Serum biomarkers in idiopathic pulmonary fibrosis

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Abstract

Within the group of Idiopathic Interstitial Pneumonias (IIPs), above all Idiopathic Pulmonary Fibrosis (IPF) poses a considerable diagnostic and therapeutic problem. Although genetic profiling indicates that IPF, Non Specific Interstitial Pneumonia (NSIP), and chronic hypersensitivity pneumonitis (HP) are distinctly different diseases, in every day practice these diseases can be difficult to tell apart. Furthermore, treatment of these diseases is notoriously difficult. Serum biomarkers reflect our understanding of the underlying pathogenesis and potentially fulfill a role in establishing a diagnosis, prognosis and therapy. While no single biomarker is currently able to accurately predict the presence or absence of an IIP, a composite of several markers holds promise for the future. Several biomarkers, such as KL-6, surfactant proteins and circulating fibrocytes, appear to contribute to our insight into disease progression and prognosis. It is however uncertain whether these markers give us additional information to common diagnostic tests and their value has as yet to be validated for every day practice. Fortunately, the potential of biomarkers is increasingly recognized and biomarker data are prospectively gathered in current placebo-controlled therapeutic trials.

Introduction

Diffuse parenchymal lung disease, synonymous with the more current name interstitial lung disease (ILD) comprises a heterogeneous group of lung diseases affecting the interstitium, the space between epithelial and endothelial basement membrane, but often also the alveolar epithelium, small airways and vessels. The cause of ILDs varies widely, including medication effects, toxic inhalation, in association with connective tissue disease (CTD), or may be idiopathic.

With the advent of the ATS/ERS classification of ILDs, a powerful tool was generated for distinguishing more precisely defined patient groups, facilitating international discussions and collaborations on ILD research, resulting in an unprecedented number of clinical trials [1]. Despite these efforts current therapy is often ineffective. Among the Idiopathic Interstitial Pneumonias (IIPs), especially idiopathic pulmonary fibrosis (IPF) and non specific interstitial pneumonia (NSIP) often pose considerable diagnostic and therapeutic dilemmas.

IPF, the most common IIP, is a devastating fibrosing lung disease of unknown cause. The majority of IPF patients are older than 60 years at the time of diagnosis, often current or former smokers, with gradual onset of dyspnea with a non-productive cough. On physical examination, bibasilar fine inspiratory crackles are typically heard and digital clubbing is seen in 25–50% of patients. There are usually no signs of auto-immune disease. Pulmonary function tests reveal a restricted lung-volume with impaired gas exchange. High-resolution computed tomography (HRCT) may show bilateral subpleural reticular changes with a basal predominance with traction bronchiectasis and honeycombing. A typical clinical presentation combined with characteristic HRCT abnormalities can lead to a confident clinical diagnosis of IPF in a multidisciplinary setting, obviating the need for surgical lung biopsy. When clinical and/or HRCT features are not considered typical of IPF, a surgical lung biopsy is often obtained. On surgical lung biopsy, IPF is associated with a histopathologic pattern of a Usual Interstitial Pneumonia (UIP). The disease’s natural course invariably leads to a fatal outcome and with a mean prognosis of approximately 3 years it is not only the most common, but also by far the most deadly of all IIPs [1], [2]. Evidence-based therapy for IPF is lacking. For example, the 2008 BTS statement on ILDs only weakly recommends one therapy for IPF [3].

Distinguishing IPF from idiopathic NSIP, using the 2002 ATS/ERS classification of ILDs, can be difficult and there has been an ongoing debate whether idiopathic NSIP is a separate entity. Currently, idiopathic NSIP is thought to form a distinct IIP [4]. Idiopathic NSIP occurs mostly in middle-aged women who never smoked, presenting with dyspnea and cough. There is usually no clubbing, auto-immune serology for antinuclear antibodies or rheumatoid factor may be positive and pulmonary function tests often reveal a restricted lung-volume. Typically, on HRCT a reticular pattern with traction bronchiectasis is observed in the lower lung zones in a peripheral or diffuse distribution. Ground-glass attenuation is a common feature, in contrast to IPF. On surgical lung biopsy, histopathologic features range from a cellular pattern with mild interstitial chronic inflammation to a fibrotic pattern with interstitial fibrosis with a uniform appearance. In order to confidently diagnose an idiopathic NSIP, a multidisciplinary setting is advised to reach a consensus, clinical-radiologic-pathologic diagnosis. In contrast to IPF, the majority of patients with idiopathic NSIP have a good prognosis [4]. A histopathologic NSIP pattern is also associated with a variety of conditions such as drug reactions, organic dust exposure and CTD. Indeed, an NSIP pattern is the most common histopathologic pattern in CTD-associated interstitial pneumonias and may even precede an overt clinical CTD. Interestingly, a large proportion of patients with idiopathic NSIP were reported to exhibit signs of undifferentiated connective tissue disease [5].

Section snippets

Diagnostic and therapeutic dilemma’s in IPF

Several problems face the clinician in diagnosing and treating patients with IPF: establishing the proper diagnosis, estimating a prognosis and deciding on and evaluating of a therapy. There is no ‘gold standard’ for the diagnosis of IPF. A fairly confident diagnosis can be made in a large proportion of patients based on clinical and radiographic data, according to the ATS/ERS statement criteria [1]. In some instances a clear diagnosis is not easily made. A typical radiographic or clinical

Candidate biomarkers

Biomarkers investigated in idiopathic fibrosing lung diseases reflect and perhaps broaden our current understanding of the events underlying the scarring of the lung. Research into the pathogenesis of IPF has advanced considerably in recent years and has shifted its focus from processes governing chronic inflammation with fibrosis as end result, to alveolar epithelial dysfunction and injury with aberrant wound repair and disordered fibroproliferation [14], [15]. A range of molecules involved in

Discussion

Biomarkers are a potentially valuable tool in diagnosing and treating patients with an IIP. However, in general the biomarkers described have several drawbacks. (1) Their specificity for a single interstitial lung disease is poor, in most cases several other diseases can cause an increase in any of these markers. (2) The biomarkers investigated have usually been tested in limited numbers of patients in a retrospective fashion and have not been validated prospectively. Validation of new

Future perspective

It is unlikely that a single biomarker will become a valuable diagnostic tool. A composite of several biomarkers holds promise. Combining measurement of five serum proteins, including three MMPs, could correctly differentiate between IPF patients and controls, with a sensitivity of 98.6% and specificity of 98.1% [63]. Simultaneous analysis of 17 serum proteins, using Luminex bead technology, correctly differentiated between healthy controls, patients with sarcoidosis and systemic sclerosis

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