Radiological pitfalls associated with the diagnosis of usual interstitial pneumonia pattern on high-resolution computed tomography and associated findings: experience from a single Italian center

Abstract

Background

The diagnostic algorithm for idiopathic pulmonary fibrosis (IPF) based on high-resolution computed tomography (HRCT) findings and multidisciplinary discussion (MDD) has been well established.

Purpose

To identify the causes of disagreement between non-thoracic and thoracic radiologist involved in MDD for the imaging diagnosis of usual interstitial pneumonia (UIP) patterns and associated findings on HRCT and to improve the understanding of IPF by non-expert radiologists through a more systematic approach to HRCT.

Material and Methods

This study included 68 patients who underwent MDD for suspected IPF. We compared the first reports generated before MDD by non-expert radiologists with the CT pattern and associated findings of IPF reported by thoracic radiologist involved in MDD.

Results

Regarding the diagnosis of CT pattern by non-expert radiologists, 30/68 patients received a discordant diagnosis, and in another 28 reports, all features of the CT pattern were described without reaching a diagnostic conclusion. The first report was concordant in only 10 patients. For 63 cases in which associated findings were reported by expert radiologists in MDD, we documented discrepancies in 47 cases where associated findings were considered absent by the first non-thoracic radiologist.

Conclusion

We found significant discrepancies in the imaging diagnosis of UIP patterns and associated findings on HRCT between non-expert and thoracic radiologists included in MDD. Therefore, in this study, we analyzed and suggested diagnostic strategies to improve non-expert radiologists’ approach to HRCT.

Keywords

Usual interstitial pneumonia idiopathic pulmonary fibrosis radiological disagreement multidisciplinary discussion high-resolution computed tomography

Background

In the last decade, idiopathic pulmonary fibrosis (IPF) has been well studied. The new challenge in the field of IPF is to accurately identify patients with the disease. The British Lung Foundation’s statistics cover the prevalence, incidence, and mortality of IPF in the UK and how they affect different demographics. This foundation reported that the rate of IPF increase was approximately 30% in the period between 2010 and 2012 when guidelines for the diagnosis of IPF were published. As regards diseases with low prevalence, the epidemiology of IPF depends on doctors’ knowledge about the disease and clinical suspicion (1).

Wells et al. (2) prefer to use the term pulmonary fibrosis rather than idiopathic interstitial pneumonias (IIPs) when they describe IPF, unclassifiable interstitial lung diseases (ILDs), fibrotic hypersensitivity pneumonitis, connective tissue disease-associated ILD, idiopathic pneumonia with autoimmune features, and drug-induced non-specific interstitial pneumonia (NSIP).

Among these disorders, IPF has the most central role because it is the most frequent pathology among idiopathic forms and has the worst prognosis. In this scenario, there are several diagnostic overlaps. All of the aforementioned disorders can mimic IPF; however, the treatment options differ, and the different disorders cannot be treated based on guidelines for IPF (2).

As there is no single common classification criterion among IIPs, Raghu et al. (3) developed a diagnostic algorithm based on multidisciplinary discussion (MDD) between pneumologists, radiologists, and pathologists experienced in the diagnosis of ILD and HRCT imaging. HRCT has a central role in the diagnosis of IPF, and the task of the radiologist is to identify a radiological pattern among typical usual interstitial pneumonia (UIP), probable UIP, indeterminate for UIP, and alternative diagnoses.

According to the American Thoracic Society/European Respiratory Society/Japanese Respiratory Society/Latin American Thoracic Association (ATS/ERS/JRS/ALAT) guideline for IPF, diagnostic procedures such as biopsy depend on the radiological pattern (4). A biopsy is not required in cases of the typical UIP pattern. With regard to probable UIP, the guidelines indicate the need for clinical equilibrium when deciding whether a biopsy should be performed for a patient with a probable UIP pattern on HRCT; it may not be appropriate for a sizeable minority of patients (up to 46%). MDD becomes crucial under such circumstances. Biopsy is necessary for patients with indeterminate for UIP because this form of UIP is now considered early UIP that needs early diagnosis, treatment, and monitoring since some studies analyzing groups of placebo patients with IPF showed a statistically significant progression without therapy (5). An early diagnosis has the important aim to start a timely therapy, even if the treatment of IPF with anti-fibrotic medication (Pirfenidone and Nintedanib) has important adverse drug reactions unlike immunosuppressant therapies used in other causes of ILDs such as connective tissue disease related ILD (6,7).

