Interstitial lung diseases (ILD) are uncommon disorders involving interstitium of the lung. The term “interstitium of the lung” refers to a potential space interposed between the basement membranes of the alveolar lining epithelium and the capillary endothelium¹⁾. This space contains connective tissue elements and the matrix components, and consists of several macromolecules including collagen, proteoglycans and glycoproteins, as well as the noncollagenous proteins, including fibronectin and laminin²⁾. Also present are small numbers of interstitial macrophages, fibroblasts and myofibroblasts. Additionally, the alveolar wall becomes anatomically altered by a variety of inflammatory cells, hyperplastic alveolar epithelial lining cells, proliferating fibroblasts, disordered collagen deposition and smooth muscle proliferation. These changes in interstitium lead to derangements of the alveolar walls and loss of functional alveolar capillary units.

Although ILDs are composed of many diverse disorders, ILDs have common features, including similarity of clinical symptoms, comparable appearance of chest readiographs, consistent alterations in pulmonary physiology and typical histology and typical histologic features³⁾. In recent years, there has been heightened interest in this area of pulmonary disease with an increasing number of cases reported⁴⁾.

Gaensler and colleaques, from Boston University, USA, reported the clinical review of 502 cases who had open lung biopsy (OLB) due to chronic diffuse infiltrative lung diseases during 30 years⁵⁾. In Korea, clinical data of 982 patients who were diagnosed as ILD from 1980 to 1990 at nine university hospitals and one general hospital in the Seoul area were analysed. Among the 982 patients, only 275 cases (28%) performed TBLB (207 cases, 21%) or OLB (68 cases, 7%), and the others were diagnosed by clinical findings and/or roentgenographic findings⁶⁾. The scientific committee of the Korean Academy of Tuberculosis and Respiratory Diseases undertook a national survey to estimate the incidence of sarcoidosis in Korea. That was limited to sarcoidosis⁷⁾, not extended to other ILD.

Overall incidence of ILD is uncertain in Korea so far; moreover, analysis of patients with ILD, proven by pathologic findings, was rare in Korea in terms of etiologic and pathologic classifications. Thus, to evaluate the incidence of disease entities and histopathology in ILDs, we analysed 100 patients with ILD who had TBLB or OLB in a tertiary referal university hospital.

The epidemiology of ILD is not carefully defined, but it is estimated that their prevalence is approximately 20 to 40 per 100,000 of the population in the United States¹⁴⁾. Winterbauer and colleagues reported male predominance in patients with diffuse interstitial pneumonitis¹⁵⁾.

Gaensler and colleagues reviewed clinical, physiological and histological data concerning 502 patients who had open lung biopsy for chronic interstitial lung disease⁵⁾. The numbers of patients with interstitial pneumonia were 130 (25.9%), granulomatous group 63 (12.5%) and pneumoconioses 74 (14.7%). In Korea, multi-center study revealed the frequency of the underlying disease for the diffuse pulmonary infiltrates. The most common etiology was miliary tuberculosis (38%), which was followed by idiopathic pulmonary fibrosis (27%), CVD-PF (15%) and diffuse pulmonary infiltrates by malignancy (10%)⁶⁾. If malignancy and infectious cause are removed from the multi-center study, the frequency of underlying diseases are similar to our study.

Our study showed that IPF was the most common disease entity (52.6%), followed by CVD (14.4%) and HP (8.5%). The proportion of IPF in ILD is higher than other studies. The incidence of noncaseating granulomatous diseases, including sarcoidosis, is relatively lower in Korea than the USA, which may be the reason why our study had more IPF and less sarcoidosis than those of Gaensler’s study (Table 8).

We included virus-induced ILD, though considered as an infectious process, because patterns of their diseases showed the typical view of ILD. Causative agents were two cases of influenza a virus and one case of adenovirus. Pathologic features were two cases of DAD and one case of BOOP pattern. BOOP pattern was induced by adenovirus.

In patients with IPF in our study, the most common type of pathology is UIP, followed by NIP (8 cases, 15%) and AIP. NIP is relatively more frequent in our study than the report of Kyoto University. They reported 5% incidence of NIP among 87 patients with ILD. DIP, which is not a rare type of IPF in the USA, was not found in our study. Multicenter study in Korea reported only 2 cases of DIP among 261 patients with IPF⁶⁾. In data of Kyoto University from 1966 to 1991, they reported 1% incidence of DIP¹⁶⁾. The reason why incidence of DIP is lower in Korea and Japan than that of the USA is unclear (Table 9).

The inidence of HP in our study is much higher than those in other studies. Especially, the incidence of HP in multi-center study in Korea was 0.7% and 1.8% in Gaensler’s study. There is no good explanation for this difference in the incidence of ILD.

The incidence of BOOP was much higher than that of multi-center study⁶⁾.

Only 3 cases of 99 cases in our study were diagnosed as DPB.

