Idiopathic airway-centered interstitial fibrosis: report of two cases

Airway-centered interstitial fibrosis（ACIF），a novel form of diffuse interstitial lung disease (ILD) of unknown cause, was recently presented.¹ There is no final conclusion on its property and denomination, and it might be a new type of idiopathic interstitial pneumonia (IIP).¹ Histopathologically, it was characterized by progressive lobular or small ACIF, and neither similar to any known category of airway disease and ILD, nor similar to known subtype of IIP. It showed a poor response to corticosteroids and poor progrnosis. It has been reported in Caucasian patients, here, we utilized the term idiopathic airway-centered interstitial fibrosis (IAIF) for the disease to report 2 Chinese patients, in order to improve understanding and diagnosis of this disease.

CASE REPORT

Case 1
A 39-year-old man was admitted to our hospital in May, 2005 for progressive polypnea for 3 years, coughing and expectoration for 1 month. The patient's health condition was good in the past. He was a heat treatment worker and smoking index was 100 cigarettes/year. His symptoms relieved after receiving antibiotic treatment in the other hospital, but pulmonary lesions failed to abate and aggravated progressively. Physical examination on admission showed no superficial lymph nodes enlargement, no clubbed-finger. Velcro rale could be heard at lower lung zones. Pulmonary function test revealed forced vital capacity (FVC), vital capacity (VC), forced expiratory volume (FEV₁) and residual volume (RV) were 68%，67%，76% and 49.9% of predicted，respectively. The ratios of FEV₁ to FVC and RV to TLC were 93% and 127.7%，respectively. The diffusing capacity of the lung for carbon monoxide (DLco) was 46.1% of predicted. Blood gas analysis demonstrated that PCO₂ was 42 mmHg, PO₂70 mmHg, andHCO₃^-25.0 mmol/L. Oxygen saturation (SO₂) by pulse oximetry was 94.0% at rest room air. The peripheral blood and heart and liver function tests were normal. Pathogens were not detected in sputum culture. Blood immunological test showed that antinuclear antibody repertoire, streptohemolysin O antibody (anti-O), rheumatoid factor, C reactive protein and blood sedimentation were all normal. Anti-HIV antibody was negative. Chest radiograph of bilateral lungs revealed small patchy streak reticular pattern. Thoracic computed tomography (CT) scan demonstrated thickening of the bilateral bronchovascular bundles, annular thickening and dilation of small airways predominantly in central hilus, and peripheral reticulonodular patterns (Figs. 1–2).

The patient underwent video-assisted thoracoscopic (surgery wedge) lung biopsy. The finding of surgical exploration showed no evidence of fluidifying and adhesion. There were extensive consolidation in middle to lower lung, grayish alternating with white. Specimen was obtained respectively from middle lobe and lower lobe of the right lung. Macroscopic observation: the size of surgery specimen was 2 cm ×1.5 cm × 1 cm (taken from middle lobe) and 2.2 cm × 2 cm × 1 cm（from lower lobe）, respectively. The cross section of the specimen was in grayish-white or grayish-yellow and the texture of which was slightly tenacious. Under light microscopy, the lesion was characterized by bronchiolar-centered patchy distribution involving subordinate pulmonary lobules, with alternating areas of normal lung or compensating emphysema. There was bronchiolar and respiratory bronchiolar epithelial proliferation in focal zone that formed into papillae protruding into the cavity. There were fibroplasias under mucous membrane and around bronchial walls, and hyperplasy of smooth muscles. The hyperplastic smooth muscles were in sarciniform surrounding bronchial walls that resulting in thickening of airway but without marked obstruction. Mucous bolts could be seen in some sections. Small amount of lymphoid and plasmacytic infiltration and anthracosis were seen in bronchial walls and interstitial tissues in the diseased regions. Hyaline degenerated small vascular hyperplasia and hyperplasia of vascular smooth muscles were apparent around airway walls with surrounding fibroplasias extending around toward lung parenchyma, and often linking proliferation of muscle fibers thus resulting in the thickening of surrounding alveolar septum, proliferation and hypertrophy of type Ⅱ alveolar epithelium in alveolar wall, architectural reconstruciton of pulmonary alveolar structure in some fields and proliferation of muscle fibers that resulting in myosclerosis. The proliferative alveolar epitheliums were seen in columnar shape (columnar epithelial metaplasia) with dilated alveolar spaces, which was called “microscopic honeycomb change”. Subpleural focal fibroplasia and muscular fibrocyte proliferation led to plaque-like fibrosis (Figs. 3–5). The case was diagnosed as having ACIF.

