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Binnen dit project over niet classificeerbare vormen van longfibrose onderzoeken wij de effecten van immunosuppressieve behandeling. We kijken hierbij naar ziekteprogressie en overleving. Middels een retrospectieve en prospectieve studie van deze patiënten onderzoeken wij onder andere de effecten van behandelingen als prednison en cyclofosfamide.

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In een retrospectieve onderzoek (opgestuurd naar tijdschrift) toonde een negatief resultaat van prednison in “possible Idiopathische Pulmonale Fibrose (IPF)” patiënten. Tot op heden is het niet duidelijk hoe we deze “possible IPF” patiënten zouden moeten behandelen; met anti-fibrotische middelen of juist met prednison. Onze resultaten suggereren om voorzichtig te zijn met prednison behandeling bij deze patiënten. Binnen het St. Antonius Ziekenhuis worden deze patiënten inmiddels behandeld met anti-fibrotisch middelen.

Twee andere lopende studies focussen zich op andere niet classificeerbare vormen van longfibrose en patiënten met een extrinsieke allergische alveolitis (EAA). De verzameling van zogeheten biomarkers (onder andere telomeer lengte) binnen bovenstaande groepen patiënten loopt op dit moment.

De prospectieve studie loopt en heeft tot op heden 318 patiënten met niet classificeerbare vormen van longfibrose, IPF en EAA geïncludeerd.


Samenvatting van de aanvraag

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The development of pulmonary fibrosis in Interstitial Lung Disease (ILD) is one of the most severe complications of disease. Pulmonary fibrosis develops due to ongoing inflammatory process in the lungs, as is found in hypersensitivity pneumonitis (HP), but can also develop after repeated lung injury of unknown cause, as in idiopathic pulmonary fibrosis (IPF). After removal of potential triggers, HP is commonly treated with immunosuppressive agents which can results in disease remission or stabilization, making immunosuppressive therapy a possible life-saving strategy. IPF patients, however, have a medium life expectancy of just 3 years and do not respond to immunosuppression.

IPF is the most severe subclass within the group of idiopathic interstitial pneumonias (IIP). Diagnosis of IPF and the other fibrotic ILD is based on a combination of clinical characteristics, exclusion of underlying causes or associations, radiological HRCT pattern, and when necessary histology. A significant part of fibrotic ILD patients can be diagnosed with either HP or a chronic form of IIP, such as IPF. However, in many cases, distinction remains challenging. In such cases, often co-existing patterns or a differential diagnosis including HP, non-IPF IIP, and/or IPF are found, which is commonly referred to as non-classifiable ILD and are often treated with a trial of immunosuppressive agents. In 2012 however, it was shown that a combination of immunosuppressive treatment in IPF lead to increased mortality and hospitalization, and nowadays physicians are hesitant to try immunosuppression in this group of patients (1), especially since new anti-fibrotic agents became available for patients with a diagnosis of IPF. In 2014 it was shown that IPF patients treated with new anti-fibrotic therapies pirfenidone or nintedanib have a lower lung function decline compared to placebo (2,3). In non-IPF IIP and in HP immunosuppression remains the cornerstones of therapy. In non-classifiable ILD, management is based on multidisciplinary evaluation, integrating all available information. Immunosuppression is the first choice of treatment, however, therapeutic response has never been evaluated in non-classifiable fibrotic ILD. Furthermore, markers that might help predict response to therapy have never been studied.

The cause of IPF is currently unknown, but mutations in telomere maintenance genes and telomeric attrition is found in up to 40% of IPF patients and these patients are therefore postulated to suffer from telomeropathy (4). In patients with telomeropathy without lung involvement it was shown that immunosuppressive agents were harmful although results are preliminary and contradicting (5). In HP on the other, cellular characterisitics of bronchoalveolar lavage fluid are used for disease diagnostic purposes and point towards an altered immune status of the patient that can benefit from immunosuppression. Furthermore, determination of serum levels of markers that predict disease progression in IPF, might be predictive on therapeutic response.

In this study we will retrospectively and prospectively analyze the effect of therapy in patients with non-classifiable ILD in comparison to patients with HP and to patients with IPF. Furthermore, we will investigate if clinical characteristics or biomarkers predict chance in lung function under therapy. In the prospective part of the study immunosuppressive dosing will be standardized and scheduled clinical follow-up for 1 year will take place. The results of this study will aid therapeutic decision making, especially in the difficult and under-investigated area of life-threatening fibrosing non-classifiable ILD.



OBJECTIVE: Evaluate response to immunosuppressive therapy in non-classifiable ILD and find biomarkers that predict disease outcome.


HYPOTHESIS: Immunosuppressive therapy can be successful in patients with non-classifiable ILD and clinical and laboratory markers can predict outcome.


STUDY DESIGN: Observational study of a retrospective cohort and a prospective cohort.


STUDY POPULATION/DATASET: Patients with non-classifiable ILD (excluding sarcoidosis and systemic disease) compared to patients with HP and IPF. Clinical and biomarker data.


INTERVENTION: No intervention.


OUTCOME MEASURES: Mortality and disease progression.


SAMPLE SIZE: Retrospective: estimation 1000 patients with the investigated diagnoses, among which 350 with non-classifiable disease. Prospective: it is estimated that a total of 256 patients will be included in two years time, among which 89 patients with non-classifiable disease.


DATA ANALYSIS: multivariate Cox and logistic regression to identify independent clinical and biomarker predictors of mortality and disease progression in non-classifiable ILD patients. Linear mixed model to calculate treatment effects on pulmonary functions over time for non-classifiable ILD patients.


COLLABORATION/CONNECTION: Prof Wuyts, ILD unit Leuven Universtity Hospital



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