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* From the Departments of Respiratory and Critical Care Medicine (Drs. Chew, Low, and Eng) and Diagnostic Radiology (Dr. Cheah), Singapore General Hospital; and Department of Cardiothoracic Surgery (Dr. Agasthian), National Heart Centre, Singapore.
Correspondence to: Huck Chin Chew, MBBS, Department of Respiratory and Critical Care Medicine, Singapore General Hospital, Outram Rd, Singapore 169608; e-mail: chinnjing{at}pacific.net.sg
Case History
A 40-year-old Chinese woman presented with complaints of recurrent cough with wheezing. She had a history of bronchial asthma for 5 years for which she was receiving inhalers prescribed by her family physician, but her symptoms worsened despite being compliant to medications. She had progressive decreased effort tolerance with increasing shortness of breath and increased frequency of wheezing episodes for which she had to seek treatment at the emergency department. She had no other medical conditions. She did not drink alcohol or smoke cigarettes. There was no occupational exposure to toxic substances. Family history was not significant.
On physical examination, her vital signs were normal but she was dyspneic. Wheezing was heard on auscultation over both hemithoraces. The rest of the examination was normal. Blood tests done showed a normal CBC count, but the renal panel showed elevated bicarbonate levels suggesting metabolic alkalosis. Arterial blood gas revealed compensated chronic hypercapnic respiratory failure. She subsequently had severe bronchospasm that required intubation and mechanical ventilation for respiratory failure.
A chest radiograph showed focal increased lung markings over the right lower zone (Fig 1 ). CT scan of the thorax including a three-dimensional reconstruction showed marked thickening of the trachea from the level of the vocal cords extending inferiorly to the segmental bronchi with irregular calcification within the thickened tracheal and bronchial wall. There was also volume loss of the right middle lobe (Figs 234 ). Bronchoscopy was then performed, which showed patchy areas of erythema, mucosal irregularity especially on the posterior membranous wall, and splaying of the main carina (Fig 5 ).
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What is the typical histologic appearance?
Diagnosis: tracheobronchial amyloidosis
Histologic Appearance: Amyloid protein takes up Congo red stain and exhibits apple-green birefringence under polarized microscopy.
Discussion
Amyloidosis refers to a process manifested by abnormal deposition of protein fibrils in extracellular tissue. Amyloid protein takes up Congo red stain and exhibits apple-green birefringence under polarized microscopy (Fig 6 ). Amyloid deposition may occur in association with inflammatory or neoplastic conditions or develop as part of a disorder of Igs. Virchow first described amyloidosis involving the lungs in 1857. The first case of amyloidosis confined to the lower respiratory tract was described by Lesser in 1857. Amyloidosis may involve the lungs as part of a systemic process or may be confined solely to the lungs. Localized pulmonary amyloidosis may involve either lung parenchyma or the airways.
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Amyloid precursor protein fibrils, which are soluble, circulate as constituents of plasma, and these subsequently undergo conformational changes leading to formation of a predominantly antiparallel ß-pleated sheet configuration that is insoluble. Multiple cofactors are involved in fibrillogenesis that are tissue specific and may influence the deposition phase of amyloid in tissue, as well as reabsorption.
Tracheobronchial amyloidosis is among the localized variants of amyloidosis. It is a rare condition with < 100 cases reported worldwide. It is characterized by deposition of amyloid material as submucosal plaques and/or polypoid tumors in the airways,12 which may be localized, diffuse or multifocal. The endobronchial form is not associated with systemic amyloidosis.13456
The morbidity and mortality of tracheobronchial amyloidosis directly corresponds to the quantity of amyloid infiltrating the airways and rate of continued amyloid deposition. Death is usually a result of progressive bronchial obstruction and subsequent respiratory failure.
Patients may be asymptomatic or present with dyspnea, wheezing, hemoptysis, recurrent pneumonia, cough, and atelectasis.13457 The anatomic distribution of amyloid deposits define three patterns of disease. Proximal or upper tracheal disease usually present with various degrees of upper airway obstruction. Mid or distal tracheal-main bronchial disease involve lobar collapse or recurrent airway and parenchymal infections, which can progress to severe obstruction of the main bronchi and respiratory failure. Distal airway disease, sparing the trachea while affecting the main bronchi and higher order airways usually present with recurrent pneumonia, cough, and bronchiectasis. However, as the symptoms are usually nonspecific, mimicking common respiratory conditions such as bronchial asthma, treatment delay is the norm rather than the exception with patients already manifesting signs of chronic disease on presentation.289
Central airway obstruction can occur as a result of a number of malignant and benign processes, which include endobronchial lesions and extrinsic compression from tumors or enlarging lymph nodes. These are listed in Table 1 .10 Treatment strategies vary according to site as well as extent of airway involvement in the disease, and can range from observation alone in otherwise asymptomatic patients to aggressive local and systemic therapy in patients with significant airway obstruction.3711121314
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There is little information on the role of radiotherapy in treatment of localized tracheobronchial amyloidosis other than isolated case reports.18192021 Radiation therapy kills plasma cells that secrete amyloidogenic proteins.2223 This may offer a more definitive form of therapy for tracheobronchial amyloidosis.212223 Colchicine is a useful adjunct in the treatment of primary systemic amyloidosis and retards the synthesis, deposition, and degradation of amyloid in tissues.28
Patients with tracheobronchial amyloidosis have symptoms similar to those caused by various airway disorders. Early recognition of this rare condition and subsequent prompt intervention are crucial to avert complications from amyloid deposition that eventually lead to respiratory failure and death.
Our patient had severe diffuse airway disease and presented with advanced respiratory failure. She required intubation and mechanical ventilation, and attempts to wean her from ventilator support failed. This is likely a result of the severe distal airway disease causing progressive respiratory failure. Subsequent workup did not reveal any presence of systemic amyloidosis, and there were no free light chains, monoclonal gammopathy, or plasma cell dyscrasias suggestive of secondary causes of amyloidosis. Despite local debulking of the trachea and stenting the subglottic lesion to decrease airway narrowing and treating remaining lesions in the distal airways with radiotherapy and colchicine, our patient died from progressive respiratory failure as a result of advanced irreversible disease.
Conclusion
Amyloidosis may involve the lungs as either part of a systemic process or may be confined solely to the lungs, usually infiltrating lung parenchyma or the airways. Tracheobronchial amyloidosis has symptoms similar to those caused by various airway disorders. One must keep an open mind and consider alternative diagnoses when dealing with any respiratory condition that is not improving despite medication.
The morbidity and mortality of tracheobronchial amyloidosis directly corresponds to the quantity of amyloid infiltrating the airways and rate of continued amyloid deposition. Death is usually a result of progressive bronchial obstruction and subsequent respiratory failure. Treatment strategies vary according to site as well as extent of airway involvement in the disease, and can range from observation alone, in otherwise asymptomatic patients, to aggressive local and systemic therapy in patients with significant airway obstruction.
Footnotes
The authors declare that no funding has been received and that no conflicts of interest exists.
Received for publication November 19, 2006. Accepted for publication March 5, 2007.
References
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