Idiopathic pulmonary fibrosis acute exacerbations: where are we now?

Abstract

Considerable controversy is haunting the treatment of IPF ‘acute exacerbation’, its most devastating complication. The consensus coined term ‘acute exacerbation’ implies that on an unknown etiology disease such as IPF, an unknown etiology superimposed acute lung injury/acute respiratory distress syndrome (ALI/ARDS) represents the end-life event in a consistent proportion of patients and are treated by high dose steroids despite unproven benefit. Inversely, ALI/ARDS treatment recommendations are based on the provision of excellent supportive care plus an extensive search and appropriate treatment of the etiologic precipitant and all intensive care clinicians in the absence of an obvious etiology, considering that occult infection is the most probable and also the most treatable underlying condition, universally administer extensive spectrum antimicrobials. Viewing the persistent high mortality in IPF ‘acute exacerbations’ treated with steroids we strongly believe that a study comparing the two arms of the steroid and non-steroid approach is greatly awaited by scientists and owed to the patients.

Keywords::

• acute exacerbation idiopathic pulmonary fibrosis
• ARDS
• diffuse alveolar damage
• idiopathic pulmonary fibrosis
• steroids

Idiopathic pulmonary fibrosis (IPF) is a chronic and irreversibly progressive diffuse parenchymal disease associated with usual interstitial pneumonia (UIP) histology [1]. IPF is the most commonly occurring of the idiopathic interstitial lung diseases (ILDs), but the one that carries the most ominous prognosis [2]. In IPF, the coexistence of inflammatory and over expanding fibrotic lung damage leads to defects in mechanics and gas exchange and manifests clinically with worsening exertional dyspnea leading to disability, ultimately ending to death due to respiratory insufficiency [3,4]. The median survival in IPF patients is estimated from 2 to 3 years from the acquisition of diagnosis although the above data appertain to the corticosteroids and immunosuppressors era of disease ‘treatment’, which may have negatively influenced prognosis [1]. In spite of these narrow survival limits, the natural history in IPF appears somewhat variable and unpredictable, since some patients experience a ‘slow’ and others a more or less ‘rapid progression’ [5]. ‘Stabilization’ of its clinical course is occasionally observed and represents mainly an ephemeral phenomenon followed by unrelenting progression [4].

In 1993, the unexpected appearance of episodes of acute respiratory failure upon the chronic course of IPF (defined as ‘exacerbations of respiratory failure’) was described and identified as the development of acute lung injury/acute respiratory distress syndrome (ALI/ARDS) of unknown etiology on IPF. Histology performed in all patients disclosed organized diffuse alveolar damage (DAD) upon UIP [6]. Similar cases were illustrated previously on an atlas of pulmonary surgical pathology [7]. Soon raised the question whether ‘their genesis was related to any superimposed cause or whether the disease itself rapidly deteriorated’ [6]. The above described variance in the natural history of the disease, that is, the development of DAD upon UIP, was more recently defined by consensus as IPF ‘acute exacerbations’, and a set of diagnostic criteria were designated including: a subacute/acute deterioration of dyspnea over 4 weeks or less; the appearance of new infiltrates on chest imaging (mainly ground-glass upon honeycomb) and the exclusion of identifiable factors of deterioration such as infection, pulmonary edema, pulmonary embolism or other [8]. The consensus-coined term of IPF ‘acute exacerbations’ presumes an ‘intrinsic’ undefined factor of disease deterioration. This implies the intriguing notion that on an unknown etiology disease, such as IPF, an unknown etiology superimposed ALI/ARDS represents the end-life event in a consistent proportion of patients [5,9]. In effect, IPF ‘acute exacerbations’ appear more frequently than previously thought and represent the most devastating complication during its clinical course because of their high, anticipated mortality [8,10].

The development of DAD of unknown etiology upon normal lungs clinically expressing ALI/ARDS also constitutes the major diagnostic criterion in another idiopathic ILD, the so called ‘acute interstitial pneumonia’ (AIP) also included in the most recent classification of idiopathic ILDs as a distinct clinical entity [2]. AIP lacks proven treatment, and its prognosis is comparable to that of known etiology ARDS and to IPF ‘acute exacerbations’. Survivors may develop fibrosing nonspecific interstitial pneumonia or UIP-type pulmonary fibrosis. In addition, at least some of older cases probably represented the development of ‘acute exacerbations’ in early unsuspected and undiagnosed IPF [11,12]. Whatever the relationship between AIP, IPF and IPF ‘acute exacerbations’, AIP is considered as the fulminant course of a de novo developing ‘idiopathic’ ILD, and according to recent guidelines, it should be distinguished from an ARDS of known etiology and treated by steroids and/or immunesuppressors [2].

