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2002 Jun - What is the current classification and recommended treatment of idiopathic interstitial pneumonia?

Dr Johnny WM Chan, Department of Medicine, QEH

Under the recent classification by Katzenstein A. and Myers J., there are four histologically distinct forms of idiopathic interstitial pneumonia. These are Usual Interstitial Pneumonia (UIP), Desquamative Interstitial Pneumonia (DIP)/Respiratory Bronchiolitis Interstitial Lung Disease (RBILD), Acute Interstitial Pneumonia (AlP) and Non-specific Interstitial Pneumonia (NSIP).

It is characterized by the presence of patchy, non-uniform, and variable distribution of histological changes. In other words, the temporal appearance is variegated and heterogeneous. There is the presence of patchy collagen fibrosis and "honeycomb" changes. Presence of fibroblastic foci, which signifies active ongoing fibrosis, is also a characteristic feature of DIP. Interstitial inflammation, composed mainly of small lymphocytes, is usually scanty and there may be occasional focal intraalveolar macrophage accumulation.

UIP is the most common idiopathic interstitial pneumonias (>60% and is usually found in elderly with a mean age of 57 with an insidious onset. The prognosis is usually poor with a mortality ranging from 50% to 70%. The mean duration from diagnosis to death ranged from 2.8 years to 6 years in reported series. Response to steroids and immunosuppressives is usually poor.

Presence of numerous macrophages evenly dispersed within alveolar spaces is the characteristic feature. There is no sharp histological distinction between the two categories and they are both closely related to cigarette smoking.4 The overall histological appearance is "monotonous uniformity". Fibroblastic foci and honeycomb changes are minimal, if not at all absent, in this category.

DIP/RBILD is less common (9% in the series of Bjoraker et al)2 and the mean age of diagnosis is 42, which is much lower than UIP. There is a male preponderance. The onset is also insidious and the response to steroids is usually good. The latter might also explain the lower mortality (0-27%) and the possibility of complete recovery.

Being previously called Hammon-Rich Syndrome, it is characterized by active diffuse interstitial fibrosis, composing of proliferating fibroblasts and myofibroblasts with minimal collagen deposition. The histological pattern appears acute and temporally uniform. There are also diffuse epithelial necrosis and alveolar collapse, together with other features of acute lung injury such as remnants of hyaline membranes in alveolar spaces.

It is uncommon (2% from Bjoraker et a1)2and the mean age of diagnosis is 49. The onset is acute and the dyspnoea is rapidly followed by respiratory failure. No treatment has been shown to be usefue and the mortality rates are high (50% to 88%). Most deaths occur within one to two months.

It possesses none of the specific histological features of the aforementioned entities and was first described in 1994.6 There are varying degrees of interstitial inflammation, fibrosis, collagen deposition and intra-alveolar macrophage accumulation. The changes are generally patchy, but they are temporally uniform, which suggest that they are at the same stage of development. A chronic inflammatory infiltrate containing lymphocytes and plasma cells within alveolar septa is characteristic, which is fTequentlyaccentuated in the peribronchiolar interstitium. Foci of BOOP-like features and patchy intra-alveolar macrophage accumulation might present in a small percentage of cases..

It occurs mainly in middle-aged adults with a mean age of 49 years, but it may occur in children. A slight female preponderance of 1:1.4 was found. Cough and dyspnoea are the most common complaints and the onset is usually insidious to subacute. The mortality rates was reported to be 0-11% and the overall median survival from Bjoraker et al was 13.5 years. The response to steroids is good and complete recovery is possible.

The above classification is different fTom the earlier Liebow's classification3 with DIP, DIP, Bronchiolitis obliterans with interstitial pneumonia (BIP), Lymphoid interstitial pneumonia (LIP) and Giant cell interstitial pneumonia (GIP). LIP has been found to be associated with immunodeficiencies, while GIP is usually a manifestation of hard-metal pneumoconiosis. Hence they are not truly "idiopathic". BOOP is also not included since it is a predominantly intraluminal rather than interstitial abnormality.

1 Katzenstein AA and Myers JL. Idiopathic pulmonary fibrosis: clinical relevance of pathological classification. AJRCCM 1998; 157:1301-1315.
2 Bjoraker JA et al. Prognostic significance of histopathological subsets in idiopathic pulmonary fibrosis. AJRCCM 1998; 157:199-203.
3 Liebow AA. Definition and classification of interstitial pneumonias in human pathology. Prog Respir Res 1975; 8:1-31.
4Carrington CB et al. Natural history and treated course of usual and desquamative interstitial pneumonias. N Engl J Med 1978; 298:801-809.
5Olsen J et al. Hammon-Rich Syndrome revisited. Mayo Clin Proc 1990; 65: 1538-1548.
6 Katzenstein AA and Fiorelli RF. Non-specific interstitial pneumonia/fibrosis: histological pattern and clinical significance. Am J Surg Pathology 1994; 18: 136-147.

