Steroid treatment based on the findings of transbronchial biopsy in idiopathic interstitial pneumonia

Idiopathic interstitial pneumonias (IIPs) are interstitial pneumonias of unknown aetiology including several different pathological entities. These are usual interstitial pneumonia (UIP), desquamative interstitial pneumonia (DIP), respiratory bronchiolitis interstitial lung disease, cryptogenic organising pneumonia or bronchiolitis obliterans organising pneumonia (BOOP), acute interstitial pneumonia, nonspecific interstitial pneumonia (NSIP), and lymphoid interstitial pneumonia (LIP) 1.

Idiopathic pulmonary fibrosis (IPF) is defined as a specific form of chronic fibrosing interstitial pneumonia limited to the lung and associated with the histological appearance of UIP on surgical biopsy 2, 3. Improvements of pulmonary function and chest radiographic and computed tomography (CT) findings in IPF by steroid treatment are minimal and the prognosis is poor. However, patients with a more cellular histology can expect longer survival 4. In addition, less parenchymal abnormality on chest radiography, presence of ground-glass and reticular opacities on CT, younger age, female sex, shorter symptomatic period (≤1 yr) with less dyspnoea, relatively preserved lung function, increased proportion of lymphocytes in bronchoalveolar lavage fluid, and a good response to corticosteroids have also been considered favourable to prognosis 3, 5–8. However, these findings described above are partly in common with those of NSIP.

In the present study, the authors examined the rationale of steroid therapy for patients with IIP, which was unlikely to be UIP but not surgically biopsied. Respiratory functions were retrospectively examined, including the change of vital capacity (VC) after the start of steroid treatment in patients whose transbronchial lung biopsy (TBLB) showed cellular interstitial pneumonia, and whose chest radiograph and CT showed irregular linear, reticular or ground-glass opacities with alveolar consolidation without honeycombing in the bilateral lung base. Respiratory function data of these patients before and after steroid therapy were compared with those of pathologically confirmed NSIP.

Materials and methods

Results

Discussion

Since Epler et al. 14 proposed the entity of BOOP and Katzenstein et al. 10 proposed NSIP, pathological differentiation between non-UIP and UIP among IIPs has become more important than ever before, because it is now well known that many non-UIP patients are steroid-responsive and more favourable in prognosis. Surgical biopsies such as VATS and OLB are considered, therefore, necessary for confirming pathological diagnosis, although BOOP may be diagnosed by TBLB in addition to clinical features of patients 15.

However, many clinicians in general would like to have less invasive approaches for the diagnosis of IIP, hesitating to persuade patients to undergo surgical biopsy under general anaesthesia, although recently there have been increasing numbers of patients who have undergone VATS. Therefore, in many instances, indication of steroids for patients with IIP, who are unlikely to have UIP, has been decided practically by clinical information, such as chest radiographs, CT and TBLB, less invasive approaches to obtain histological specimens.

Pulmonary function testing enables noninvasive quantitative measurement of the severity of IPF, and repeated testing to monitor the course of IPF appears useful for evaluation of disease progression 16. Although clinical criteria such as physical examination and chest radiography can be useful for following patients with IPF, these criteria are difficult to quantitate 17. For these reasons, many researchers have attempted to determine the parameters in pulmonary function testing most reliable for predicting the prognosis of IPF.

In order to give the scientific rationale for using TBLB findings in the decision of steroid indication for patients with IIP, unlikely to be UIP, the extent of the improvement of pulmonary function after steroid therapy between those patients and patients with pathologically confirmed NSIP was compared. NSIP is steroid responsive and more favourable in prognosis than UIP 9, 10. In the present study, “non-UIP” patients were defined as patients having dense mononuclear cell infiltrates in thickened alveolar septa in TBLB and irregular linear, reticular or ground-glass opacities with alveolar consolidation, but without honeycombing in bilateral lung base in chest CT and radiographs. It was demonstrated that steroid responsiveness in “non-UIP” patients was not different from that in NSIP patients and appeared better than that in fibrosing NSIP patients when the effect of steroid was estimated by the improvement of VC. van Oortegem et al. 18 demonstrated that improvement in forced vital capacity (FVC) of >10% from baseline after 3 months of treatment by steroids with or without immunosuppressive agents was predictive of subsequent improvement in IPF. Hanson et al. 19 also reported that IPF patients with ≥10% reduction in FVC with 1 yr of treatment had a lower survival rate than those with <10% reduction or with improvement in FVC. These reports suggesting that the increase in VC is associated with the prognosis of IPF may justify administering steroids to “non-UIP” patients.