After final diagnosis, the patient was treated with methylprednisolone 480 mg pulse therapy and symptomatic treatment, but only a poor result was obtained. The disease aggressively progressed. After 8-month follow-up the patient died of respiratory failure.

Case 2
A 53-year-old man was admitted to our hospital in March 2004 for coughing, expectoration and progressive polypnea for 3 years. The patient's health condition was good in the past, no history of vocational contact, 400 cigarettes/year smoking index. He began to cough with small amounts of white phlegm associated with asthma after movement at the beginning of 2001 without any predisposing cause. His disease developed progressively with symptoms on and off occasionally after receiving antibiotic treatment. In February 2004, he began coughing up yellow sputum and his asthma aggravated progressively. He had been diagnosed as having “secondary tuberculosis” in the other hospital and had been treated with antituberculosis and antiinflammatory for 4 days followed by intermittent anti-inflammatory, but the symptoms remained stable without significant amellioration. Physical examination upon admission revealed no enlargement of superficial lymph nodes. Concentrated fine moist rales could be heard at lower lung zones. Pulmonary function test showed forced FVC was 59% of predicted, VC, total lung capacity (TLC), FEV₁ and RV were all 60% of predicted. The ratios of FEV₁ to FVC and RV to TLC were 107% and 103%, respectively. DLco was 51% of predicted. Blood gas analysis demonstrated that PCO₂ was 23.1 mmHg, PO₂ 89 mmHg, andHCO₃^-24.4 mmol/L. SO₂ by pulse oximetry was 97.2% at rest room air. The peripheral blood test and heart and liver function tests were all normal. Pathogens were not detected in sputum culuture. Blood immunological test showed that antinuclear antibody repertoire (ENA polypeptide repertoire, double strand DNA antibody), rheumatism series (anti-O, rheumatoid factor, C reactive protein) and blood sedimentation were all normal. Anti-HIV antibody was negative. Complement C₃was 0.86 g/L. Immunoglobulins were within normal range except a slight increase of IgE (450 IU/ml). Ultrasonograph revealed hepatic adipose, gallstone and renal stone, and marked splenomegaly. Chest radiographs revealed diffuse reticulonodular infiltrates predominantly in the central zone of bilateral lungs. Thoracic CT scan demonstrated fibrous thickening of bronchovascular bundles bilaterally, annular thickening of small airways predominantly in central hilus of lungs, peripherally with reticulonodular shadows yet without honeycomb pattern, and perimediastinum cystic shadow (Fig. 6).

The patient underwent thoracotomy on the left side assisted by thoracoscope for open lung biopsy. No evidence of fluidifying and adhesion were found during surgical exploration. CT scan confirmed that the perimediastinum cystic shadow was pericardial cyst and yellow fluid was drawn out. three pieces of lung tissues samples were taken respectively from upper lobe and lower lobe of the left lung, and the size of which was 2.2 cm ×1.4 cm ×1.4 cm (lingular segment of superior lobe), 2.1 cm ×1.5 cm ×0.6 cm (apicoposterior segment of superior lobe) and 2.4 cm ×2.0 cm×1.4 cm (posterior basal segment of lower lobe), respectively. There was pigmentation on pleura surface. No significant hyperemia and edema were found. The cross section of the specimens was grayish-white or in dust color and the texture of which was mild. Under light microscopy, the case displayed almost similar histological features like case 1 (Figs. 7-10). The lesion was characterized by bronchiolar-centered patchy distribution involving subordinate pulmonary lobules, with alternating areas of normal lung or compensating emphysema. There were fibroplasias under mucous membrane and around bronchial walls, and hyperplasy of smooth muscles that resulting in thickening of airway. The other main lesions which were shown in the former case can be seen as follows: hyperplasia of vascular smooth muscles and hyaline degeneration of small vascular, goblet cell metaplasia (microscopic honeycomb change), myosclerosis, reconstruciton of pulmonary structure and subpleural plaque-like fibrosis, and so on. The case were diagnosed as having ACIF. After final diagnosis, the patient was treated with methylprednisolone 480 mg pulse therapy and symptomatic treatment, but results were poor. He had dyspnea and his illness aggravated progressively. After 6-month follow-up the patient died of acute respiratory distress syndrome (ADRS).