According to the Joint Statement of the American Thoracic Society and the European Respiratory Societyl, only usual interstitial pneumonia (DIP) is the histopathological pattern that identifies patients with IPE The other entities of idiopathic interstitial pneumonias such as DIP, AlP and NSlp1,7 are considered separate entities and to be excluded from the IPF category.

The optimal timing, choice and the duration of treatment for IPF are still contentious, mainly due to the lack of sufficient good-quality medical evidence. It is a disease of poor prognosis, with a mean survival of 2.6 to 6 years4,5and a mortality rate ranging from 59% to 70%7. However, no treatment modalities have consistently shown by randomized, double-blind placebo-controlled studies to improve the symptoms and survival, not to
mention "curing" of the disease.1-3 Partial yet mostly transcient response to treatment occurs in only 10 to 30% when assessed by objective quantitativecriteria.1 On the other hands, these treatmentagents, which includes prednisolone, azathioprine, cyclophosphamide, colchicine, D-penicillamine etc., are also associated with significant side effects.

The International Consensus Committee believes that treatment is not indicated for all patients. This is particularly so when the treatment side effects outweigh the potential benefits. The contraindications include age >70, extreme obesity, concomitant major illness such as cardiac disease, diabetes mellitus, osteoporosis, severe impairment in pulmonary function and endstage honeycomb lung on radiological evaluation.1

Although the exact time for initiating treatment is unknown, it is believed that the response might be better when treatment is started early in the course of disease, before irreversible fibrosis has developed.1,3 It is hence recommended that if therapy would be offered to a patient, it should be started at the first clinical or physiological evidence of impairment or documentation of decline of lung function.

Before the initiation of therapy, patients should be well informed about the nature of their disease and the potential risk and side effects of the treatment regimens, as well as the potential benefits that these might offer.1,3 The treatment regimens recommended by the International Consensus Committee is combined therapy with prednisolone and either azathioprine or cyclophosphamide. A discernable objective responsive to therapy may not be evident during the first three months of therapy. The Committee recommended that combined therapy should be continued for at least six months, if there no complications or adverse effects of the medications.

Clinical, radiological and physiological parameters should be used to assess the response to treatment and clinical course to treatment. From the

International Consensus statement, a fitvourable response to therapy is defined the presence of two or more of the following, documented on two consecutive visits over a 3- to 6-month period during the first 12 months: . a decrease in symptoms, specifically an increase in the level of exertion required before the patient must stop because of breathleness or a decline in the frequency of severity of cough; reduction of parenchymal abnormalities on chest X-rays or HRCT scan; Physiological improvement defined by two or more of the following:
. 10% increase in TLC or VC (or at least 200 ml change),
. 15% increase in sighle-breath DLco (or at least 3mllminlmmHg change),
. an improvement or normalization of O2saturation (4% increase) or Pa02 (4mmHg increase from the previous measurement) achieved during a formal cardiopulmonary exercise test.

Similar criteria were also laid down by the Committee to define a "stable' (and presumed favourable) response and a "fllliure' to respond to therapy. After more than 18 months of therapy, therapy should be individualized on the basis of response and the tolerance of the patient to the therapy. The therapy should only be continued indefinitely in individuals with objective evidence of continued improvement or stabilization. On the other hand, . some literature argues that indiscriminate prolonged treatment with high dose corticosteroids of more than 10mg per day for more than 3 months should not be encouraged, unless other more corticosteroid-responsive lesions (such as DIP or NSIP) are identified histologically.3 For those patients without open lung biopsies, HRCT thorax appearance with a quantitative calculation of the degree of fibrosis may also predict the response to corticosteroid therapy and long-term surviva1.6

In conclusion, treatment of IPF has been controversial and the decision to treat should be carefully considered. The patient should be kept well-informed of the risk-benefit profile. Once started, the response and
the possible side effects of the treatment should be carefully monitored to decide on the optimal duration of treatment.

1King TE et al. Idiopathic pulmonary fibrosis: diagnosis and treatment. International consensus statement.AJRCCM 2000; 161:646-664.
2 Michaelson JE et al. Idiopathic pulmonary fibrosis: a practical approach to diagnosis and management. Chest 2000; 118:788-794.
3 Taylor DA and du Bois RM. Idiopathic interstitial pneumonias: are-appraisal of idiopathic pulmonary fibrosis. Int J Tuberc Lung Dis 2001; 5(12): 1086-1098.
4 Carrington CB et al. Natural history and treated course of usual and desquamative interstitial pneumonia. N Engl J Med 1978; 298:801-809.
5 Bjoraker JA et al. Prognostic significance of histophathological subsets in idiopathic pulmonary fibrosis.AJRCCM 1998; 157:199-203.
6 Gay SE et al. Idiopathic pulmonary fibrosis: predicting response to therapy and survival. AJRCCM 1998; 157:1063-1072.
7 Katzenstein AA and Myers JL. Idiopathic pulmonary fibrosis: clinical relevance of pathological classification. AJRCCM 2000; 157:1301-1315.