Idiopathic pulmonary fibrosis (IPF) represents the most common form of idiopathic interstitial pneumonia (IIPs) and is characterized by the gravest prognosis with a median survival of 3–5 years (1), irrespective of treatment. The past 10 years, large multicenter placebo-controlled clinical trials have significantly shifted the therapeutic dial of IPF (2–4) from harmful agents to Ref. (5) to therapies able to slow down the disease progression (2–4). It is important to note that the efficacy of the antifibrotic agents, pirfenidone, and nintedanib has been tested only in the context of IPF; thus, accurate and timely diagnosis seems to be imperative. It is important to note that disease diagnosis does not represent anymore an academic exercise since it directly influences and guides therapeutic decisions.

Histologically, IPF is characterized by the pattern of usual interstitial pneumonia (UIP), which is denoted by spatial and temporal heterogeneity (6). It is of utmost importance to highlight the fact that UIP pathology is not exclusive to IPF, as it may characterize other diseases including chronic hypersensitivity pneumonitis (HP), connective tissue disorders-associated ILDs, asbestosis, or drug toxicity. In other words, all IPF have UIP pathology, but not all UIP are IPF. High-resolution computed tomography (HRCT) revolutionized the diagnosis of IPF. The presence of honeycombing in a predominantly peripheral and bibasilar distribution has a sufficient positive-predictive value (PPV) for underlying UIP pathology obviating the need for tissue confirmation (7–9). Even in that case, exclusion of other causes of UIP is mandatory to finally establish IPF diagnosis. Furthermore, IPF diagnosis represents a dynamic process and, therefore, close monitoring of the patient is mandatory. In particular, therapeutic decisions can be altered based on disease natural course and treatment responsiveness on an individual basis. In addition, disease diagnosis could be revisited in light of emerging symptoms compatible with connective tissue disorder or exposure to potentially harmful environmental agents.

The patient with IPF typically presents with progressive dyspnea on exertion of insidious onset and non-productive cough. The most characteristic clinical finding is the presence of Velcro rales that can be proven an extremely useful diagnostic tool for early disease diagnosis (10). Clubbing is almost found in 30–50% of patients; yet, its prevalence is much higher following disease progression and development of pulmonary hypertension. Multisystemic manifestations in the context of IPF are highly uncommon and should alert the physician toward alternative diagnoses. Median time from onset of symptoms to first evaluation in an ILD center quite often exceeds 1 year and the length of delay has been associated with increased mortality (11, 12).

Pulmonary function tests usually exhibit a restrictive pattern with concomitant reduction in diffusing capacity of carbon monoxide (DLco). However, the absence of restriction does not exclude the diagnosis of IPF, especially in the context of combined pulmonary fibrosis and emphysema, which is characterized by relatively preserved lung volumes with disproportionately reduced DLco (13). There are also cases discovered early and presumably with an initial FVC > 100% that do not fulfill the criteria of a restrictive pattern, nevertheless, fibrosis is evident on HRCT.

According to current diagnostic criteria (1), HRCT plays a pivotal role in the diagnostic procedure. There are three diagnostic categories based on HRCT appearance: UIP pattern, possible UIP pattern, and inconsistent with UIP. The definition of each category is based on morphological as well as distribution characteristics. UIP pattern is characterized by the presence of reticular abnormalities and honeycombing (with or without traction bronchiectasis) with a subpleural and basal predominance in the absence of inconsistent features. The above radiological features in the absence of honeycombing constitute the possible UIP pattern. Inconsistent features can be categorized as those involving distribution (upper or mid lung and peribronchovascular predominance) and those involving morphology (extensive ground glass opacities, consolidation, mosaic attenuation, nodules, discrete cysts).

The presence of honeycombing is not synonymous with IPF, as it can be seen in other diseases as chronic HP, collagen tissue-related interstitial lung diseases, asbestosis, drug-induced lung toxicity, sarcoidosis, postradiation pneumonitis, and post ARDS. Minimal honeycombing can also be encountered in cases of fibrotic NSIP, which represents a major component of the differential list.

The distribution of honeycombing can offer significant information. Typically, in IPF, it has a subpleural and basilar distribution. Chronic HP can be a great mimic of IPF. However, sometimes in chronic HP, honeycombing can be more marked in the upper/mid lung zones giving a hint to the actual diagnosis. The same upper lobe predominance of honeycombing can be seen in sarcoidosis as well. Furthermore, in sarcoidosis, the fibrotic process often follows the expected perilymphatic route, thus creating a “swath” of honeycombing extending from the hilum to the periphery of the lung. In patients who develop fibrosis post ARDS, it has a striking anterior distribution (Table 1).

Besides the distribution of honeycombing, there are other findings on HRCT that increase suspicion toward certain diagnoses. Silva et al. (14) studied 66 patients with biopsy proven IPF, HP, and NSIP. The presence of lobular areas with decreased attenuation, centrilobular nodules, and cysts favored the diagnosis of HP. The best predictors of NSIP were the presence of subpleural sparing and the absence of honeycombing.

In the appropriate clinical setting in patients with a UIP pattern, IPF diagnosis can be established without the need for surgical lung biopsy (SLB). In the cases of possible UIP and inconsistent with UIP, a SLB is recommended in order to reach a final diagnosis. When SLB is necessary, close cooperation with the thoracic surgeon is necessary in order to point the optimal sites for biopsy in order to increase the possibility of an accurate diagnosis. Areas of honeycombing should be avoided in lung sampling since they may reveal non-specific end-stage lung damage and absence of spatial and temporal heterogeneity suggestive of UIP. Samples should be obtained from at least two different lobes, because of the possibility of discordant findings (UIP in one lobe and NSIP in another). In such cases, the UIP pattern drives diagnosis and prognosis as well (15, 16).

Regarding histopathology, current guidelines have classified patients into four categories: UIP, probable UIP, possible UIP, and not UIP (1). Specific combinations of HRCT and SLB pattern with the integration of clinical data are evaluated by a multidisciplinary (MDT) team in order to achieve a final diagnosis.

MDT approach is acknowledged as a major advance in IPF diagnosis. It refers to the constructive exchange of views between a respiratory physician, radiologist, and pathologist with expertise in the field of ILDs. The added value of MDT diagnosis is its association with higher levels of diagnostic confidence and better interobserver agreement (17, 18). Walsh et al. (19) were the first to evaluate the agreement between different multidisciplinary teams in diffuse lung diseases after the 2013 ATS/ERS update (20) on the classification of IIPs. Inter-MDT agreement was acceptable for cases of IPF (weighted kappa coefficient, κw = 0.71), while it was moderate for NSIP (κw = 0.42) and rather disappointing for HP (κw = 0.29) reflecting the lack of diagnostic guidelines for the last two clinical entities. This indirectly impacts the accuracy of IPF diagnosis as well, given the fact that NSIP and HP are frequently major components of its differential.

The 2011 guidelines are a clear step forward considering that they provide clear guidance on an evidence-based approach. The most crucial caveat of these guidelines is that, in a significant percentage of “real-life” patients with IPF, lack clinical practicality regarding diagnosis, prognosis, and therapeutic decisions.

VT, AT, and SC wrote the manuscript. SP and DB revised the manuscript for important intellectual content.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.