avoid defining the precise site of involvement, instead referring to peripheral airways (<2 mm diameter) as “small airways.” Lastly, clinical bronchiolitis syndromes may demonstrate more than one histologic pattern temporally and spatially. These factors conspire to preclude defining a mutually exclusive classification system. Therefore definitive diagnosis of a specific bronchiolitis entity requires clinical, diagnostic (imaging, PFTs), and frequently, histopathologic evaluation. Definitive diagnosis depends on excluding bronchial and alveolar involvement seen in alternative diagnoses. The remainder of this section will focus on diseases predominantly affecting the bronchioles. A hybrid classification schema based on both histopathologic findings and clinical syndromes is presented in Figure 50-2 . The early branch points in this schema are driven by histopathologic findings, whereas later branch points are driven by clinical syndromes and exposures.
Infectious Bronchiolitis
Although relatively rare in adults, infectious bronchiolitis is common in infants and young children. Community-acquired respiratory viruses are the most common cause of infectious bronchiolitis, especially respiratory syncytial virus. Rhinovirus is the second most commonly identified virus; other viruses and bacteria may also causes disease . Infection damages bronchiolar epithelial cells. Edema, epithelial sloughing, and mucus secretion cause small airway obstruction and atelectasis. In severe cases there may be peribronchiolar lymphocytic infiltration and even mural necrosis ( Fig. 50-3A ; see Fig. 50-2 , classified under the Chronic/Cellular Bronchiolitis heading,). Bronchiolitis in infancy (especially non–respiratory syncytial virus) has been associated with an increased risk for subsequent wheezing and bronchial hyperreactivity. Although a direct link to chronic obstructive pulmonary disease has not been shown, unusual sequelae may include BO (proliferative and constrictive), bronchiolectasis, and localized emphysema.
Typically affecting children younger than 2 years of age, bronchiolitis begins as an acute upper respiratory tract infection with rhinorrhea or nasal congestion and cough. Within days, the cough worsens and dyspnea and fever develop. Although wheezing, chest wall retractions, and cyanosis may be seen, respiratory failure is uncommon. Examination typically demonstrates mildly depressed oxygen saturation, tachypnea, mild chest wall retractions, expiratory wheezing, and crackles; in more severe cases, nasal flaring, grunting, pronounced chest wall retractions, prolonged expiratory phase, and cyanosis may be seen. Epithelial sloughing with bronchiolar obstruction may cause hyperinflation and gas exchange abnormalities. Generally, infectious bronchiolitis is diagnosed based on clinical signs and symptoms. When obtained, radiographs generally show hyperinflation; nodular shadows may appear in areas of focal atelectasis or pneumonia. Symptomatic treatment with nasal bulb suctioning, supplementary oxygen, and hydration is usually all that is necessary; patients usually recover within weeks. Although inhaled bronchodilators are commonly used in severe cases, their efficacy remains uncertain. There is no proven role for corticosteroids or antibiotics, although the former are sometimes used empirically in hopes of preventing progression. Elevated cysteinyl-leukotriene levels have been reported, and leukotriene modifiers have been shown to reduce respiratory symptoms and wheezing after respiratory syncytial virus bronchiolitis in some but not all studies.
Bronchiolitis From Inhaled or Ingested Toxins
A generalized inflammatory response of the peripheral airways may follow inhalation of toxicants in gas, vapor, fume, or aerosol states (see Chapter 75 ). The location of damage is determined in part by the toxicant solubility. Highly soluble irritants such as sulfur dioxide and ammonia dissolve in the lining fluid of the upper airway, causing damage primarily there. Less soluble gases such as oxides of nitrogen are able to pass into and therefore damage the peripheral airways. Such exposures are a significant industrial and environmental hazard. Oxides of nitrogen, for example, may be found in silo gas (silo filler’s disease), jet and missile fuel, metal pickling fumes, and certain fires. Other fumes, such as diacetyl used in food flavoring, have been implicated in bronchiolitis as well as the development of BO (see the discussion of constrictive bronchiolitis below). Bronchiolitis may also result from systemic toxicant exposure as seen after administration of busulfan, gold, or penicillamine. These causes of bronchiolitis are identified in Figure 50-2 under both proliferative and constrictive BO headings.
Three clinical patterns may develop following toxicant exposure, based on several factors, including the type of toxicant, duration and intensity of exposure, and host factors ( Fig. 50-4 ). Acutely, patients may develop cough, dyspnea, cyanosis, hemoptysis, hypoxemia, and loss of consciousness. These symptoms and signs may last hours to weeks before resolving. In patients exposed to higher concentrations, pulmonary edema and acute respiratory distress syndrome may develop immediately or following a latent period of up to 30 hours. Although most patients recover, some may die from respiratory failure. Finally, some patients develop irreversible obstructive (i.e., BO) or restrictive (i.e., organizing pneumonia) abnormalities 2 to 8 weeks after exposure. This may even be seen in patients who had no initial illness; it is characterized by the gradual onset of dyspnea and nonproductive cough and may result in respiratory failure and death.
