Pulmonary Manifestations of Amyloidosis

Amyloidosis is a disease characterized by the deposition of abnormal proteins in extracellular tissue. The deposits originate from serum derived or locally produced proteins. (Sipe et al., 2010) The term “amyloid” was first used by Rudolph Virchow in 1854. (Saleiro et al., 2008) According to the Nomenclature Committee of the International Society of Amyloidosis 2010 recommendations, an amyloid fibril protein must occur in tissue deposits and exhibit affinity for Congo red and green birefringence when viewed by polarization microscopy. Furthermore, the protein must have been unambiguously characterized by protein sequence analysis (DNA sequencing in the case of familial diseases). In this chapter, we will focus on the pulmonary manifestations of amyloid. We will discuss the classification, presentation, symptoms, diagnostic testing and therapeutic options with regards to amyloid in the respiratory tract. Amyloidosis had been classified over the years based on the site of deposition and presence or absence of other diseases. (Thompson & Citron, 1983) The term “Generalized” or “Systemic” had been used to describe deposition in multiple anatomic sites and “localized” used to describe deposition in one anatomic site. The term “secondary” used to describe patients with coexistent disease like multiple myeloma and “primary” for patients with no such coexistent disease. (Utz et al., 1996)


Introduction
Amyloidosis is a disease characterized by the deposition of abnormal proteins in extracellular tissue. The deposits originate from serum derived or locally produced proteins. (Sipe et al., 2010) The term "amyloid" was first used by Rudolph Virchow in 1854. (Saleiro et al., 2008) According to the Nomenclature Committee of the International Society of Amyloidosis 2010 recommendations, an amyloid fibril protein must occur in tissue deposits and exhibit affinity for Congo red and green birefringence when viewed by polarization microscopy. Furthermore, the protein must have been unambiguously characterized by protein sequence analysis (DNA sequencing in the case of familial diseases). In this chapter, we will focus on the pulmonary manifestations of amyloid. We will discuss the classification, presentation, symptoms, diagnostic testing and therapeutic options with regards to amyloid in the respiratory tract. Amyloidosis had been classified over the years based on the site of deposition and presence or absence of other diseases. (Thompson & Citron, 1983) The term "Generalized" or "Systemic" had been used to describe deposition in multiple anatomic sites and "localized" used to describe deposition in one anatomic site. The term "secondary" used to describe patients with coexistent disease like multiple myeloma and "primary" for patients with no such coexistent disease. (Utz et al., 1996)

Classification of pulmonary amyloidosis
Amyloid in the respiratory tract has been classified by authors at The Mayo Clinic as associated with systemic amyloidosis and localized pulmonary disease. (Utz et al., 1996) The most common cause of the respiratory amyloid disease is secondary to systemic AL Amyloidosis which accounts for up to 80% of pulmonary amyloid. (Pitz et al., 2006) Moreover, it has been reported that 88% of patients with systemic amyloid have pulmonary disease. (Smith et al., 1979) Amyloidosis localized to the respiratory tract was first recognized by Lesser in 1877. (Lesser, 1877) Amyloidosis at present is best classified by the protein fibrils and then by the location of sites involved clinically. To date, there are 27 known extracellular fibril proteins identified in humans. Table 1 lists some of the common protein subunits. Clinically there are three broad classifications of pulmonary involvement. The amyloid deposition may predominantly www.intechopen.com Please use Adobe Acrobat Reader to read this book chapter for free.
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involve the tracheobronchial tree with nodules or submucosal infiltration. There can also be predominant interstitial localization. A third presentation is with single or multiple pulmonary parenchymal nodular deposits. A combination of radiographic and bronchoscopic studies provides this classification of pulmonary amyloidosis. Interestingly, it is uncommon for interstitial and tracheobronchial involvement to develop in the same patient.