In the present study, a close relationship was shown between radiographic appearance not typical for UIP and dense mononuclear cell infiltrates in thickened alveolar septa. However, there were three patients who met radiographic criteria but did not meet the histological criteria for “non-UIP” patients. One of these patients died 2.5 yrs after steroid therapy, and the response to steroids in one patient was minimal. As the third patient could not be followed-up after TBLB, evaluation by spirometry was impossible. Radiographic examination is an initial and important step in identifying steroid-responsive IIP patients. However, IIP patients showing nontypical radiographic appearance for UIP (irregular linear, reticular or ground-glass opacities with alveolar consolidation without honeycombing) could expect a further beneficial effect of steroids without undergoing surgical biopsy if cellular interstitial pneumonia is obtained in TBLB.

Several differential diagnoses could be considered for TBLB specimens of “non-UIP” patients. Clinical findings supported the diagnosis of interstitial pneumonia of unknown aetiology in all patients in the present study. In addition to CT findings and short periods from initial symptoms to first visit to hospital, dense mononuclear cell infiltration in alveolar septa in TBLB specimens of “non-UIP” patients could raise the possibility that NSIP, including cellular NSIP, appears most probable in diagnosis among several differential diagnoses. Recently, high-resolution CT findings in NSIP have been extensively examined. Major CT findings in NSIP are bilateral patchy areas of ground-glass opacity with or without areas of consolidation in the lung base. Irregular linear opacities, thickening of bronchovascular bundles and bronchial dilatation are also frequently seen 20, 21. CT findings in these cases are compatible with those in NSIP.

LIP is another differential diagnosis. However, many cases of LIP are associated with underlying systemic diseases such as collagen vascular diseases and autoimmune disorders, and idiopathic cases are few. In addition, LIP is more cellular than any other IIPs, such as NSIP. DIP can be denied because of lack of densely packed macrophages in the alveoli. Patient 7 is the only patient who had alveolar macrophages in the alveoli, but the infiltration of macrophages is slight, and this patient was a nonsmoker.

Hypersensitivity pneumonitis should also be considered as another differential diagnosis. However, distribution of hypersensitivity pneumonitis is usually dominant in the upper lobe, and irregular linear and air space opacities are inconsistent with hypersensitivity pneumonitis. Hospitalisation of these patients did not result in recovery from their diseases. In addition, no granulomatous lesions were found in any of the TBLB specimens of patients in the “non-UIP” group.

Mononulear cell infiltration in the thickened alveolar septa is also found in BOOP. However, alveolitis in BOOP is usually limited in areas of organising pneumonia 22, and there were no intraluminal organised polyps in any of the specimens in the present study. Moreover, the dominant CT pattern in BOOP is circumscribed areas of air space consolidation in a multifocal distribution 23. Such a pattern was not found in “non-UIP” patients in this study.

Infectious diseases such as Mycoplasma pneumoniae pneumonia were denied by the favourable response to steroids without use of antimicrobial drugs such as macrolides and fluoroquinolones.

Typical idiopathic pulmonary fibrosis (histologically usual interstitial pneumonia) could be diagnosed by clinical criteria 3, 24 without surgical biopsy. Transbronchial lung biopsy is considered to be necessary to rule out other diffuse lung diseases such as granulomatous diseases. However, in some instances, transbronchial lung biopsy could be a diagnostic tool in combination with clinical data including chest radiographs and computed tomography. More importantly, clinicians could administer steroids to such patients without surgical biopsy under the prediction of favourable response to steroid therapy.