Respiratory Bronchiolitis
Respiratory bronchiolitis (RB) is a pathologic entity characterized by pigmented alveolar macrophage accumulation in respiratory bronchioles and adjacent alveoli. Peribronchiolar inflammation or fibrosis and epithelial metaplasia extending into adjacent alveoli (lambertosis) may be present (see Fig. 50-3B ). Although nearly universally seen in cigarette smokers, it may also be seen following mineral dust exposure. RB rarely causes symptoms or physiologic abnormalities. It is most commonly incidentally diagnosed by imaging (see Fig. 50-2 , classified under the Peribronchiolar heading). In some cases, more extensive fibrosis extends into the alveolar septa. In these cases the term RB-associated interstitial lung disease (RB-ILD) is applied (see Chapter 63 ). In RB-ILD, patients present with subacute cough, dyspnea, and crackles. PFTs show restriction and reduced diffusing capacity. High-resolution CT (HRCT) imaging shows a distinctive pattern of bronchial wall thickening, centrilobular nodules, reticulation, and diffuse or patchy ground-glass opacities. RB and RB-ILD may represent a single entity along a continuum of disease severity. Although smoking cessation leads to resolution or stabilization of disease in one third of patients, some develop progressive ILD. Improvement with corticosteroid treatment has been described but not studied prospectively.
Diffuse Panbronchiolitis
Diffuse panbronchiolitis (DPB) is an obscure inflammatory disease of the respiratory bronchioles. Since its first description in 1969, more than 1000 cases have been identified in Japan. On histologic examination DPB is characterized by the triad of bronchiolocentric inflammation, lymphoid hyperplasia, and accumulation of interstitial foam cells (see Fig. 50-2 , classified under the Peribronchiolar/Interstitial heading, and Fig. 50-3C ). Notably, similar findings are also seen in bronchiectasis, underscoring the importance of developing a diagnostic approach to bronchiolitis that considers clinical, functional, radiographic, and histopathologic findings.
Given the rarity of DPB, epidemiologic data are limited. It affects Japanese and, less commonly, other East Asian populations. It is rarely diagnosed in Western countries and in persons of non–East Asian descent, although underrecognition may account for some of this. Clinically, DPB has a slight male predilection, and symptoms manifest in early to mid adulthood. Chronic sinusitis is exceedingly common and frequently precedes pulmonary symptoms. Before diagnosis, patients report years of nasal discharge or congestion, cough, dyspnea, and sputum production that exceeds 50 mL/day. Radiographs demonstrate hyperinflation, diffuse small nodular opacities, and, in advanced disease, ring shadows and “tram track” opacities consistent with bronchiectasis. In early disease, HRCT findings may include centrilobular nodules, including “tree in bud” pattern, and air trapping on expiratory images. Mosaic perfusion is atypical. In advanced disease, bronchiolar wall thickening, dilation, and cysts are seen. PFTs demonstrate a progressive airflow obstruction with reduced diffusing capacity. Less commonly, a mixed obstructive-restrictive pattern may be observed. Although clinical diagnostic criteria have been proposed for Japan, surgical lung biopsy is required in countries and populations in which the disease is rare. If untreated, DPB leads to bronchiectasis, pulmonary hypertension, respiratory failure, and ultimately death. Although the etiology of DPB remains obscure, both genetic and environmental factors are believed to be important. Human leukocyte antigen (HLA)-Bw54 is associated with a 13.3-fold increase in risk for diffuse panbronchiolitis. Polymorphisms of the genes for interleukin (IL)-8 and MUC5B have been associated with diffuse panbronchiolitis.
Macrolides are the cornerstone of treatment. Although the exact mechanism of action remains undefined, anti-inflammatory and immunoregulatory properties of macrolides are likely important because their antimicrobial properties alone do not explain their benefit. Airway neutrophilia is common in DPB. Macrolides inhibit proinflammatory cytokine production, including neutrophil chemoattractants IL-8 and leukotriene B 4 ; bronchoalveolar lavage fluid levels of IL-8 and leukotriene B 4 are reduced after erythromycin treatment. Other potential mechanisms include blockage of adhesion molecules required for neutrophil trafficking, inhibition of mucin, and water secretion into the bronchiolar lumen. Notably, 14- and 15-membered lactone ring macrolides (e.g., erythromycin, clarithromycin, azithromycin) are effective in treating DPB, whereas 16-membered lactone ring macrolides (e.g., tylosin, spiramycin) are not. For severe cases, lung transplantation has been performed, although the disease may recur in the allograft.
Originally DPB was a highly mortal disease. In the 1980s, 5- and 10-year survivals were approximately 62% and 33%, respectively. With macrolide therapy, increased disease diagnosis, and early, aggressive treatment of bacterial infections, 10-year survival now exceeds 90%. Recurrent respiratory infections are common, and Pseudomonas infection, often arising late in the disease, is associated with markedly increased mortality.
Follicular Bronchiolitis
Follicular bronchiolitis (lymphoid hyperplasia) is characterized by peribronchiolar hyperplastic lymphoid follicles with germinal centers (see Fig. 50-3D ). It has been described with primary pulmonary lymphoid hyperplasia or as a secondary event in collagen vascular diseases (especially rheumatoid arthritis and Sjögren syndrome), underlying congenital or acquired immunodeficiencies, bronchiectasis, or other infections (see Fig. 50-2 , classified under the Lymphoid Aggregates heading). Most patients report slowly progressive exertional dyspnea, fever, recurrent pneumonia, and cough. PFT findings may show restrictive, obstructive, or mixed patterns. HRCT findings include small (<3 mm) centrilobular or peribronchial nodules and ground-glass opacities. The natural history of this condition is unknown. Treatment is directed at the underlying disease.