Tracheobronchial amyloidosis
Pulmonary nodules of amyloid deposits can be found in the larynx, tracheobronchial tree and lung parenchyma. Discrete nodular deposits in the larynx were described in 1919 (New, 1919). Tracheobronchial amyloidosis is characterized by deposits in the trachea and large bronchi. This is the most common form of primary pulmonary amyloidosis. (Sugihara et al., 2006) Isolated tracheal disease is very rare with less than 20 cases reported in the literature as of 2006. (Sharma & Katlic, 2006) It typically presents in the fifth and sixth decade of life and is slightly more common in females than males. (Berk et al., 2002) As previously mentioned, tracheobronchial amyloid deposition can occur in two forms: nodular or unifocal disease and diffuse submucosal disease. Tracheobronchial amyloidosis has been associated with tracheobronchopathia osteochondroplastica (TBO) by some authors. (Jones & Chatterji, 1977) Tracheobronchopathia osteochondroplastica is a disorder characterized by the deposition of calcified or cartilaginous submucosal nodules in the airways. (Capizzi et al., 2000) The uncertainty is related to the fact that most patients with TBO do not show evidence of amyloid deposition. (Mimori et al., 1998) In a retrospective review of a series at The Mayo Clinic of 17 patients with biopsy proven tracheobronchial amyloidosis concluded that this form of pulmonary amyloid appeared to be a type of localized amyloid, with protein fibril deposition only present in the tracheobronchial tree. (Utz et al., 1996) This form is quite rare with less than 150 cases published in the medical literature. Although tracheobronchial amyloidosis often follows a relatively stable course, it can present with significant morbidity in patients with extensive airway involvement. It may require repeated therapeutic bronchoscopies in an attempt to prevent progression of airway involvement. Three patterns of airway involvement have been described by Berk et al: (1) proximal, (2) mid or main bronchial, and (3) distal disease. (Berk et al., 2002) Although tracheobronchial amyloidosis is most commonly caused by the AL form of amyloid fibril deposition, AA amyloidosis has also been reported in a case of tracheobronchial amyloidosis complicating mediastinal fibrosis. (Hoag & Yung, 2008)

Diffuse interstitial amyloid
Diffuse amyloid deposition in the lung parenchyma is usually associated with systemic AL amyloidosis. It is characterized by widespread amyloid deposition involving small vessels and the interstitium. There is little association between the extent of amyloid deposition in the lung and level of functional compromise. A Mayo clinic series included 35 patients who had pulmonary involvement with primary systemic amyloidosis. Celli and coauthors reported case series of 12 patients with AL lung disease, of which only 1 patient his clinical outcome dictated by his pulmonary involvement. (Celli, 1978) Cordier and colleagues reported that only 10% of patient deaths were due to AL lung disease in their series. (Cordier, 1986) Pathologists at John Hopkins have examined the association between cardiac and pulmonary amyloid. (Smith et al., 1979) They found that all patients with pulmonary amyloid deposition had cardiac amyloid disease. They concluded that histologic and clinical pulmonary disease in AL patients was principally a marker of severe cardiac infiltration.

Nodular amyloidosis
Amyloid nodules in the lung parenchyma are usually incidental findings on chest radiographs and usually need to be differentiated from neoplastic lesions. These nodules are typically located peripherally or subpleurally, and they can also be bilateral in some cases. If