Although the drugs now used in IPF are anti-fibrotics and no biomarkers for diagnosis or prognosis have yet been identified, several works identified molecules included in the pathogenesis and progression of disease that may be therapeutic targets and molecules translated from other diseases such as severe asthma (8); other authors identified a specific polymorphism of the TOLLIP gene that determines a different response to N-Acetylcysteine therapy (9). As in other ILDs where there is a therapy based on pathogenesis and immunosuppressants, in IPF, biomarkers are being searched for with the aim of a targeted and personalized therapy (10).

Finally, the diagnosis of IPF is important because the drugs recommended for this disorder are specific and at the same time, the therapies approved for other lung diseases increase the mortality in IPF (11). The ultimate goal is to diagnose the IPF for which approved drugs exist; however, the main problem is all the other forms for which there are only off-label drugs available.

The experience and competence of the radiologist and MDD are the most important factors associated with correct diagnosis and therapy. The aim of the present study was to highlight the discrepancies in radiological diagnosis of the UIP pattern on HRCT between the initial interpretation by radiologists without specialist training in thoracic imaging and subsequent classification by a thoracic radiologist included in MDD with MDD consensus. Grewal et al. (12) recently published a similar study on the benefits of MDD in the diagnosis and management of IPF. The discrepancy between the first and second opinion shows the dangerous impact of radiological disagreement on clinical management. Our aim, therefore, is to highlight the most common mistakes of non-expert radiologists to highlight the importance of an HRCT interpretation algorithm for ILDs, which would allow even non-expert radiologists to accurately distinguish between non-fibrosing and fibrosing disorders and subsequently to identify the correct UIP pattern versus non-UIP pattern.

We will also focus on the effect of discordant diagnosis by less experienced radiologists with regard to associated findings of UIP wherein early diagnosis and treatment are as important as the treatment itself (13).

Indeed, the co-existence of dilated esophagus, pulmonary emphysema, consolidations (< 3 cm), indirect signs of pulmonary hypertension on HRCT, coronary artery calcification, and pneumothorax contributes to poor diagnosis and is associated with a decreased quality of life of patients and an increased risk for death.

Material and Methods

This retrospective study included 68 patients (age range = 46–85 years; mean age = 73.4 years) who underwent MDD between December 2016 and September 2018 for suspected IPF based on medical history (familiarity, absence of clear causes of pulmonary pathology), clinical-laboratory, or radiological data that needed an integrated management of several specialists (pulmonologist, radiologist, and pathologist) for a correct diagnostic-therapeutic planning.

Eleven patients (mean age = 60.5 years) among those with suspected probable and indeterminate for UIP underwent surgical lung biopsy for a histological examination. In the other 57 patients not eligible for lung biopsy (because of age-associated risk for procedural complications and co-existence of co-morbidities), the diagnosis of suggested by MDD was supported by respiratory function testing, clinical history, family history of IPF, and HRCT aspects. MDD included specialists in respiratory diseases, pathologists, and a single thoracic radiologist (with > 5 years of experience in thoracic imaging and referent of the IPF community, a regional centralized reference system for the diagnosis of IPF) who re-evaluated the external HRCT images of every outpatient. In each case, the expert thoracic radiologist in MDD assigned a specific CT pattern according to the official ATS/ERS/JRS/ALAT guidelines: typical UIP pattern; probable UP; and indeterminate for UIP (3), giving an important suspicion to MDD.

We considered the radiological diagnosis in MDD a standard reference and evaluated the agreement between the radiological diagnosis of MDD and the previous radiological diagnosis performed by a non-thoracic radiologist. With the aim of comparing the opinion of the expert radiologist of MDD with that of radiologists not dedicated to UIP, we revised previous external HRCT studies by 15 radiologists, from five peripheral centers not dedicated to thoracic imaging and classified the reports into five categories: typical UIP; probable UIP; indeterminate for UIP; alternative diagnosis (3); plus an additional category where no diagnostic conclusion was reached.