Defining Bronchiolitis Obliterans
BO can be stratified into “constrictive” and “proliferative” bronchiolitis. Although not absolute, this stratification is largely supported by histopathologic and clinical evidence. Unique entities featuring BO are listed in Figure 50-2 ; more common entities are discussed in greater detail below. Histologically, constrictive bronchiolitis defines a submucosal and peribronchiolar fibrotic process that circumferentially and externally compresses the bronchiolar lumen ( Fig. 50-5A ). Patchy and focal in distribution, progressive fibrosis observed in constrictive bronchiolitis ultimately results in slitlike or completely obliterated bronchiolar lumens. Clinically, patients describe progressive dyspnea and nonproductive cough. Auscultation demonstrates early inspiratory crackles and occasional squeaks. PFTs demonstrate obstruction and air trapping. Radiographs may have normal findings or show hyperinflation. HRCT can demonstrate ground-glass nodules, air trapping, and, in advanced disease, bronchiectasis. Today the most common cause of constrictive bronchiolitis is chronic allograft rejection in recipients of lung transplantation.
Histologically, proliferative bronchiolitis is defined by the proliferation of intraluminal polypoid organizing fibroblastic tissue (see Fig. 50-5B ). Isolated proliferative bronchiolitis is rare, observed only in specific inhalational (e.g., nitrogen gas) exposures or localized injuries. Much more commonly, fibroblastic tissue extends from the bronchioles into adjacent alveoli. The term organizing pneumonia defines this organizing fibroblastic tissue in alveoli. Given the relatively common coexistence of proliferative bronchiolitis and organizing pneumonia, the term bronchiolitis obliterans with organizing pneumonia (BOOP) had been employed. There is little overlap, however, between the clinical entities featuring constrictive bronchiolitis and those featuring BOOP. Further, BOOP presents as a restrictive pattern on PFTs compared with the obstructive pattern seen in constrictive bronchiolitis. For these reasons, this nomenclature caused confusion. In response to this confusion, in 2002 the American Thoracic Society and European Respiratory Society jointly recommended abandoning the term BOOP in favor of organizing pneumonia with appropriate qualifiers. When idiopathic, for example, the term cryptogenic organizing pneumonia is used. In rare situations, acute injury causing proliferative bronchiolitis may progress into constrictive bronchiolitis.
Despite this evolution in nomenclature, “bronchiolitis obliterans” continues to be used imprecisely in clinical practice and in biomedical literature. The terms BOOP , bronchiolitis obliterans with intraluminal polyps, and bronchiolitis obliterans applied to both BO and organizing pneumonia persist. Importantly, organizing pneumonia tends to be responsive to corticosteroid treatment, whereas constrictive bronchiolitis is typically resistant. This absence of a precise nomenclature makes studies of the epidemiology, clinical features, and treatment responsiveness of “bronchiolitis obliterans” difficult to interpret. Given the substantial differences in both etiology and prognosis, we favor using the term proliferative or constrictive to more clearly define bronchiolitis obliterans.
Bronchiolitis Obliterans after Lung Transplantation
Over the last 3 decades, surgical and medical advancements have improved survival after transplant, resulting in increased demand for this procedure. Despite these advancements, chronic lung allograft dysfunction (also known as chronic rejection) remains the major cause of morbidity and mortality in lung transplant recipients surviving beyond the first postoperative year. Although new phenotypes of chronic lung allograft dysfunction have been identified, BO is the most common form, observed in 50% of recipients by 5 years after transplant. Importantly, given the patchy nature of BO, diagnosis by transbronchial biopsies is unreliable. In response, the International Society for Heart and Lung Transplantation devised clinical criteria for BO based on spirometric airflow obstruction “for which there is no other cause” ( Table 50-1 ). Termed bronchiolitis obliterans syndrome (BOS), this syndrome does not require histopathologic confirmation. Most literature in human lung transplantation employs BOS as a surrogate marker for BO.
| BOS 0 | FEV 1 > 90% of baseline and FEF 25%-75% > 75% of baseline * |
| BOS 0 p | FEV 1 81%–90% of baseline and/or FEF 25%-75% < 75% of baseline |
| BOS 1 | FEV 1 66%–80% of baseline |
| BOS 2 | FEV 1 51%–65% of baseline |
| BOS 3 | FEV 1 < 50% of baseline |
* Baseline is the best FEV 1 and FEF 25%-75% obtained after transplant.
The onset of BOS is variable based on donor, recipient, and environmental factors discussed below. It presents at a median of 16 to 20 months after transplant. Patients have a median survival of 3 to 4 years after diagnosis. They report progressive dyspnea and, occasionally, dry cough. In advanced disease with bronchiectasis, the cough is productive. Spirometry demonstrates irreversible airflow obstruction with reduced diffusing capacity. CT findings in early BOS demonstrate air trapping (see Fig. 50-1 
and see to ). As BOS progresses, findings consistent with bronchiectasis may be seen.
