Pathology of Airway-Centered Interstitial Fibrosis

Airway-centered idiopathic fibrosis (ACIF) is one of a few relatively recently described entities with combined features of airway fibrosis and chronic interstitial lung disease. It is characterized by female predominance, progressive onset of dyspnea, and dry cough,[1] and it appears to start in the upper lobes and later spreads to the lower lobes. Histologically, it shows the presence of a bronchiolocentric pattern of lung injury resulting in centrilobular fibrosis and mild chronic inflammatory cell infiltrate, which extends into the adjacent interstitium. Other conditions with features of bronchiolocentric interstitial lung disease that are histologic variants of idiopathic interstitial pneumonia include bronchiolocentric interstitial pneumonia, bronchiolitis interstitial pneumonia, and centrilobular fibrosis.[2]

Airway-centered idiopathic fibrosis was initially described by Yousem et al in 2002 as “idiopathic bronchiolocentric interstitial pneumonia."[3] These authors described 10 patients with a unique histologic pattern of bronchiolocentric chronic inflammation with small airway fibrosis in wedge biopsies obtained from the patients with progressive dyspnea and dry cough.[3]  In 2004, Churg et al coined the term "airway-centered idiopathic fibrosis."[4]

The etiology and pathogenesis of airway-centered idiopathic fibrosis (ACIF) remain to be determined. Some have speculated that this condition may result from exposure to various noxious environmental agents. Although the patients described in the literature were either current smokers or ex-smokers with modest degrees of cigarette consumption, smoking is not believed to have a significant contribution in its pathogenesis.

Various authors have suggested a few possibilities that might play a role in its etiopathogenesis. Yousem et al suggested that airway-centered idiopathic fibrosis could be a burnt-out phase or an unusual form of hypersensitivity pneumonitis.[3] They described two patients in their series with a history of avian exposure. Although the serum precipitins were negative in these patients, the lung biopsies demonstrated a histologic pattern similar to that of hypersensitivity pneumonitis but with more extensive fibrosis and less inflammation without any granulomas.[3] In a case report, a patient had clinical, radiologic, and serologic evidence of hypersensitivity pneumonitis with a pattern of airway-centered idiopathic fibrosis on histology.[5]

Churg et al failed to find any clinical, serologic, or histologic evidence of hypersensitivity pneumonitis in their series of 12 patients.[4] Instead, they documented a history of exposure to various environmental substances such as wood smoke and chalk dust in their cohort of patients; however, their role in etiopathogenesis has not been established. Overall, airway-centered idiopathic fibrosis may represent a pattern of lung injury in response to environmental agents that are currently not known.

In a retrospective analysis (1982-1988) of lung biopsies obtained from 49 patients with clinical, radiologic, and histopathologic diagnosis of idiopathic pulmonary fibrosis, 12 patients had a histologic pattern of centrilobular fibrosis (6 men, 6 women; mean age 58.4 years).[6]  An interesting finding was the presence of foreign bodies in the bronchiolar lumina (41% cases) and extensive necrosis of bronchiolar epithelium leading to regeneration (91% cases), a feature not described by other authors. Based on these findings, the authors hypothesized that fibrosis as well as necrotic changes in the bronchiolar epithelium could have been caused by chronic aspiration of gastric contents.[6] The pattern described in this report appears to be different from that of airway-centered idiopathic fibrosis in which bronchiolocentric fibrosis is the predominant feature with intact bronchiolar epithelium without any necrosis or regeneration. Moreover, the study did not include data on prognosis for comparison with the previous studies.

A retrospective study (1995-2012) of 68 Brazilian patients with airway-centered idiopathic fibrosis found that hypersensitivity pneumonitis was the cause in 42.6% (n = 29) of patients, followed by gastroesophageal reflux disease in 25% (n = 17), collagen vascular disease in 5.9% (n = 4), a combination of these in 22% (n = 15), and idiopathic in 4.4% (n = 3).[1]  

Fukuoka et al described peribronchiolar metaplasia (PBM) as the only histologic finding in surgical biopsies of 15 patients with clinical history of interstitial lung disease.[7] In this study, PBM seems to have similar demographics to that of airway-centered idiopathic fibrosis, because both groups involved similar age groups and showed a female predilection. However, in contrast to airway-centered idiopathic fibrosis and in terms of prognosis, all patients (with a mean follow-up of 2.4 years) with PBM had good prognosis with no mortality reported.[7] PBM has been described as an incidental histologic finding without any clinical significance in a considerable proportion of lung biopsies obtained from patients with chronic interstitial lung disease. Whether PBM represents a stage in the development of airway-centered idiopathic fibrosis or an incidental finding without any significance is not yet known.

No definitive factors are known to have an established role in the etiopathogenesis of airway-centered idiopathic fibrosis. Further studies with a larger number of subjects are needed to elucidate its exact cause. The condition remaining idiopathic would not be a surprise, much like other idiopathic interstitial pneumonias.