Therefore, the clinical development of ALI/ARDS and its histological counterpart DAD occurs in three different clinical settings. In ALI/ARDS where it develops abruptly in 1-week time interval upon normal or diseased lungs and shares a multitude of etiologies; in AIP where it develops more insidiously in 8 weeks upon normal lungs and is considered a distinctive unknown etiology ILD different from any etiology ALI/ARDS, and finally, in IPF ‘acute exacerbations’ where it develops in 4-week period upon UIP lungs, also considered as an idiopathic event [13]. The development of DAD at different time intervals in different clinical settings carries enormous skepticism on our ability to set diseases’ definitions and may represent an obstacle in the acquisition of the appropriate therapeutic decision. In effect, ALI/ARDS treatment recommendations are based on the provision of excellent supportive care plus an extensive search and appropriate treatment of the etiological precipitant [14]. In such patients, all intensive care clinicians in the absence of an obvious etiology, and considering that occult infection is the most probable and also the most treatable underlying condition, universally administer extensive spectrum antimicrobials. Inversely, in AIP and IPF ‘acute exacerbations’, recent guidelines recommended high-dose steroids as salvage therapy despite unproven benefit [15] and despite the fact that known and unknown etiology IPF ‘acute exacerbations’ appear indistinguishable, suggesting that the acquisition of the ‘idiopathic’ etiology is often weak [16]. The above dualism on DAD treatment might constitute an oxymoron.

So far, the etiology of IPF ‘acute exacerbations’ remains elusive leading to the development of several hypotheses not always mutually exclusive. Thus, either an intrinsic acceleration of the disease process is proposed (i.e., idiopathic acceleration of an idiopathic disease) or a superimposed additional hit to the lung such as occult infections, gastroesophageal reflux disease, lung surgery, bronchoalveolar lavage, air pollution or other not yet identified [8]. The lack of experimental data to support the first hypothesis and the encountering in everyday practice of well-defined cases that cause an identical syndrome to IPF ‘acute exacerbations’ could lead to two interesting consequences. The first is to question whether IPF ‘acute exacerbations’ are events in the natural history of the disease, which have truly unknown etiology, and the second to speculate that IPF ‘acute exacerbations’ could probably represent an umbrella term under which many distinct causes could be contained, realizing that although common and sometimes coexisting, however, they are very difficult to be investigated due to the critical and frail condition of these patients. The above may also be valid for AIP.

Infection, although an exclusion criterion, is thoroughly sought in every suspected or definite case of IPF ‘acute exacerbation’. Knowing that the diagnostic yield in lower respiratory tract infections, despite an aggressive search, is far beyond 100% [17] and that IPF patients, especially when immunosuppressed, are infections prone, renders elusive not only the etiology of (some of) the exacerbations, but most importantly impossible to apply properly even its own definition criteria. The same could be argued for gastric aspiration as a cause of the exacerbation, since it is also present in the majority of stable IPF patients [18], whereas other potential triggers such as lung surgery have a more obvious mechanism that causes the respiratory deterioration (oxygen toxicity and mechanical stress of the aerated lung in addition to several others).

In the last few years, the scientific community has witnessed how ‘prescriptive’ clinical practice guidelines on therapeutic decisions of critical importance have completely reversed their recommendations based on data from the results of well-designed and well-executed clinical research studies. As an example in the field of intensive care medicine, hydrocortisone was widely used in septic shock besides evidence for limited benefit. Multicenter, randomized, double-blind controlled trial provided the appropriate evidence to ‘dissect facts from fiction’ and to ‘end the unconditional love for steroid use’ as the latest surviving sepsis guidelines demonstrate [19–22].

Even more recently, the results of the randomized, double-blind, placebo-controlled trial on triple therapy of prednisone, azathioprine and acetylcysteine for pulmonary fibrosis not even proved that the ‘officially’ recommended treatment for IPF was ineffective but also harmful, and will certainly lead to the complete alteration of the recommendations against the use of this combination [1,23]. Knowing how powerful properly conducted studies financed by scientific sources such as the National Heart, Lung and Blood Institute are to provide medical knowledge and to reduce bias, we strongly believe that in IPF, a study similar to the CORTICUS and PANTHER studies, comparing the two arms of the steroid and nonsteroid approach in the therapeutic management of ‘acute exacerbation’ of IPF is greatly awaited by scientists and owed to the patients. Uncontrolled preliminary clinical data appear to shed doubts upon the steroids approach on IPF acute exacerbations [24]

In conclusion, the scientific community needs evidence whether IPF ‘acute exacerbations’ represent an intrinsic process of the disease or not because this will have enormous diagnostic and most importantly therapeutic implications. Certainly, by changing approach, we are not going to save IPF patients but according to Hippocrates ‘do not harm’ them. Till then, we suggest to avoid steroids on unproven etiology DAD upon UIP, and follow ALI/ARDS recommendations, waiting for evidence [2,14,15,25].

Financial & competing interests disclosure

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending or royalties.

No writing assistance was utilized in the production of this manuscript.