BO represents the final histologic lesion likely resulting from injury to the airway epithelium and subcellular matrix via both alloimmune and nonalloimmune mechanisms. Alloimmune T-cell reactivity plays a central role in the development of BO ( Fig. 50-6 ). Acute rejection is considered the most significant single risk factor for subsequent BOS. Although high-grade (≥A3) rejection is a major risk factor for BOS, even minimal (grade A1) rejection may increase the risk. Additionally, frequent rejection, lymphocytic bronchiolitis, and lymphocytic bronchitis are associated with increased risk for BOS. Enhanced expression of donor major histocompatibility complex (MHC) antigens has been found in bronchiolar and alveolar epithelium of lung transplant recipients with BOS. Recipient-derived T cells may recognize these antigens as foreign, resulting in a cascade of lymphocyte activation, proliferation, and differentiation. This concept is supported by the demonstration of activated T-cell infiltrates in allograft rejection. A predominant CD4 + cell population is associated with acute rejection; a predominant CD8 + cell population is associated with BOS. Animal models demonstrate that BO results from a type 1 T helper alloimmune response. The high incidence of BOS despite T-cell targeted immunosuppression, however, underscores the importance of alternate pathways to BOS.
Humoral immunity resulting in antibody-mediated rejection is increasingly recognized as a second important driver of BOS ( Fig. 50-7 ). Donor and recipient HLA locus mismatch is associated with increased risk for BO. Further, donor-specific alloantibodies developing de novo after transplant can damage airway epithelium and endothelium and up-regulate cytokines associated with BOS. Although the link between the emergence of donor-specific antibodies and subsequent BOS is strong, the diagnosis of antibody-mediated rejection remains a challenge. Defining the specific histologic features of antibody-mediated rejection is a work in progress.
BO may also develop through an autoimmune pathway ( Fig. 50-8 ). Through a variety of insults, injury may expose lung self-antigens, which are then presented to autoreactive T cells. This presentation induces either a cellular or humoral response ultimately resulting in BO. One such antigen is type V collagen (col[V]), expressed on the basement membrane of small airway epithelial cells and perivascular and peribronchiolar tissues. In murine models of acute rejection, anti-col(V) antibody deposition has been observed. Further, col(V)-induced oral tolerance prevents both acute and chronic rejection. Interestingly, administration of anti-MHC class I antibodies in mice induces anti-col(V) antibody generation with resultant airway lesions resembling BO in human lung transplant recipients. Autoantibodies to the airway epithelial antigen K-α1 tubulin increase fibrotic growth factors and other transcription factors related to BO. In lung transplant recipients, circulating autoantibodies against both col(V) and K-α1 tubulin are strongly linked with the subsequent development of BOS. These responses support a link between alloimmunity and autoimmunity.
Finally, innate immunity plays a role in BOS. Toll-like receptors on lung epithelium and antigen-presenting cells regulate the adaptive immune response ( Fig. 50-9 ). Loss- and gain-of-function Toll-like receptor polymorphisms are associated with differential risk for BOS. Although the mechanisms may be myriad, it is possible that clinical and environmental risk factors for BOS, including primary graft dysfunction, gastroesophageal reflux and aspiration, community-acquired viruses and cytomegalovirus, air pollution, and fungal and bacterial colonization, may operate in part via the innate immune pathway. Some, for example, cytomegalovirus, may also increase the risk for BOS by increasing MHC antigen expression or through molecular mimicry.
Bronchiolitis Obliterans after Allogeneic Stem Cell Transplantation
BO is an uncommon complication of allogeneic stem cell transplantation, seen in 2% to 3% of patients and in 6% to 10% of those who develop chronic graft-versus-host disease (GVHD). The histologic and clinical features of the disease are virtually identical to those seen in lung transplantation. As in lung transplantation, the morbidity and mortality associated with a surgical approach to diagnosis of BO has led investigators to avoid surgery by defining a BO syndrome based on clinical, radiographic, and spirometric criteria. This BOS is nearly always preceded or accompanied by typical findings of GVHD: mucositis, esophagitis, and/or and skin rash. Four to 6 months after the onset of GVHD patients develop dyspnea and a nonproductive cough that may be severe and rapidly progressive. Physical examination may reveal scattered wheezing and frequently bibasilar crackles. Hypoxemia is common. Spirometry and radiographic findings are the same as those observed in BOS in lung transplantation. Relative to lung transplantation, however, we have less understanding of the mechanisms driving BOS in stem cell transplantation. The rarity of BO following autologous stem cell transplantation and its histologic similarities to BO in lung transplantation lends support to alloimmune T-cell–mediated pathogenesis. Other mechanisms, however, have been proposed. The most significant risk factor for BOS is GVHD. Other risk factors include busulfan or methotrexate administration at the time of transplant, older age, poor lung function before transplant, and respiratory viral infection within the first 100 days after transplant.
Bronchiolitis Obliterans and Connective Tissue Diseases
BO may present uncommonly with connective tissue or collagen vascular diseases. Most literature linking BO and connective tissue diseases refers to cases of “BOOP.” However, constrictive BO has been reported in association with some diseases. Constrictive BO is most well characterized in rheumatoid arthritis. When present, it primarily affects women with long-standing rheumatoid arthritis who are smokers. The onset and progression of dyspnea and nonproductive cough are rapid, as is the rate of progression of airflow obstruction. Unfortunately, no consistent response to corticosteroids has been documented, and the prognosis for these patients generally is poor, although a subset of patients may have a more insidious course. Penicillamine, used to treat rheumatoid arthritis, has been implicated as a potential cause of BO, but confirmation of an etiologic relationship is lacking. BO has also been reported in systemic lupus erythematosus, in Sjögren syndrome, and in scleroderma, where reflux and chronic microaspiration may play an important role.