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Pleural effusions
Pleural effusions have also been reported in patients with systemic amyloid disease. The incidence of pleural effusion in amyloidosis is not known. Effusions can be unilateral or bilateral, and they can present with either exudative or transudative chemistries. (Berk et al., 2003) One of the first reports of amyloid-associated pleural effusion included five patients by Kavuru and colleagues. (Kavuru et al., 1990) These authors found that pleural effusions in the majority of their patients (60%in their series) were believed related to either congestive heart disease or nephrotic syndrome, and only 40% of pleural effusions were "idiopathic". Despite this they found that even those patients with transudative effusions had pleural infiltration with amyloid on biopsy. The Amyloid Program at Boston University reported their 7 year experience with 636 patients. (Berk et al., 2003) Thirty five patients in this series (6%) had large recurrent pleural effusions along with another 10-15% with less significant effusions. They compared patients with primary systemic amyloidosis and coincident cardiomyopathy without pleural effusions and patients with recurrent large pleural effusions. They noted exudative chemistries in pleural fluid of 37% of their patients along with chylothorax in another two patients. In contrast to the conclusions drawn by Kavuru et al., their hypothesis was that direct amyloid infiltration of the parietal pleural was responsible for large recurrent pleural effusions. Their claim was supported by thoracoscopic descriptions of pleural studding and histologic evidence of amyloid infiltrating pleural surfaces on biopsy. (Kavuru et al., 1990) After extensive comparisons between the two groups using echocardiography, they concluded that cardiac dysfunction alone was not sufficient to produce the pleural effusions in their cohort. The paucity of chylous effusions in patients with AL amyloid despite the propensity of mediastinal lymphadenopathy points towards direct amyloid infiltration of lymph nodes by amyloid as the cause of chylothorax as opposed to a compression of lymph nodes. Although uncommon, pleural effusions in patients with primary pulmonary amyloidosis can be hemorrhagic. (BoydKing et al., 2009) www.intechopen.com Please use Adobe Acrobat Reader to read this book chapter for free.
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The clinical presentation of pulmonary amyloidosis
Pulmonary amyloid may present with symptoms or may be found as an incidental finding on thoracic imaging. Patients present to pulmonologists in a number of ways: patients with systemic amyloidosis may present with respiratory symptoms; localized forms of amyloid may be detected incidentally on imaging or biopsy; and patients may present with respiratory symptoms that warrant pulmonary workup leading to the diagnosis of amyloidosis. (Lachmann & Hawkins, 2006;Sipe et al., 2010;Thompson & Citron, 1983) Tracheobronchial amyloidosis usually presents in fifth decade of life with symptoms of cough, dyspnea, wheezing, and hemoptysis. (Berk et al., 2002) In addition, hoarseness is frequently reported. The most common symptoms of amyloid involvement with the respiratory system are cough, wheezing, dyspnea on exertion, and hemoptysis; none of which are uniquely specific to the diagnosis of pulmonary amyloidosis. One elderly male presented with diffuse alveolar hemorrhage. (Shenin et al., 2010) Amyloid nodules in the lung parenchyma are most often asymptomatic and are usually incidental findings on imaging studies; however, they sometimes can produce space occupying effects, most often if they limit either air or blood flow in the lungs. These nodules tend to calcify, and sometimes they may cavitate. They can cause lumenal narrowing of the airways and thus may lead to post obstructive atelectasis and/or pneumonia. Diffuse alveolar-septal amyloidosis related to systemic AL disease may present with symptoms of dyspnea or even more frightening symptoms of hemoptysis due to dissection of pulmonary arteries infiltrated by amyloid protein deposits (Cools et al., 1996;Road et al., 1985) or massive pulmonary embolism related to thrombosis of inferior vena cava. Mediastinal or hilar adenopathy is less common than extrathoracic adenopathy in patients with systemic AL disease. However, these patients may sometimes present with cervical nodes that may enlarge, become tender or recede in periods mimicking sarcoidosis. Pleural effusions in patients with amyloidosis will cause dyspnea and may at times require repeated thoracenteses to relieve symptoms.

General considerations for diagnosis
When systemic amyloid disease is present, consideration for pulmonary evaluation for amyloid involvement should be based upon symptoms and clinical suspicion. The delay from time of presentation to the diagnosis of pulmonary involvement has been up to 17 months in some series. (O'Regan et al., 2000) In a patient with systemic amyloidosis, exercise limitation or cough should prompt an evaluation for lung involvement. In the setting of isolated pulmonary disease, amyloid is often low on the differential diagnosis. Pulmonary amyloidosis can be evaluated with plain films, computed tomography, bronchoscopy and pulmonary function testing. Figure 1 depicts an algorithm of a diagnostic approach for patients with systemic amyloidosis.