Airway-centered idiopathic fibrosis is a relatively new entity, and its exact incidence and prevalence are not known. Three case series have described 10, 12, and 68 patients, respectively.[1, 3, 4]  A few others describe 1-2 case reports of this entity. Airway-centered idiopathic fibrosis has also been described under several names, such as idiopathic bronchiolocentric interstitial pneumonia, centrilobular fibrosis, and peribronchiolar metaplasia.

As noted earlier, this condition is more common in females (the male-to-female ratio is 2:1) and involves a wide age range (23-69 years), with a mean age of 46 years. It has been described in white, black, and Asian patients.

Most patients with airway-centered idiopathic fibrosis present with respiratory symptoms. Progressive dyspnea and chronic cough are the most common symptoms. Wheezing and chest pain are uncommon presenting symptoms. Physical examination reveals bibasilar inspiratory crackles.

Pulmonary function testing reveals a restrictive pattern with a decrease in total lung volumes, forced vital capacity (FVC), forced expiratory volume in 1 second (FEV1), and carbon monoxide diffusion capacity. Residual volume (RV) to total lung volume ratio and FVC to FEV1 ratio are within normal limits.

Bronchioloalveolar lavage (BAL) fluid analysis does not show any specific findings, but there may be a mild increase in lymphocytes with 1-4% eosinophils.

Chest radiography shows bibasilar reticular interstitial infiltrates, diffuse reticulonodular infiltrates that are predominant in central zones, thickening of bronchial walls, and small central ring shadows.

High-resolution computed tomography (HRCT) scanning demonstrates peribronchovascular interstitial thickening and traction bronchiectasis with thickened airway walls and surrounding fibrosis. Conglomerate fibrotic masses adjacent to the central airways may be present. Bronchiolectasis and honeycombing are less commonly seen features. Rarely, ground glass attenuation may be noted.

A bronchiolocentric pattern of lung injury can be seen in a wide variety of conditions, such as rheumatologic/connective tissue disorders, pneumoconiosis, and the chronic stage of hypersensitivity pneumonitis. Chronic aspiration should also be considered.[8, 9]  It is important to obtain an extensive clinical history for any exposure to allergens, antigens, occupational agents, and drugs, as well as any history of connective tissue disorders, before a patient can be diagnosed with idiopathic airway-centered interstitial fibrosis. Perform laboratory testing to rule out autoantibodies.

Important conditions to consider in the differential diagnosis of airway-centered interstitial fibrosis on histology are hypersensitivity pneumonitis, respiratory bronchiolitis-interstitial lung disease, nonspecific interstitial pneumonia (NSIP), and usual interstitial pneumonia.

Hypersensitivity pneumonitis

Hypersensitivity pneumonitis classically shows a triad of bronchiolocentric interstitial pneumonitis with poorly formed granulomas, cellular bronchiolitis, and interstitial chronic inflammatory infiltrate. However, this triad is seen in only 60-80% of the cases. Clinically, the patients are characterized by a history of exposure to antigens and the presence of serum antibodies against the allergen. The characteristic features on imaging are centriacinar nodules and ground glass attenuation, which is a rare and focal finding in airway-centered interstitial fibrosis. On histology, airway-centered interstitial fibrosis shows more extensive fibrosis and less inflammation compared with hypersensitivity pneumonitis. Differentiating between these two conditions is important because the hypersensitivity pneumonitis has a much better prognosis.

Respiratory bronchiolitis-interstitial lung disease

Respiratory bronchiolitis-interstitial lung disease (RB-ILD) shows a bronchiolocentric pattern with a predominance of pigment-laden macrophages within the bronchiolar lumen and in the surrounding alveolar spaces. In contrast, airway-centered interstitial fibrosis shows minimal amount of pigmented macrophages in the bronchiolar lumina and alveolar spaces. Imaging studies reveal bilateral ground glass opacities. RB-ILD hasa more favorable prognosis compared with that of airway-centered interstitial fibrosis, and it responds to smoking cessation in most cases. Steroids are required only in refractory RB-ILD cases.

Obliterative bronchiolitis

Obliterative bronchiolitis may show some overlapping features with airway-centered interstitial fibrosis as bronchiolar wall fibrosis and lumen narrowing may be seen. However, obliterative bronchiolitis differs from airway-centered interstitial fibrosis in the extent of the fibrosis and the involvement of interstitium. In early stages of obliterative bronchiolitis, the bronchioles show concentric mural fibrosis with lumen narrowing. Organizing granulation tissue may be seen within the bronchiolar lumina in some cases. In late stages of obliterative bronchiolitis, the lumen is completely obliterated due to progressive fibrosis, and the interstitial septa show minimal and focal involvement. Clinically, patients with obliterative bronchiolitis demonstrate an obstructive pattern on pulmonary function testing. Imaging studies show nonspecific features such as hyperinflation. This condition invariably has a progressive course with a poor prognosis.