Treatment of Bronchiolitis Obliterans
Unfortunately, treatment of constrictive BO is often ineffective. Although there is little evidence that smooth muscle contraction plays a significant role, β-adrenergic agonists are frequently attempted to provide symptomatic relief. Literature supporting the important role of early administration of corticosteroids frequently contains mixed populations, including cases of BOOP. This is particularly true of BO after exposure to toxic fumes. Nevertheless, in an individual patient, a trial of corticosteroid therapy should be considered; if a response is identified, the corticosteroid should be continued for at least 2 to 3 months, then reduced slowly, to minimize the likelihood of relapse. In some cases it may be necessary to continue low-dose or alternate-day therapy for months or years.
Treatment of established BOS after lung transplantation remains disappointingly ineffective. Augmentation or changing immunosuppression has been tried with variable response. Thrice-weekly azithromycin does improve lung function in patients with a subset of BOS demonstrating neutrophilia on BAL. Statins may be associated with decreased rejection and BOS, perhaps by inhibiting expression of MHC class II molecules or by a variety of other antiinflammatory and immunomodulatory effects. Uncommonly used, extracorporeal photophoresis may decrease the rate of decline in FEV 1 in established BOS. Limited data and marginal efficacy in conjunction with the burden of delivering this intensive treatment have tempered enthusiasm for this potential therapy. For severe BOS, retransplant is the only definitive treatment and may be an option for some. The rates of recurrent BOS after a second transplant are similar to those of first transplant.
The most effective strategy for BOS therapy in lung transplant is primary prevention. Substantial attention is paid to identifying and treating patient-specific risk factors for BOS. Examples include surveillance bronchoscopy for acute rejection, cytomegalovirus-specific antiviral prophylaxis, reducing aspiration through lifestyle modifications and gastric fundoplication, and treatment of certain community-acquired respiratory viral infections.
As in lung transplant recipients, the response to BOS therapy in stem cell transplant patients is poor. Bronchodilators and corticosteroids do not generally improve airflow, and the use of immunosuppressive agents to treat chronic GVHD, although occasionally effective, has not consistently changed the course of BO. Macrolide antibiotics are sometimes used empirically, but there is little evidence to support this practice. Prophylaxis against GVHD and viral infection may reduce the risk for subsequent BOS.
Bronchopulmonary Dysplasia
Bronchopulmonary dysplasia (BPD) is a respiratory complication of premature birth. Since the first description of BPD in 1967, the management of prematurity has evolved, including the use of antenatal glucocorticoids, perinatal surfactant, and modified mechanical ventilation. This evolution has resulted in different clinical and histopathologic entities termed “old” and “new” BPD. Old BPD was identified in newborn babies with infant respiratory distress syndrome following prolonged treatment with high concentrations of inspired oxygen and positive pressure ventilation. Characteristic histologic features include unusual abnormalities of the bronchioles, including marked metaplasia, obliteration, and cystic changes. The entity also has been described in adults after adult respiratory distress syndrome and may be more frequent than is currently recognized. The pathologic process includes significant fibrosis of alveolar septa and resembles the honeycombing seen in other fibrotic interstitial lung diseases.
Contemporary management of premature infancy has improved survival of increasingly immature infants, who may experience “new” BPD. New BPD is milder clinically and probably reflects developmental arrest in an immature lung rather than barotrauma and oxygen toxicity. Histopathologic examination reveals enlarged air spaces with simplified alveolar and alveolar-capillary development. Unlike in the original disease, airway abnormalities are uncommon.
Localized Disorders
Many of the specific causes of localized abnormalities of bronchi also underlie abnormalities of the upper airway. Examples are neoplasms, extrinsic compression, granulomatous disease, malacic lesions, and trauma. However, the manifestations, diagnosis, and therapy of localized bronchial disorders are substantially different from similar disorders in the larynx or trachea.
Neoplasms
Because lung cancers are common, any endobronchial mass must be evaluated carefully for possible malignancy. All histopathologic types of primary lung cancer may protrude into a bronchus and narrow or occlude it. Malignant endobronchial tumors often have an irregular, rather than smooth, surface on bronchoscopic examination. Primary malignant tumors of the lung are described in detail in Chapters 53 and 54 .
Of patients with extrapulmonary malignancies metastatic to the lung, approximately 5% have predominantly endobronchial metastases. The most common primary malignancies are renal cell, colonic, rectal, cervical, and breast carcinomas and malignant melanomas. In most instances the manifestations of the primary tumor are apparent before the endobronchial metastasis is discovered. Metastatic malignancies of the lung are discussed in detail in Chapter 55 .
In patients with lymphomas or leukemia, malignant infiltrations of the bronchial mucosa are rare. In Hodgkin disease or non-Hodgkin lymphoma, the endobronchial malignant cells may originate in bronchus-associated lymphoid tissue, may invade the bronchial mucosa by direct extension from hilar or peribronchial lymph nodes, or may seed the bronchial mucosa via lymphatic or blood vessels. Leukemic infiltration of bronchial mucosa is a rare late manifestation of chronic lymphocytic leukemia.