Radiographic evaluation
As previously described, the nodular form amyloidosis is most often an incidental finding on thoracic imaging. The plain chest radiograph can be normal in as many as half of patients with pulmonary nodular amyloidosis. (O'Regan et al., 2000) Amyloid nodules are generally described as rounded with sharp, discreet margins, and they are occasionally cavitary www.intechopen.com  Fig. 1. Flow diagram of a decision pathway for the evaluation and treatment of respiratory amyloidosis in appearance. One case report found that a lesion of amyloid measured 282 Hounsfield units, which is significantly less dense than blood. (M'Rad et al., 1988) Pulmonary nodular amyloidosis are predominantly subpleural and peripheral with a random distribution. Imaging of patients with diffuse alveolar-septal disease may show infiltrative opacities on chest plain radiographs. In systemic amyloidosis, diffuse interstitial disease is most common. This may be reticular nodular on computed tomography imaging. Interlobular septal thickening and diffuse irregular lines with some honeycombing can be seen at the lung bases peripherally, and traction bronchiectasis can also be seen. Some report that diffuse cystic changes may predominate. (Wink, 2003) Tracheal and bronchial wall thickening or discrete tumor masses may be a CT finding of tracheobronchial amyloid. The presence of multifocal masses with calcification should prompt a differential diagnosis of carcinoma, Wegener's Granulomatosis, relapsing www.intechopen.com Please use Adobe Acrobat Reader to read this book chapter for free. Just open this same document with Adobe Reader. If you do not have it, you can download it here. You can freely access the chapter at the Web Viewer here.
polychondritis, tracheobronchial tuberculosis, pulmonary hyalinizing granuloma, tracheobronchopathia osteochondroplastica along with tracheobronchial amyloidosis. (Bhadra et al., 2010;Carter & Patchefsky, 1998;Gibbaoui et al., 2004) Circumferential calcification involving the membranous airway should suggest amyloidosis as other forms of airway thickening do not involve this portion. Positron emission tomography (PET) may demonstrate increased uptake of 18 F-flourodeoxyglucose (FDG) in patients with nodular amyloidosis. (Currie et al., 2005;Kung et al., 2003;Seo et al., 2010) From the studies of PET with pathology confirming amyloidosis, the standardized uptake value (SUV) ranged from 1.8 to 6.81, suggesting the need for biopsy to exclude malignancy. Coincident pulmonary nodular amyloid and adenocarcinoma has been reported in a patient with systemic AL amyloidosis. (Miyazaki et al., 2011) An uncharacteristic speculated appearance of the nodule in question in this case highlights the need for careful review of thoracic imaging in conjunction with a high index of suspicion. Coincident carcinoma and amyloid deposits have been described in thyroid medullary carcinoma. (Westermark et al., 2007)

Pulmonary function testing
Pulmonary function testing (PFT) in patients with pulmonary involvement of amyloidosis is similarly variable due to the variety of presentations. Overall, pulmonary functions can be normal or exhibit obstructive or restrictive disease. When tracheobronchial amyloidosis is present, the most common finding is airflow limitation as demonstrated by a reduced ratio of forced expiratory volume in the 1st second (FEV 1 ) to forced vital capacity (FVC) of less than 70%. The severity is dependent on the degree and location of amyloid deposition. In as series of patients with tracheobronchial amyloidosis from Boston, those with proximal disease tended to have more severe airflow limitation than those with more distal disease, although both groups had significant air trapping present with elevated residual volumes. (O'Regan et al., 2000) With the nodular form of pulmonary amyloidosis, direct compression of central airways may lead to obstructive patterns on PFTs. Evidence of a fixed upper airway obstruction not only suggests central airway disease but also portends a higher probability of progressive central obstructive disease. (Bhadra et al., 2010) Restriction may be present as would be expected in patients with significant pleural effusion, or in very severe cases of diffuse alveolar-septal disease. Diffusing capacity for carbon monoxide is most often preserved.