In the remaining patients (31.4%) who had TBLB, biopsy specimens were too small to be clarified pathologically.

Our study showed that male to female ratio was equal in IPF. This difference originated from female predominance in NIP of our study. Age of patients with IPF was higher than that of other disease groups. In CVD-PF, male to female ratio was nearly equal. Interestingly, the age of onset in most patients with DPB is over 40 years old in Japan but, in our study, the mean age was 23 years, which is younger than that in Japanese cases.

Regarding the usefulness of PFT in assessing patients with ILD, lung volumes, DLco and arterial oxygen pressure with exercise were considered to be the best index of the overall disease process¹⁷⁾. IPF, CVD-PF and HP showed restrictive pattern of PFT in more than half of the patients, but sarcoidosis and pneumoconiosis had mainly normal PFT findings. In sarcoidosis, we had 3 patients with Stage 1 and one patient with Stage 3. The patients with Stage 1 had normal ventilatory function and the patients with Stage 3 had restrictive pattern. Because there were no complicated cases of pneumoconiosis in our study, PFT seemed to be the normal pattern. Combined obstructive and restrictive pattern was predominant in DPB. In BOOP, it did not show a specific pattern due to the small number of cases.

In CVD-PF, the most common underlying disease was RA. Lower incidence of SLE may be due to avoidance of OLB in cases of lupus pneumonitis because obvious serologic and other non-invasive diagnostic approaches are possible. The most common type of pathology in CVD-PF was UIP and DAD. Kazenstein reported the association of CVD with NIP, but we did not find any NIP in CVD-PF.

Treatment is usually offered to patients with ILD, including advanced fibrotic disease. A trial of steroids is the first line of medication. Should the disease not respond or be progressive, the dosage of prednisone can be increased, or immunosuppression with cyclophosphamide should be considered¹⁸⁾.

In our study, the most common cause of death was infection and the most common type of pathology in dead patients was UIP. The focus of infection was the lung. Therefore, pneumonia was the major cause. Panos and co-workers reported studies of the clinical course of IPF. In their study, mortality was most frequently due to respiratory failure; other causes of death included heart failure, bronchogenic carcinoma, ischemic heart disease, infection and pulmonary embolism¹⁹⁾. Epler et al. analysed 48 patients with BOOP. Among them, 37 cases were treated by steroid and 4 cases of treated patients expired due to progressive disease (2 cases) or other cause (2 cases)²⁰⁾. Guerry-Force and associates described that patients with UIP died of respiratory illness (10 of 17 cases) more than patients with BOOP (4 of 15 cases)²¹⁾. Carrington performed a 24-year period of observation of patients with UIP and patients with DIP. The result was that only one fourth of the patients with DIP died, and nearly one third had fully recovered 11 to 22 years later, but nearly all patients with UIP progressed, and two thirds died. So, they suggested that DIP should have a better prognosis because the criteria of DIP include the absence of marked fibrosis²²⁾. In the USA, CVD-PF accounts for 1600 deaths per year. This number represents 25 percent of all ILD mortality and 2 percent of all respiratory deaths. In our study, patients with CVD-PF composed 14.4% of the entire number of ILD, AND the death rate was 26.7% of patients with CVD-PF. Among 12 dead patients of ILD, the dead patients with CVD-PF were 4 cases (33.3%). This incidence is comparative to that in the USA.

In general, patients with ILD who received immunosuppressants, including steroids and cyclophosphamide, had been faced with difficult problems of infection with bacteria, virus or protozoa. To these patients, infection was fatal. In our study, the group treated with steroids had a higher mortality rate than the group treated with no steroids. This finding must be interpreted in consideration that patients receiving steroids were more severe than patients without steroid treatment.

Another problems in patients with ILD is pulmonary hypertension. In our study, one case died of corpulmonale. Kennedy and et al. researched the prevalence of pulmonary hypertension in patients with ILD. 70% had ausculatory findings consistent with pulmonary hypertension²³⁾. Current data suggest that the etiology of pulmonary hypertension in the interstitial disease is multifactorial and involves the following: 1) primary lesions of the pulmonary vessels (e.q., vasculitis in sarcoidosis)²⁴⁾, 2) compression and/or destruction of pulmonary vessels by the interstitial process²⁵⁾ and 3) vasoconstriction of vessels mediated by hypoxia or acidosis²⁶⁾.

Also, during follow-up, squamous cell lung ca developed in one case with UIP. Patients with IPF have an increased risk of developing bronchogenic carcinoma. In a retrospective review of 205 patients with pulmonary fibrosis, Turner-Warwick and co-workers found the 20 (9.8%) had developed bronchogenic carcinoma. The excess relative risk of lung cancer in patients with fibrosis compared with the general population was 14.1, controlling for age, sex and smoking history²⁷⁾.

Further evaluation about ILD and long-term follow-up must be done.