The lung is involved in one third to one half of patients with acquired immunodeficiency syndrome (AIDS) and Kaposi sarcoma (see Chapter 90 ). Endobronchial lesions are seen frequently, but they rarely cause airway obstruction or hemoptysis. The lesions are usually multiple, bright red or violaceous, and flat when visualized through the bronchoscope. On CT scans, Kaposi sarcoma may appear as irregular and ill-defined, sometimes flame-shaped, nodules, with peribronchovascular interstitial thickening beginning in the perihilar region and extending toward the periphery. The diagnosis of endobronchial Kaposi sarcoma is established when a patient with AIDS has widespread extrapulmonary Kaposi sarcoma and characteristic-appearing endobronchial lesions. Biopsy of the endobronchial lesions is seldom necessary for diagnosis and may be hazardous because of excessive bleeding.
Benign lung tumors frequently originate from cells in the airways, including nerves (schwannomas, neurofibromas, neurilemomas), smooth muscle (leiomyomas), cartilage (chondromas), blood vessels (hemangiomas), fat cells (lipomas), glands (cystoadenomas, oxyphilic adenomas), and epithelium (papillomas). These tumors often narrow or obstruct bronchi. By bronchoscopic examination, the tumors often are smooth, round, and well localized. Benign tumors of the lung are described in detail in Chapter 56 .
Bronchial Compression
When peribronchial lymph nodes are enlarged by carcinoma, lymphoma, or granulomatous infection, they may narrow the adjacent bronchi. Although sarcoidosis frequently results in enlarged hilar and mediastinal lymph nodes, bronchial narrowing from compression by lymph nodes in sarcoidosis is rare. In infants with congenital heart defects such as tetralogy of Fallot and transposition of the great vessels with ventricular septal defect, bronchial compression by dilated pulmonary arteries is an occasional complication.
Mediastinal Fibrosis (see Chapter 54 and 84 )
In patients with pulmonary histoplasmosis or tuberculosis, an interesting and rare complication is mediastinal fibrosis, also called sclerosing or fibrosing mediastinitis. In such patients, it appears that fungal or bacterial antigens from granulomatous foci in mediastinal lymph nodes stimulate fibrogenesis in surrounding tissue, perhaps because of unusual sensitivity to the antigens. The fibrosis may result in narrowing or occlusion of vital mediastinal structures, and the structures affected depend on the specific lymph nodes involved by the original infection. Mediastinal fibrosis originating from subcarinal or hilar lymph nodes may result in occlusion of main-stem bronchi, pulmonary blood vessels, or the esophagus. Mediastinal fibrosis originating from right paratracheal lymph nodes commonly produces obstruction of the superior vena cava and azygos veins. CT and magnetic resonance imaging are useful for diagnosing and following this condition. No medical intervention has been shown to be effective. Patients sometimes benefit from endovascular and/or endobronchial stenting.
Bronchial Anthracofibrosis
Bronchial stenosis or obliteration with anthracotic pigmentation in the mucosa was first described as a discrete clinical entity in 1998, in a retrospective analysis of 28 patients from Korea. Characterized by multifocal bronchial stenosis, especially in the upper and right middle lobes, with multiple pigmented anthracotic lesions, the condition is thought to be due to prolonged exposure to biomass fuel. There is a very strong association between bronchial anthracofibrosis and tuberculosis. The diagnosis can be made at bronchoscopy, but bronchial anthracofibrosis is often mistakenly identified as mediastinal fibrosis or endobronchial tuberculosis.
Foreign Bodies
Accidental inhalation of foreign bodies is a major cause of death in children, resulting in approximately 2000 deaths annually in the United States. The foreign bodies, which may be seeds, nuts, nails, or a variety of other objects, most frequently lodge in the right main-stem bronchus. Children with aspirated foreign bodies may present with immediate cyanosis, cough, and wheezing or with the delayed onset of pneumonia or bronchiectasis. Suspected aspiration of a foreign body is an indication for immediate bronchoscopic examination of the airways. In the presence of asphyxia, rigid bronchoscopy is appropriate. In most other situations, foreign bodies can be extracted with the flexible bronchoscope, but personnel and equipment for rigid bronchoscopy should be available (see Chapter 23 ).
Granulomatous Inflammation
In patients with pulmonary tuberculosis, spillage of infected material into the middle and lower lobes occasionally causes localized endobronchial infection. Endobronchial tuberculosis may present with hemoptysis, bronchorrhea, or localized bronchial obstruction, causing lobar collapse and persistent postobstructive pneumonitis. These findings may develop during active pulmonary infection by tuberculosis or many years after its treatment. The diagnosis is established most readily by fiberoptic bronchoscopy. The typical finding is the presence of localized endobronchial gelatinous granulation tissue. The mucosa may be nodular, red, and ulcerated, and often the diagnosis of bronchogenic neoplasm is suggested until pathologic examination of biopsy material has been carried out.
In patients with pulmonary sarcoidosis, localized endobronchial granulomatous inflammation rarely may lead to stenosis of bronchi. PFT results often show airway obstruction, but the common causes of the obstruction are the structural distortion of bronchi and bronchioles that accompanies pulmonary fibrosis, nonspecific bronchial hyperreactivity, or laryngeal sarcoidosis. Only rarely is bronchostenosis present.