Diagnostic bronchoscopic findings
The bronchoscopic findings of pulmonary amyloidosis vary with the classification of disease. In patients with interstitial or pulmonary nodular disease the endobronchial appearance on bronchoscopy may be entirely normal. In contradistinction to the interstitial variety, those with tracheobronchial amyloidosis commonly have significant visible pathology. The lesions of tracheobronchial amyloid can be nodular, sessile, or polyploidy. The sessile lesions have been described as hard yellow plaques that may be expansive or thinner longitudinal irregularities. Cobblestoning of the mucosa may be present. The sessile lesions may cause significant airway stenosis, and these regions of stenosis can be diffuse. The nodules or polypoid lesions may suggest endolumenal carcinoma to both the experienced and inexperienced bronchoscopist. These nodules are usually firm, non mobile, and covered with hypervascular mucosa. Because of the hypervascularity in conjunction with the infiltrated submucosa, the endobronchial lesions in tracheobronchial amyloidosis www.intechopen.com Please use Adobe Acrobat Reader to read this book chapter for free.
Just open this same document with Adobe Reader. If you do not have it, you can download it here. You can freely access the chapter at the Web Viewer here. are quite friable, and bleed easily with minimal bronchoscopic contact. (Hoag & Yung, 2008) In contradistinction to tracheobronchopathia osteochondroplastica (TBO), the membranous trachea and mainstem airways are not spared. Tracheobronchial amyloidosis was associated with TBO in 22% in one series. (Piazza et al., 2003) Ultimately, the diagnosis of pulmonary amyloidosis requires histologic confirmation. An excellent overview of the pathologic features of pulmonary amyloidosis has been published. (Katzenstein, 1997) Congo red staining that produces green birefringence under polarized light remains the gold standard for diagnosis. Classic teaching is that these lesions have a tendency to bleed. An increased risk of hemorrhage during biopsies of amyloidotic tissues may result from increased fragility of involved blood vessels, reduced elasticity of tissues and rarely to an acquired deficiency of clotting factors 9 or 10. So while endolumenal forceps biopsy is required, preparation for potential airway bleeding is advisable. Strange et al. reported on the fatal hemorrhage and air embolism complicating a routine transbronchial biopsy of a patient with pulmonary amyloidosis. (Strange et al., 1987) Treatment with low level Neodymium: Yttrium Aluminum Garnet (Nd:YAG) laser or argon plasma coagulation (APC) can be effective in controlling bleeding from the central airway amyloid lesion. Both approaches offer non contact therapy. Application of electrocautery can create rebleeding by disruption of the coagulum. The non-contact therapies (APC and Nd:YAG Laser) does not disrupt the bleeding site and remove the coagulum created by its application. Pretreatment with endobronchial epinephrine injections into the lesions may decrease the bleeding risk. Effective biopsy may be obtained by the use of Wang needle or endobronchial forceps. Biopsy of the lesions may be difficult due to calcifications, and small biopsy specimens are open to sampling errors. False positive results also do occur in routine practice, usually as a result of poor Congo red staining. A confirmatory stain with Thioflavine T, which fluoresces yellow-green, may be helpful. (Saleiro et al., 2008) Any bronchoscopic finding suggesting tracheobronchopathia osteochondroplastica should be stained with Congo red due to the similarity of endobronchial appearance. (Bhadra et al., 2010) When the tissue is too calcified or when the operator feels uncomfortable with handling larger volume bleeding open surgical biopsy may be warranted. Like any tumor mass, malignant or non-malignant, post obstructive pneumonia can develop in pulmonary amyloidosis. Protected brush samples or clean bronchoalveolar lavage for culture should be obtained when there is a high grade stenosis or evidence of mucopurulent drainage. Once histologic evaluation with Congo red staining has been performed, immunochemistry to determine protein fibril type should be performed. Anatomical and functional evaluation of the various organs involved in systemic amyloidosis should also be performed. (Hawkins et al., 1990) Radiolabeled Serum Amyloid P (SAP) component localizes specifically to amyloid deposits in vivo in proportion to the amount of amyloid present and enables diagnosis, quantification and monitoring of amyloid to be performed scintigraphically. (Hazenberg et al., 2007)