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Fig. 1. Chest radiograph of case 1 revealing small patchy streak reticular pattern in both lungs.
Fig. 2. Lung HRCT scan of the same patient presenting in Fig. 1 revealed thickening of bilateral bronch ovascular bundles and small nodular patterns (A: upper field; B: middle-lower field).
Fig. 3. Low power view of case 1 showing patchy distribution and inter-focal compensating emphysema (HE, Original magnification×40).
Fig. 4. Magnifying observation of Fig.3 showing marked hyperplasy of peribronchiolar fibrous tissue and smooth muscles (arrows) and bronchilar epithelial metaplasia (★) in focal zones, with alternating areas of roughly normal lung and emphysema (HE Original magnification×100).
Fig. 5. Another field of vision of above case showed that there was subpleural focal fibrosis (★) associated with surrounding hyperplasy of peribronchial smooth muscles (black arrows) and bronchilar epithelial metaplasia (red arrow). (HE, original magnification×40).
Fig. 6. Lung CT scan of case 2 demonstrating thickening of the bilateral bronchovascular bundles and reticulonodular patterns.
Fig. 7. Low power view of case 2 showing patchy distribution and inter-focal compensating emphysema (HE Original magnification×40).
Fig. 8. Magnifying observation of Fig. 7 showing the hyperplastic muscles in the wall of the bronchiole (red arrow) and small arterial branch (★) and surrounding bronchilar epithelial metaplasia (microscopic honeycomb lung, black arrows). (HE, original magnification×100).
Fig. 9. Another field of vision of case 2 showed that there were marked hyperplasy of fibrous tissues and smooth muscles under mucous membrane and around bronchial walls, but the inflammatory cells infiltration was not significant. (HE, original magnification×100).
Fig. 10. Low-magnification angiograph of case 2 showed that there was subpleural focal fibrosis (★) associated with surrounding bronchilar epithelial metaplasia (arrows) (HE Original magnification×40).

DISCUSSION

Churg et al¹in 2004 reported 12 patients in the discussion of “ACIF”. The patients had the following characteristics: (1) the precise cause of the disease was unknown, and a small number of cases has a history of possible inhalational exposures or smoking history. (2) Clinically, the patients presented with chronic cough and progressive dyspnea. Pulmonary function tests showed restrictive ventilatory disorder pattern. (3) CT of chest revealed bronchovascular fibrosis and interstitial infiltrates predominantly in central zone of hilus pulmonis. (4) Pathologically, somewhat different from the known airway diseases or ILD, it was characterized by central-bronchiolar or centrilobular patchy distribution, peribronchiolar fibroplasia associated with smooth muscle hyperplasia and hyperplasy of smooth muscles in vessel walls and extending around toward lung parenchyma. There were pulmonary architectural reconstruction, metaplastic bronchiolar epithelium (honeycomb lung formation under microscope), and subpleural focal pulmonary fibrosis. (5) Patients were treated with corticosteroids and bronchodilators but with poor outcome. Follow-up data showed 40% died within 1 to 10 years. ACIF was recognized as a new form of IIP and an independent pathological entity.

The two cases described in this report presented with a similar radiological and pathological features to those reported by Churg et al.¹ Both patients had no history of vocational and environmental exposures, but had smoking history. The diagnoses of autoimmune disease (AID) and collagen vascular disease were ruled out based on clinical and laboratory examinations. No evidence of ILD of known cause. Chest CT revealed fibrous thickening of bronchovascular bundles, bronchiectasis, crico-thickening of small airways, diffuse reticulonodular patterns yet without honeycomb changes. Histopathologically, it is different from the known airway diseases, ILD and IIP which includes usual interstitial pneumonitis (UIP) and non-specific interstitial pneumonia (NSIP), etc. Pathologically, it was characterized by bronchiolar or lobular-centered patchy distribution, peribronchiolar fibroplasias associated with hyperplasia of smooth muscles, hyperplasia of vascular smooth muscles (VSM), with focus of lesion extending around to lung parenchyma. There were pulmonary architectural reconstruction and respiratory epithelial metaplasia, and subpleural focal fibroplasias. There was no necrosis of respiratory epithelial cells and the inflammatory cell infiltration was not obvious. Pulse corticosteroids and symptomatic treatment had been attempted with poor outcome. Patients' condition worsened progressively and died of respiratory failure at 6- and 8-month follow-up, respectively, with 44 months duration from onset to death. The above discussion supports the idea that the disease described in our report is a new form of IIP. It is recommended that for which a unified name “IAIF” should be given so as to standardize the diagnosis, treatment and study of this disease.