Bronchocentric granulomatosis is an uncommon inflammatory lesion defined morphologically by the presence of necrotizing granulomas surrounding bronchi. The entity develops most commonly in asthmatic patients with allergic bronchopulmonary aspergillosis, and considerable evidence suggests that the granulomatous bronchitis is an immunologic response to endobronchial fungi. Cases have also been reported in association with other infections (mycobacterial or fungal) and with rheumatologic disease, and a significant proportion are idiopathic. The bronchi may be narrowed or obliterated because of the inflammatory reaction itself or because of associated mucoid impaction.
Broncholithiasis
Broncholithiasis is defined as the presence of a calcified fragment of tissue within a bronchus. Any disorder that leads to calcification of lung tissue or of lymph nodes may result in broncholithiasis. This most often happens when hilar or peribronchial lymph nodes become calcified as a result of granulomatous infections such as histoplasmosis or tuberculosis, or less commonly from actinomycosis, coccidioidomycosis, cryptococcosis, or silicosis. Necrotizing pneumonias and bronchiectasis may lead to calcification of bronchial cartilage, which can fragment to produce broncholiths. Occasionally, retained foreign bodies may become calcified. Broncholithiasis manifests clinically when calcified stones erode or break loose into the airways (see later). These stones are composed of 85% to 90% calcium phosphate and 10% to 15% calcium carbonate and thus closely resemble the composition of bone.
Amyloidosis
Amyloidosis is defined on the basis of the extracellular deposition of the fibrous protein amyloid. In both the primary and secondary forms of the disease, amyloid can deposit endobronchially, producing hoarseness, wheezing, or stridor, or incidental findings at the time of bronchoscopy. The airway mucosa demonstrates irregular thickening with waxy firm deposits that may appear white, gray, or yellow. As many as 30% of patients with primary amyloidosis are symptomatic. Pulmonary involvement is usually associated with amyloid of the light chain variety. The definitive diagnosis of endobronchial amyloidosis requires biopsy and demonstration of amyloid deposits, as defined by their green birefringence when viewed with polarized light after staining with Congo red. A recent report suggests that confocal endomicroscopy may identify early-stage tracheobronchial amyloid. Endobronchial amyloid has been treated successfully with neodymium : yttrium-aluminum-garnet (Nd : YAG) laser therapy.
Tracheomalacia and Bronchomalacia
Softening of the tracheal or bronchial walls may contribute to narrowing and collapse of the airways during exhalation. This can develop as a result of inherited disease (e.g., congenital polychondritis) or may be acquired as a result of trauma, infection, chronic inflammation (e.g., relapsing polychondritis), or emphysema. Less commonly, bronchomalacia may be found in infants because of inadequate development of bronchial cartilage. These infants generally present with dyspnea, atelectasis, or recurrent pneumonias. CT scans, maximal flow-volume curves, and direct visualization by bronchoscopy are all helpful in confirming the diagnosis. Pharmacologic treatment is rarely effective, and stents or surgical intervention may be necessary for patients who are very symptomatic.
Traumatic Injury (see Chapter 76 )
Tears or complete ruptures of main-stem bronchi or the bronchus intermedius are occasional complications of blunt trauma to the chest. The diagnosis should be suspected in any posttraumatic patient with new onset of cough, respiratory distress, subcutaneous and mediastinal emphysema, or pneumothorax. The associated presence of hemoptysis or hemothorax indicates bronchial vascular damage. Occasionally the development of manifestations of bronchial tears may be delayed days or weeks after the traumatic injury.
Clinical Features of Localized Disorders
Patients with localized endobronchial lesions generally present with symptomatic, physical, or radiographic manifestations of the lesion itself or of underlying conditions (e.g., malignancy, infection, AIDS, or sarcoidosis). Only the manifestations of the lesions themselves will be described in this section.
The most common symptoms of localized endobronchial disease are cough, hemoptysis, wheeze, dyspnea, and fever and chills secondary to postobstructive pneumonia. If an endobronchial lesion only partially obstructs a bronchus, patients may show manifestations of chronic pulmonary infections, such as lung abscess (see Chapter 33 ) or bronchiectasis (see Chapter 48 ). A history of recurrent pneumonias in the same segment or lobe of the lung should prompt a careful evaluation for partial bronchial obstruction by an endobronchial lesion. Similarly, for any edentulous elderly patient with a history of a severe anaerobic pulmonary infection, endobronchial obstruction should be considered.
Symptoms of broncholithiasis include cough, hemoptysis, fever associated with purulent sputum, and expectoration of stones. Often the cough in broncholithiasis is productive of a mixture of gritty, sandy particles and purulent or bloody sputum.
The physical examination in patients with localized endobronchial lesions may reveal fever and tachypnea. When a bronchus is narrowed but not completely obstructed, examination of the chest may reveal a unilateral palpable rhonchus, a localized wheeze during a forced expiratory maneuver, or a prolonged sibilant sound that persists after the expiratory or inspiratory effort has ended, the “bagpipe sound.” Once the obstruction is complete, there is a loss of breath sounds and tactile fremitus over the portion of the lung distal to the obstruction.
In patients with localized endobronchial disease, the chest radiograph may show no abnormality. Radiographically apparent lung collapse depends on the completeness of the obstruction and on the extent to which collateral ventilation from adjacent lung is present. In infants the pores of Kohn, the sites of collateral ventilation, are poorly developed. Hence the likelihood of complete collapse from localized bronchial disease is great in this age-group. Other findings on the plain chest radiograph include mediastinal adenopathy with or without calcification, lung abscess, bronchiectasis, or pneumonia. The presence of air bronchograms in a consolidated region of the lung suggests that the bronchus supplying that region is at least partially patent.