Follow up of the patient with pulmonary amyloid
Several non-invasive methods of surveilling the progress of disease include computed tomography imaging and pulmonary function testing, especially serial spirometry. Proximal disease can present as pattern of fixed airway obstruction on flow volume loops, (Lachmann et al., 2006) or progression of disease may be apparent with progression flow limitation as www.intechopen.com Please use Adobe Acrobat Reader to read this book chapter for free.
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Management of pulmonary amyloidosis
The outcome of patients with pulmonary amyloidosis reported in the literature is variable. From a series of 21 patients with primary pulmonary amyloidosis, the median survival was 16 months and no patients were alive at five years. (Utz et al., 1996) The survival of this cohort was much shorter than would be expected in comparison to patients with systemic amyloidosis without pulmonary involvement. As some have suggested that respiratory failure is rarely the direct cause of death in patients with amyloidosis, it seems that its presence is a marker of more severe disease. In contrast, in another series over 15 years with 10 patients reported survival averaged 8 years. (O'Regan et al., 2000) In this series death was predominantly caused by respiratory complications. Due to the variability of amyloid involvement in the pulmonary system, the treatment for respiratory amyloidosis ranges from observation to bronchoscopic or surgical resection based on severity and symptomatology. Management decisions are mostly based on an individual basis. Systemic amyloidosis can be treated with chemotherapy while localized forms are typically treated with local interventions.

Chemotherapy
Infiltrative and systemic disease has been amenable to chemotherapy with oral melphalan and prednisone. (Kyle et al., 1997) A prospective study done at The Mayo Clinic in patients with systemic amyloidosis showed that combination therapy with melphalan, prednisone and colchicine or melphalan and prednisone resulted in prolonged survival compared to colchicine alone. The median duration of survival after randomization was 8.5 months in the colchicine group, 18 months in the group assigned to melphalan and prednisone, and 17 months in the group assigned to melphalan, prednisone, and colchicine (p<0.001). (Wechalekar et al., 2008) The National Amyloidosis Center in The United Kingdom has divided its treatment strategies for systemic AL disease into low dose, intermediate and high dose regimens. They recommend one of the intermediate dose regimens involving riskadapted CTD (cyclophosphamide, thalidomide and dexamethasone) or oral mel-dex (melphalan, dexamethasone) as first line therapy, and autologous stem cell transplantation as an alternative treatment. (Cohen et al., 2007) Stem cell transplantation has been attempted with variable success in more severe disease. Recent phase 2 trials in systemic amyloidosis showed that risk-adapted Stem Cell Transplant with adjuvant thalidomide and dexamethasone is feasible and results in low treatment related mortality and high hematological and organ response rates in patients. (Cohen et al., 2007) There are several ongoing trials at amyloid centers in the United States and internationally, and physicians are encouraged to refer their patients to be enrolled in these studies in order to determine best practices.

Therapeutic bronchoscopy
In light of poor responses of tracheobronchial amyloid to systemic therapy, the majority of these patients will require endobronchial therapy. Bronchoscopic therapies remain the key to airway management in these patients.

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Ablative therapy with Neodymium: Yttrium Aluminum Garnet (Nd:YAG) or Carbon Dioxide (CO 2 ) laser has been fairly successful. It appears that amyloid is very sensitive to photoablation. (Saleiro et al., 2008) Nd:YAG laser therapy is the most commonly utilized and is not only ablative but has significant hemostatic effects which is of particular benefit in these friable lesions. Laser ablation is the standard of care for endobronchial amyloidosis. In a retrospective series of 32 patients over 19 years, sixteen had persistent asymptomatic endolumenal disease. (Piazza et al., 2003) Two patients had endolumenal procedures with subsequent requirement of surgical resection. Each patient had no evidence of recurrent endolumenal amyloid after 5 to 8 years. Herman et al. reported on 13 cases of tracheobronchial amyloid successfully treated with Nd:YAG laser. (Herman et al., 1985) Follow up of another patient with CT imaging showed stabilization of the lesions after laser resection. (M'Rad et al., 1988) In a series by Diaz-Jimenez three of 11 laser ablations required termination because of significant hemorrhage. (Diaz-Jimenez et al., 1999) In addition to photoablative strategies, cryotherapy has also been utilized to treat tracheobronchial amyloidosis. (Maiwand et al., 2001) Like other endolumenal therapies, multiple treatments (21 procedures over an 11 year follow up) over the patient's disease course are often required. Rigid bronchoscopy has been utilized to mechanically debulk the amyloid lesions and for serial dilation of stenotic airways. In addition, the rigid bronchoscope has been used to help with potential bleeding when undergoing biopsy or laser photoablation. Placement of silicone stents has been utilized in conjunction with the ablative therapies to help prolong the airway stability. (Yang et al., 2003) The use of airway stents after dilation may also be considered in select patients. Serial therapeutic bronchoscopies are not uncommon. (Gibbaoui et al., 2004) If large mediastinal amyloid masses or lymphadenopathy cause central airway obstruction airway stenting is an option. As in all benign airways disease it is always preferential to implant a silicone stent. If a self expanding metallic stent is the only option, the authors recommend a fully covered stent. Operator experience should not be the determinant of the type of stent placed. Because of the complex nature of these patients, the high risk of significant bleeding, and the potential for repeated procedural requirements, it is recommended that these patients be referred to a formally trained interventional pulmonologist or thoracic surgeon with significant experience in managing high grade central airway obstruction. Localized tracheobronchial amyloidosis can cause post obstructive pneumonia. (Daniels et al., 2007) When evidence suggests a post obstructive state, appropriate empiric antibiotics should be started. Once bronchoscopic cultures are obtained, a strategy of proper deescalation of therapy should be employed based upon the culture results.