Yousem et al²in 2002 described 10 patients in the discussion of idiopathic bronchiolocentric interstitial pneumonia (IBIP).The clinical presentation of IBIP resembles those of patients with allergic pneumonia but without granuloma and history of exposure to anaphylactogen. The disease was characterized predominantly by peribronchial fibrosis. Eighty percent of patients were female. It has a poor prognosis with 33% died at 3–5 years follow-up. The authors of this paper assumed that the disease described by Yousem and Dacic² was a variant of allergic pneumonia or NSIP, or a new form of IIP. Pathologically, the cases reported in our study resemble the above mentioned disease, no evidences of allergic pneumonia and NSIP, but with poorer prognosis and the course of disease from onset to death was only 44 months. De Carvalho et al ³ in 2002 described 12 patients who characterized pathologically by lobule-centered fibrosis. These cases were different from the cases reported in our study in that there were marked necrosis and regeneration of bronchiolar epithelium, and basophilia substances and foreign substances in air spaces in their cases. De Carvalho et al³ assumed that this may be associated with inhalational factors. The categorization of IIP has experienced a long process of revising since there are a lot of points yet to be enriched and improved.^4,5 Therefore, to get a better understanding of ACIF, it is essential to find more cases for a further study.^1-3

In differential diagnosis, ACIF is often confused with the following diseases that characterized by small airway dysfunction.^1-3 (1) Hypersensitivity pneumonitis (HP). HP is characterized by focal extending around bronchiole, but it is different from ACIF because there are granuloma tuberoses in 60%–80% of HP cases and who had an exposure history to anaphylactogen. (2) Respiratory bronchiolitis- associated interstitial lung disease (RBILD). The latter is characterized pathologically by the accumulation of pigmented macrophages within respiratory bronchioles and neighboring air spaces. This disease responds well to corticosteroids and with favorable prognosis, which can be easily differentiated from ACIF.^4,5 (3) Obliterative bronchiolitis (OB). ACIF often is confused with OB pathologically because there are marked bronchiolar restriction and obstruction and obliteration in OB. And there are extending of peribronchiolar fibrosis to the neighbouring alveolar septum and of bronchia epithelial metaplasia, yet these features were mild and focal. Airway test revealed marked restrictive airflow, which is different from ACIF. (4) Diffuse panbronchiolitis (DPB). DPB is characterized predominantly by infiltrates of lymphocytes and plasmocytes, but without marked fibrosis of airtube walls and hyperplasy of smooth muscles. Clinically, the patients often have a history of sinusitis, and this disease responds well to antibiotics, which can be differentiated.^6,7

Acknowledgements: We are grateful to Dr. LIU Hong-rui for providing help for pathologic diagnosis，and to the IAIF patients and their family.

REFERENCES

1. Churg A，Myers J, Suarez T, Gaxiola M, Estrada A, Mejia M, et al. Airway-centered Interstitial Fibrosis：a distinct form of aggressive diffuse lung disease. AM J Surg Pathol 2004; 28: 62-68.

2. Yousem SA, Dacic S. Idiopathic bronchiolocentric interstitial pneumonia. Mod Pathol 2002; 15: 1148-1153.

3. de Carvalho ME, Kairalla RA, Capelozzi VL, Deheinzelin D, do Nascimento Saldiva PH, de Carvalho CR. Centrilobular fibrosis: a novel histological pattern of idiopathic interstitial pneumonia. Pathol Res Pract 2002; 198: 577-583.

4. American Thoracic Society. Idiopathic pulmonary fibrosis: diagnosis and treatment. International consensus statement. American Thoracic Society/ European Respiratory Society. Am J Respir Crit Care Med 2000; 161: 646-664.

5. American Thoracic Society, European Respiratory Society. American Thoracic Society/European Respiratory Society International Multidisciplinary Consensus Classification of the Idiopathic Interstitial Pneumonias. Am J Respir Crit Care Med 2002; 165: 277-304.

6. Tsang KW. Diffuse panbronchiolitis: diagnosis and treatment. Clin Pulm Med 2000; 7: 245-252.

7. Iwata M, Colby TV, Kitaichi M. Diffuse panbronchiolitis: diagnosis and distinction from various pulmonary diseases with centrilobular interstitial foam cell accumulations. Hum Pathol 1994; 25: 357-363.