Pathology of Airway-Centered Idiopathic Interstitial Pneumonia 

Updated: Jun 21, 2012
  • Author: Renu K Virk, MD; Chief Editor: Philip T Cagle, MD  more...
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Definition

Airway-centered idiopathic fibrosis (ACIF) is a relatively recently described entity with combined features of airway fibrosis and chronic interstitial lung disease. It is characterized by female predominance, progressive onset of dyspnea, and dry cough. Histologically, it shows the presence of bronchiolocentric pattern of lung injury resulting in centrilobular fibrosis and mild chronic inflammatory cell infiltrate, which extends into the adjacent interstitium.

ACIF was initially described by Yousem et al in 2002 as “idiopathic bronchiolocentric interstitial pneumonia.” [1] 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. The term airway-centered idiopathic fibrosis was coined by Churg et al in 2004. [2]

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Epidemiology

ACIF is a relatively new entity, and its exact incidence and prevalence are not known. Two case series have described 10 and 12 patients, respectively. Additionally, 4 single case reports of this entity exist. ACIF has been described under several names such as idiopathic bronchiolocentric interstitial pneumonia, centrilobular fibrosis, and peribronchiolar metaplasia.

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

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Etiology

The etiology and pathogenesis of ACIF remains to be determined. Some have speculated that ACIF 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 ACIF could be a burnt-out phase or an unusual form of hypersensitivity pneumonitis. [1] They described 2 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 hypersensitivity pneumonitis but with more extensive fibrosis and less inflammation without any granulomas.

Recently, a patient with clinical, radiological, and serological evidence of hypersensitivity pneumonitis with ACIF pattern on histology was reported. However, the second largest series by Churg et al failed to find any clinical, serological, or histological evidence of hypersensitivity pneumonitis in their series. [2] Instead, they documented 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, ACIF may represent a pattern of lung injury in response to environmental agents that are currently not known.

De Carvalho et al conducted a retrospective analysis of lung biopsies obtained from patients with clinical, radiological, and histopathological diagnosis of idiopathic pulmonary fibrosis and found 12 patients with a histological pattern of centrilobular fibrosis. [3] The 12 patients included equal number of men and women with a mean age of 58.4 years. An interesting finding in their study 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. The pattern described by de Carvalho et al appears to be different from ACIF in which bronchiolocentric fibrosis is the predominant feature with intact bronchiolar epithelium without any necrosis or regeneration. Moreover, the study didnot include data on prognosis for comparison with the previous studies.

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. [4] In this study, PBM seems to be similar to ACIF in demographics because both have similar age-group involvement and show female predilection. However, in contrast to ACIF 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. 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 ACIF or an incidental finding without any significance is not known.

Currently, no definite factors are known to have an established role in etiopathogenesis of ACIF. 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.

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Location

ACIF appears to start in the upper lobes and later spreads to the lower lobes.

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Clinical Features and Imaging

Most patients with ACIF 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. It can show mild increase in lymphocytes with 1-4% eosinophils.

Chest radiograph 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) demonstrates peribronchovascular interstitial thickening and traction bronchiectasis with thickened airway walls and surrounding fibrosis. Conglomerate fibrotic masses adjacent to central airways may be present. Bronchiolectasis and honeycombing are less commonly seen features. Rarely, ground glass attenuation may be seen.

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Gross Findings

Very limited data are available on gross findings. Colombat et al described gross findings in an explant lung from a patient who was diagnosed with a disorder similar to ACIF. [5] The lungs were small with smooth pleural surface and peribronchovascular and peribronchiolovascular bundle fibrous thickening that was more evident in lower lobes. The upper and middle lobes demonstrated diffuse fibrosis, but no honeycomb change was noted.

Yi et al described the cut surface of wedge biopsies as grayish-white with slight tenacious texture. [6]

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Microscopic Findings

As the name indicates, ACIF is an airway-centered disease with predominant centrilobular involvement in a secondary lobule. Lung wedge biopsy specimens show 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 lumina.

Airway-centered idiopathic fibrosis (ACIF). Low-po 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, bronchioles show peribronchiolar subepithelial or adventitial fibrosis with none-to-mild mononuclear inflammatory cell infiltrate (see the image below).

Airway-centered idiopathic fibrosis (ACIF). Bronch 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 cases series by Churg et al. [2, 1] The bronchiolocentric idiopathic interstitial pneumonia described is possibly the inflammatory phase of ACIF as described by Churg et al. [2]

The smooth muscle in the wall of bronchioles and vessels may show hyperplasia. The adjoining fibrotic alveolar walls may show bronchiolar metaplasia. The bronchiolar lumen and alveolar spaces contain 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.

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.

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Special Stains/Immunohistochemistry

Masson’s trichrome stain (see the image below) can be used to highlight the bronchiolocentric pattern of fibrosis.

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

Underlying molecular mechanisms of ACIF have not been studied.

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Prognosis and Predictive Factors

A significant proportion of patients with ACIF have relatively poor prognosis. In the study by Yousem et al, with a mean follow-up of 4 years, 33% of the patients were dead of pulmonary disease. [1] 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. [2] In a minor proportion of patients, the disease appeared stable or rarely reversible with steroid treatment. 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.

Steroids are the mainstay of the treatment. Lung transplantation is required in patients with progressive disease who do not respond to steroids.

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Differential Diagnosis

Bronchiolocentric pattern of lung injury can be seen in a wide variety of conditions such as rheumatological/connective tissue disorders, pneumoconiosis, and the chronic stage of hypersensitivity pneumonitis. Obtaining an extensive clinical history for exposure to allergens, antigens, occupational agents, and drugs and connective tissue disorders before a patient can be diagnosed with idiopathic airway-centered interstitial fibrosis is important. Laboratory testing should be done to rule out autoantibodies.

The important differential diagnoses of ACIF on histology are hypersensitivity pneumonitis, respiratory bronchiolitis-interstitial lung disease, and nonspecific interstitial pneumonia.

Hypersensitivity pneumonitis

Hypersensitivity pneumonitis (HSP) 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 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 ACIF. On histology, ACIF shows more extensive fibrosis and less inflammation as compared to HSP. Differentiating ACIF from HSP is important because the latter has a much better prognosis.

Respiratory bronchiolitis-interstitial lung disease

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

Obliterative bronchiolitis

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

In addition to the above-mentioned diseases, ACIF needs to be differentiated from nonspecific interstitial pneumonia and usual interstitial pneumonia.

Nonspecific interstitial pneumonia

ACIF may look similar to the fibrosing pattern of nonspecific interstitial pneumonia (NSIP) due to the temporally homogenous linear fibrosis. However, in NSIP, relative sparing of bronchiolocentric areas with predominant involvement of the interstitium is seen. Distinguishing this entity from ACIF is importlant, as NSIP has better prognosis.

Usual interstitial pneumonia

Usual interstitial pneumonia (UIP)pattern is characterized by 4 histological features, temporal heterogeneity, fibrogenic foci, interstitial fibrosis with honeycomb change, and subpleural location with predominant involvement of peripheral parts of the lobules. In contrast, ACIF shows predominant centrilobular involvement with absent fibrogenic foci. Temporal heterogeneity and honeycomb changes are not seen in ACIF.

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