Radiation therapy
External beam radiotherapy has been successfully utilized in tracheobronchial amyloidosis in a patient believed not to be a candidate for endolumenal therapy due to the diffuse nature of the airways disease. (Monroe et al., 2004) A total of 24 Gy was delivered in 12 fractions, and colchicine was given as an adjunctive therapy. Improvements were measured by sequential pulmonary function testing, radiographic imaging, bronchoscopic evaluation, and performance status. Kurrus et al. published a case report demonstrating a benefit of external beam radiation (20 Gy in 10 fractions) in causing local response in a patient with localized tracheobronchial disease. (Kurrus et al., 1998) The authors noted decreased thickness of the airway wall and www.intechopen.com Please use Adobe Acrobat Reader to read this book chapter for free.
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Pleural drainage
Large recurrent pleural effusions in patients with amyloidosis will often require repeated thoracenteses followed by pleurodesis. (Berk et al., 2003;Berk et al., 2005) In a case series reporting on 35 patients with recurrent amyloid pleural effusions at Boston University, chest tubes were placed in 18 patients after a failure of diuresis and intermittent thoracenteses. Seven patients had the chest tube removed without chemical pleurodesis because of unremitting large volume drainage. Eight patients underwent talc slurry pleurodesis via chest tube with symphysis achieved in those with output less than 100 ml/day while in those patients with more than 200 ml/day, the pleurodesis failed uniformly. Video-assisted thoracoscopic surgery with talc insufflation achieved success in 2 patients, and another 2 patients had PleurX™ catheters placed for continued intermittent drainage.

Conclusions
In conclusion, although amyloid in the respiratory tract is not a common occurrence, physicians should be aware of the various manifestations. Symptoms of pulmonary amyloidosis are very non specific and hence require a high degree of clinical suspicion. The workup should include a complete physical examination, pulmonary function testing, appropriate clinical imaging followed by biopsies and pathology confirmation of amyloid. The treatment strategy needs to be individualized to the particular patient's clinical status and symptomatology, and may range from close observation to locally directed and systemic therapeutic options. Airway interventions, including debulking of amyloidomas with rigid bronchoscopy, laser photoablation, or airway stents should be performed by an experienced interventional pulmonologist or thoracic surgeon. This will help reduce the risks of these therapies and allow the most expansive treatment options in a rare condition with un-defined best practices. Future therapies will focus on strategies that involve preventing formation or propagation of insoluble beta-pleated sheets and/or enhance their degradation. Two ubiquitous molecules, serum amyloid P (SAP) and heparin sulfate proteoglycan (HSP), promote beta pleated sheet formation and inhibition of proteolytic degradation. (Gillmore et al., 2010) Drugs that target these molecules may be of interest in the future. Please use Adobe Acrobat Reader to read this book chapter for free. Just open this same document with Adobe Reader. If you do not have it, you can download it here. You can freely access the chapter at the Web Viewer here.