Chronic cough with dual pathologies of pulmonary ossification

Abstract

An 81-year-old man presented with chronic cough, which did not respond to the initiation of combined bronchodilator/inhaled corticosteroid therapy. CT of the chest revealed calcified nodules throughout the trachea sparing the posterior membrane, and tiny peripheral parenchymal nodules with basal interlobular septal thickening and calcification. Flexible bronchoscopy demonstrated endobronchial nodularity from the proximal trachea to the mid-sections of both main bronchi, sparing the posterior membrane. Histopathology revealed submucosal fibrous connective tissue and benign bone, confirming a diagnosis of tracheobronchopathia osteochondroplastica. CT was consistent with a concurrent diagnosis of dendriform pulmonary ossification. These two rare phenomena often present with non-specific symptoms, and the diagnosis can be made with imaging in both conditions. There is a role for bronchoscopy in the diagnosis of tracheobronchopathia osteochondropastica, and the endobronchial appearance could be diagnostic. The concurrence of both phenomena in our case might represent activity of a common cellular pathway of ossification in both sites.

Background

Tracheobronchopathia osteochondroplastica (TO) is a rare disease of unknown aetiology characterised by nodular chondrification and ossification of airway cartilage.¹ Airway narrowing may result. Clinical presentation is non-specific and diagnosis is made with bronchoscopy or CT.

Pulmonary ossification is the formation of mature bone in lung parenchyma. It occurs secondary to parenchymal disorders or as an idiopathic phenomenon. Dendriform pulmonary ossification (DPO) is characterised by calcific lesions branching along terminal airways and is usually diagnosed with high-resolution CT (HRCT). Idiopathic DPO is very rare. Pulmonary parenchymal ossification is not associated with TO.

We report a case of concurrent TO and DPO, two rare phenomena not previously reported in the literature.

Case presentation

An 81-year-old man presented with a 5-year history of cough and sputum production. He reported production of one tablespoon daily of clear-yellow sputum, occurring on the background of sinus congestion and recurrent lower respiratory tract infections. He sought medical attention from his primary care provider after a protracted illness with increased cough and sputum above baseline symptoms, for which he had been treated in the community for asthma without success. He had symptoms of gastro-oesophageal reflux disease. His medical history included hypertension, type 2 diabetes mellitus, osteoarthritis and prostatomegaly. He was a never-smoker. He had history of asbestos exposure. His regular medications were irbesartan, rosuvastatin, prazosin and budesonide/eformoterol.

He presented to an emergency department and a chest X-ray was performed which revealed left lower zone subsegmental atelectasis. He was diagnosed with mild community acquired pneumonia but he failed to completely respond to oral antibiotics in the community. He was referred to a respiratory physician for further investigation.

Examination revealed an oxygen saturation of 97% on room air, no clubbing, patent nasal passages, no cervical lymphadenopathy and normal bronchovesicular sounds with no crepitations.

The initial impression was that of acute bronchitis with possible underlying bronchiectasis, his budesonide/eformoterol was ceased and additional investigations were arranged.

Investigations

Serum calcium was 2.39 mmol/L, albumin 37 g/L, creatinine 96 µmol/L, 25-OH-cholecalciferol level 86 nmol/L and parathyroid hormone level 2.8 pmol/L.

A HRCT chest was performed (figure 1) which demonstrated tracheobronchial irregularity with calcification and tiny peripheral and subpleural nodules with nodular interlobular septal thickening and calcification at the lung bases.

Figure 1.

(A–C) Axial chest CT images set to mediastinal window highlighting pathology in the trachea (see discussion and follow-up below). (D) Sagittal chest CT image set to mediastinal window demonstrating proximal luminal narrowing of the trachea by pathology described below. (E) Axial chest CT image set to mediastinal window cropped to the basal left lower lobe demonstrating dendriform calcifications of similar density to bone. (F) Axial chest CT image set to lung window cropped to the basal left lower lobe demonstrating peripheral reticulonodular change in the area of calcification seen in E.

Pulmonary function testing revealed mild reversible obstruction and a normal flow-volume curve. Flexible bronchoscopy demonstrated endobronchial nodularity extending from proximal trachea to the mid-sections of both main bronchi, sparing the posterior membrane (figure 2).

Figure 2.

Bronchoscopic photographs demonstrating exophytic nodularity of the tracheal wall, sparing the posterior membrane. (A) Distal trachea. (B) Carina. (C) Proximal left main bronchus.

Endobronchial biopsy with histopathology revealed normal bronchial mucosa overlying fibrous connective tissue and fragmented nodules of benign bone (figure 3).

Figure 3.

Microscopic photograph demonstrating a high-power view of bronchial mucosa and underlying submucosa, which contains benign bone.

The constellation of imaging findings, endobronchial appearance and histology confirmed a pathological diagnosis of TO and radiological diagnosis of DPO.

Outcome and follow-up

The patient’s Symbicort was stopped and he was referred to the chest physiotherapy clinic for sputum clearance input and referred to pulmonary rehabilitation. With better understanding of the aetiology of his symptoms and appropriate interventions (chest physiotherapy and pulmonary rehabilitation), he symptomatically improved. At a 6 months review, his symptoms were under good control.