Middle lobe syndrome refers to chronic or recurrent radiographic evidence of collapse of the right middle lobe (RML). Originally it was postulated that the cause was tuberculous adenitis of lymph nodes in the RML causing bronchial compression. Obstructive middle lobe syndrome can result from extrinsic compression by inflammatory lymphadenopathy or from endobronchial tumors. However, in most patients, bronchoscopy and CT scans do not demonstrate obstruction. This nonobstructive middle lobe syndrome is thought to relate to the normal, relatively long length and narrow caliber of the RML bronchus or to the relatively ineffective collateral ventilation normally present in this lobe. The anatomy itself leads to poor mucus clearance from the RML and to mucus plugging of peripheral airways. The poor collateral ventilation of the RML limits reexpansion once there is atelectasis. Patients with middle lobe syndrome often report multiple episodes of recurrent RML pneumonia. In addition, bronchiectasis is found in approximately 50% of patients with middle lobe syndrome. The most common clinical features of middle lobe syndrome are recurrent infection, chronic productive cough, chest pain, or dyspnea.
Diagnosis of Localized Disorders
In patients with only partial obstruction of a bronchus, comparing radiographs obtained at full inspiration with those obtained at full expiration may assist in establishing the diagnosis. Upon inspiration, the negative intrathoracic pressure distends the partially obstructed bronchus, and air enters the distal lung. Upon expiration, the obstruction becomes complete, and air is trapped behind it. The result is a mediastinal shift away from the affected side on expiration. CT scans may identify hyperinflation, compressing lymph nodes, or calcifications in patients with broncholithiasis, or subtle endobronchial abnormalities.
The definitive procedure for diagnosing localized bronchial abnormalities is direct examination of the bronchi via fiberoptic bronchoscopy. In general, any visualized abnormality should be biopsied and the biopsied materials submitted for histologic examination as well as for culture. If the lesion is friable and bleeds easily during its examination and manipulation, rigid bronchoscopy may be required.
Routine PFT results in general do not distinguish between localized and widespread bronchial obstruction. In patients with bronchial compression or mediastinal fibrosis, skin tests for histoplasmosis or tuberculosis may be positive. In bronchocentric granulomatosis, peripheral blood eosinophilia and serum precipitins for Aspergillus may be present. Because bronchocentric granulomatosis is probably a hypersensitivity reaction to Aspergillus, galactomannan levels are typically normal. In endobronchial amyloidosis, immunoelectrophoretic analysis of blood or urine shows evidence of monoclonal gammopathy in 90% of cases.
Treatment
The appropriate therapy for localized lesions of the bronchi depends on the specific underlying cause. Treatment of bronchial obstruction is described in Chapter 23 . In some patients with inoperable obstructive neoplasms of the trachea, main-stem bronchi, or bronchus intermedius, the use of the Nd : YAG laser, electrocautery, or argon plasma coagulation can provide immediate relief; the therapeutic effects of cryotherapy, brachytherapy, and photodynamic therapy are slower in onset. Bronchial obstruction from extrinsic compression or endobronchial granulomatous inflammation may be relieved by medical treatment of the underlying condition (e.g., lymphoma, tuberculosis), but irreversible fibrotic narrowing often requires surgical resection or stenting. There are reports that airway and vascular obstruction due to mediastinal fibrosis may improve with corticosteroids or with stenting, and that anthracofibrosis may improve with antituberculous treatment, but prospective trials are lacking. Foreign bodies usually can be removed with specialized wire claws or baskets inserted through a bronchoscope. When they are lodged in central airways, removal of foreign bodies is performed most effectively via a rigid bronchoscope. Broncholithiasis is often self-limited, requiring no further evaluation or treatment. However, if hemoptysis, persistent cough, atelectasis, or infection is present, bronchoscopic evaluation should be considered for stone removal. Antibiotics should be administered to treat postobstructive infections. Occasionally, surgical intervention is required to manage persistent or recurrent broncholithiasis. In infants with bronchomalacia, effective treatment may require long-term ventilation of the lungs until normal cartilage is formed, which usually happens by 6 months to 2 years of age. Patients with suspected traumatic bronchial injury should undergo immediate endotracheal intubation and fiberoptic bronchoscopy followed by thoracotomy.
Tracheobronchial Stents
Although prostheses have been used to relieve tracheal and bronchial obstruction for many years, recent technical advances have made the procedure easier and more effective. More than 20 types of tracheobronchial stents are now available, in metal, mesh, or silicone rubber; insertion usually can be accomplished by fiberoptic bronchoscopy without general anesthesia. Stents have been used effectively to relieve airway obstruction caused by malignancy, postinflammatory stenosis, and tracheobronchomalacia, and to occlude tracheoesophageal fistulas. The success rate is greater than 80% to 90% in selected patients. Fenestrated or mesh stents are more effective for benign lesions than for neoplasms, which tend to grow through the metal mesh. Careful patient selection, choice of the correct stent, and an experienced bronchoscopist are important determinants of success. Virtual bronchoscopy using CT is often useful in planning stent placement.