Other interstitial pneumonias

In addition to the above-mentioned diseases, airway-centered interstitial fibrosis needs to be differentiated from NSIP and usual interstitial pneumonia.[10]

Nonspecific interstitial pneumonia

Airway-centered interstitial fibrosis may look similar to the fibrosing pattern of NSIP due to the temporally homogeneous linear fibrosis. However, in NSIP, relative sparing of the bronchiolocentric areas with a predominant involvement of the interstitium is seen. Distinguishing this entity from airway-centered interstitial fibrosis is importlant, as NSIP has a better prognosis.

Usual interstitial pneumonia

The pattern of usual interstitial pneumonia is characterized by four histologic features, temporal heterogeneity, fibrogenic foci, interstitial fibrosis with honeycomb change, and a subpleural location with predominant involvement of the peripheral parts of the lobules. In contrast, airway-centered interstitial fibrosis features a predominant centrilobular involvement with absent fibrogenic foci. Temporal heterogeneity and honeycomb changes are not seen in airway-centered interstitial fibrosis.

Very limited data are available on the gross findings of airway-centered interstitial fibrosis. Gross findings in an explant lung from a patient who was diagnosed with a disorder similar to airway-centered interstitial fibrosis revealed small lungs with a smooth pleural surface and peribronchovascular and peribronchiolovascular bundle fibrous thickening that was more evident in the lower lobes.[11]  The upper and middle lobes demonstrated diffuse fibrosis, but no honeycomb change was noted.

In another report of two cases, the cut surface of wedge biopsies was described as grayish-white with a slight tenacious texture.[12]

As the name indicates, airway-centered interstitial fibrosis is an airway-centered disease with predominant centrilobular involvement in a secondary lobule. Lung wedge biopsy specimens show a patchy distribution with a dominant bronchiolocentric pattern of involvement on low-power examination (see the image below). The bronchiolar walls are thickened with distortion of the lumina.

Airway-centered idiopathic fibrosis (ACIF). Low-power view showing predominant centrilobular fibrosis located around bronchioles and vessels with sparing of the peripheral part of the lobule.

On high power, the bronchioles show peribronchiolar subepithelial or adventitial fibrosis with none to mild mononuclear inflammatory cell infiltrate (see the image below).

Airway-centered idiopathic fibrosis (ACIF). Bronchiolar wall showing fibrosis and smooth-muscle hyperplasia. The bronchiolar lining epithelium is intact.

The fibrosis extends into adjoining interstitial septa and gradually fades out. Chronic inflammatory cell infiltrate, if present, is noted around the bronchioles and into the adjacent interstitial septa, with relative sparing of peripheral part of the acinus. The inflammatory component was more prominent in cases described by Yousem et al compared to those of a case series reported by Churg et al.[3, 4] The bronchiolocentric idiopathic interstitial pneumonia described is possibly the inflammatory phase of airway-centered idiopathic fibrosis as observed by Churg et al.[4]  

The smooth muscle in the wall of the bronchioles and vessels may show hyperplasia. The adjoining fibrotic alveolar walls may show bronchiolar metaplasia. The bronchiolar lumen and alveolar spaces contain a minimal amount of alveolar macrophages. The subpleural and peripheral lobular space is relatively spared by the fibrosis and inflammation. Architectural remodeling is absent. Microscopic honeycomb change is rare but can be seen.

Kuranishi et al found fibroblast foci (50%), honeycombing (30%), geographic heterogeneity (27%), and organizing pneumonia (37%) in their cohort of 68 patients.[1]

Negative findings

The bronchiolar lumen or alveolar spaces do not show any organizing tissue polyps. Significant inflammation is generally absent and fibrogenic foci are absent. The interstitium does not show any granulomatous inflammation.

Masson trichrome stain (see the image below) can be used to highlight the bronchiolocentric pattern of fibrosis of airway-centered interstitial fibrosis.

Airway-centered idiopathic fibrosis (ACIF). Collagen staining highlighting the peribronchiolar and perivascular fibrosis with relative sparing of the surrounding interalveolar septa.

A significant proportion of patients with airway-centered interstitial fibrosis have relatively poor prognosis. Features associated with a worse prognosis appear to include resting oxygen saturation, organizing pneumonia in the airway, fibroblast foci, and the presence of microscopic honeycombing.[1, 8]

In the study by Yousem et al, with a mean follow-up of 4 years, 33% of the patients died of pulmonary disease.[3] Similarly, in the case series by Churg et al (with a mean follow up of 2.9 years), 50% of patients with available follow-up data were either dead of disease or had progressive disease.[4] In a minor proportion of patients, the disease appeared stable or rarely reversible with steroid treatment.[4] The 5-year mortality in the study with 68 patients was 32.5%; 1 of 15 patients without cough (7%) and 19 of 53% (36%) with cough died.[1]

None of the histologic features has been found to be helpful in predicting the prognosis. However, in one study, the patients who died of disease had severe pulmonary involvement at the time of diagnosis.

Managing the underlying cause of airway-centered interstitial fibrosis, and steroids are the mainstay of the treatment. Lung transplantation is required in patients with progressive disease that does not respond to steroids.