Discussion

Nodular calcification involving the anterolateral tracheal wall and sabre-sheath trachea on CT chest, with sparing of the posterior membrane, pointed strongly to the diagnosis of TO, which was confirmed on flexible bronchoscopy. TO is a disease characterised by nodular chondrification and ossification of airway cartilage, sparing the posterior membrane of the trachea. It occurs as a result of submucosal calcium phosphate deposition and benign proliferation of bone and cartilage. Airway narrowing may result.

TO is an uncommon disease of the large lower airways. Autopsy studies suggest an incidence of 1 in 400 and bronchoscopic studies 2–7 in 100.² The aetiology is unknown, but has been reported in association with allergic rhinitis, Klebsiella ozaenae colonisation and IgA deficiency.^{1 3 4} Proposed pathogenic mechanisms include metaplasia of elastic connective tissue, or ecchondrosis and exostosis arising from airway cartilage rings.¹ The clinical presentation varies, and symptoms are non-specific. The most common presentation is chronic cough, but sputum production, wheeze, hoarse voice and dyspnoea may occur.¹ The symptomatic overlap with small airways disease can lead to a misdiagnosis of asthma leading to ineffective bronchodilator therapy, as we saw in our case prior to referral.⁵ Haemoptysis has been reported, including large volume haemoptysis.^{6 7} It is often diagnosed incidentally during the investigation for another medical condition. Diagnosis is made with chest CT, bronchoscopy or both. CT imaging demonstrates multiple calcified or non-calcified nodules extending into the large airways. Nodules are seen arising from the walls of the proximal tracheobronchial tree, typically sparing the posterior membrane.⁴ Histopathology is not necessary in the setting of diagnostic CT and bronchoscopy, but if performed may demonstrate epithelial squamous metaplasia, calcification, submucosal cartilage and ossification with or without haematopoietic bone marrow.³

The additional finding of peripheral dendriform calcific reticulonodular changes on CT in our case was consistent with concurrent DPO.

Pulmonary ossification refers to the formation of mature bone in lung parenchyma, with or without marrow elements. It can be idiopathic or secondary to an underlying parenchymal disorder, most commonly idiopathic pulmonary fibrosis/usual interstitial pneumonia. Idiopathic pulmonary ossification has been associated with gastro-oesophageal reflux disease, obstructive sleep apnoea and chronic neurological disorders, indicating low-level gastric acid aspiration might contribute to its occurrence.^{8 9} The molecular pathogenesis of pulmonary ossification is unclear, but an inflammatory cytokine milieu may contribute to transformation of fibroblasts to osteoblasts, alveolar macrophages to osteoclasts and provide essential growth factors for collagen and extracellular matrix deposition.⁸ DPO branches along terminal airways and is rare, with one autopsy series of 1393 autopsies revealing an autopsy prevalence of 0.4%.¹⁰ DPO is typically asymptomatic unless diffuse or extensive, in which case night sweats, chest discomfort or spontaneous pneumothorax can occur.^{8 11 12} Diagnosis is usually made based on characteristic CT chest findings of peripheral 1–5 mm nodular calcific densities forming contiguous, branching structures of bone density on mediastinal window.^{8 13} Biopsy with histopathology confirms the diagnosis but is rarely required or clinically indicated. When extensive, pulmonary function testing may reveal a restrictive physiology with impaired gas diffusing capacity.⁸ In our case DPO was asymptomatic and had little clinical relevance, however, the co-occurrence of two rare disease processes involving pathologic pulmonary ossification is notable.

To our knowledge, there are no previously reported cases of concurrent TO and DPO and given their rarity a common underlying disease mechanism is possible. Immunohistochemical studies in TO have demonstrated expression of bone-morphogenic protein-2 (BMP-2) in mesenchymal cells, chondrocytes and immature cartilage matrix within new submucosal nodules, and transforming growth factor beta (TGF-β) in nodule-associated chrondocytes and osteocytes as well as nodule-adjacent normal tracheal cartilage.¹⁴ The role growth factors play in driving parenchymal ossification however are limited to animal models, but there are data suggesting expression of BMP-2, TGF-β and interleukins 1 and 4 is involved.^{8 15} The lack of histological proof of DPO in our case limits conclusions which can be made, however, overexpression of a common molecular pathway could feasibly explain the co-occurrence of two rare pathologies, perhaps driven by a pathological response to a provoking stimulus (such as gastro-oesophageal reflux).

Conclusion

Workup for chronic cough with sputum production revealed biopsy-proven tracheal ossification, and imaging findings highly suspicious for parenchymal ossification. The clinical presentation and investigation findings of TO and DPO were typical of previously reported cases. Lung biopsy would have been necessary to prove pulmonary ossification, but this approach was not taken due to risk of complications for little perceived clinical benefit. Symptoms were almost certainly attributable only to TO, and the bystander diagnosis of DPO represents a rare incidental finding. The simultaneous occurrence of two rare disorders of ossification is notable. Treatment in our case was focused on management of symptoms, and cough was adequately improved with recognition of the cause and introduction of chest physiotherapy and sputum clearance techniques.

Learning points.

• Tracheobronchopathia osteochondroplastica and dendriform pulmonary ossification are two rare pulmonary pathologies of which pulmonologists should be aware, both of which can be identified on CT.

• Presentation of pulmonary ossification is non-specific, and treatment aimed at relief of symptoms and (if relevant) identification and treatment of underlying conditions.

• If workup progresses to bronchoscopy, tracheobronchopathia osteocondroplastica can be identified by its characteristic endobronchial appearance and the presence of ossification within biopsied bronchial nodules.

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