We also considered the presence/absence of additional and associated findings on HRCT highlighted in the existing literature, such as a dilated esophagus (14), pulmonary emphysema (15), consolidations (<3 cm), indirect signs of pulmonary hypertension, coronary artery calcification (16,17), and pneumothorax (18) (PTX), identified by the expert radiologist involved in MDD and underestimated by non-thoracic radiologists. In particular, regarding indirect signs of pulmonary hypertension on HRCT, we evaluated whether there was an increase in the diameter of pulmonary arteries (mPAD) or in the pulmonary artery to aorta ratio (PA:A ratio) and whether the segmental pulmonary artery diameter to segmental bronchus diameter ratio was > 1 (19) in addition to the evidence for right ventricular hypertrophy (20).

IPF complications are not a strict imaging diagnosis; however, these associated aspects should be suspected, investigated, and identified by a radiologist with the aim to correlate them with clinical and laboratory information in MDD for early documentation of the development of complications that are often underestimated. Finally, data about the discrepancy between the first non-expert opinion and that of the expert thoracic radiologist involved in MDD with regard to the diagnosis of the UIP pattern and recognition of associated findings were subjected to statistical analysis. Statistical analyses were conducted using R v 3.4.4 (R Core Team; R Foundation for Statistical Computing, Vienna, Austria; https://www.R-project.org/). Cohen’s k coefficient was used to express and determine inter-observer agreement. The level of agreement was categorized as follows: poor = 0 > k ≤0.20; fair = 0.20 > k ≤0.40; moderate = 0.40 > k ≤0.60; good = 0.60 > k ≤0.80; and excellent = 0.80 > k ≤1.00.

Results

Regarding disagreements about the CT pattern-based diagnosis between the non-thoracic radiologist and thoracic radiologist in MDD, discrepancies were noted between the first non-expert opinion and the second review because of a discordant diagnosis of the UIP pattern for 30/68 patients. In the other 28 reports, the first radiologist had well documented all the features of the CT pattern without reaching a diagnostic conclusion, which is fundamental for correct diagnostic-therapeutic planning. In the remaining 10 patients, the first non-thoracic radiologist reported a concordant diagnosis. The assignment of the HRCT pattern by both the thoracic radiologist involved in MDD and the first non-thoracic radiologist for all 68 patients is listed in Table 1.

Table 1.

UIP pattern.

HRCT pattern for thoracic radiologist of MDD	HRCT pattern for non-thoracic radiologist
Typical UIP	Typical UIP	Probable UIP	Indeterminate for UIP	Alternative diagnosis	Without diagnostic conclusion
45	9	5	6	4	21
Probable UIP
18	4	1	4	2	7
Indeterminate for UIP
3	0	0	0	3	0
Alternative diagnosis
2	2	0	0	0	0

The first column documents the diagnosis of the thoracic radiologist in MDD in comparison with the HRCT pattern assigned by the first non-thoracic radiologist classified into five categories: typical UIP, probable UIP, indeterminate for UIP, and alternative diagnosis, plus an additional category where no diagnostic conclusion was reached.

HRCT, high-resolution computed tomography; MDD, multidisciplinary discussion; UIP, usual interstitial pneumonia.

The thoracic radiologist involved in MDD assigned the typical UIP pattern in 45/68 patients; while the first diagnosis in nine cases was concordant, in 21 cases it described HRCT features without suggesting a diagnostic conclusion, in 15 cases the first report was discordant for probable UIP in five cases, indeterminate for UIP in six cases, and alternative diagnosis in four cases (emphysema in one case, chronic obstructive pulmonary disease in one case, and NSIP in two cases). In the five patients for whom the first non-expert diagnosis was probable UIP, the misdiagnosis was based on the imprecision differentiation between honeycombing and peripheral traction bronchiectasis or bronchiolectasis. In the case of the six indeterminate for UIP diagnoses, the first radiologist reported irregular reticulation without reference to bronchiectasis and honeycombing.

In the case involving discordant emphysema, honeycombing was mistaken for paraseptal emphysema by the non-thoracic radiologist who did not notice the presence of thick walls typical of honeycombing. Lastly, in the two cases involving discordant NSIP, the first non-thoracic radiologist did not pay attention to the subpleural architectural distortion.

Among the 18 cases assigned to probable UIP pattern by the thoracic radiologist during MDD, non-thoracic radiologists assigned a diagnosis that agrees only in one case, a diagnosis without diagnostic conclusion in seven patients, and discordant diagnosis in 10 cases reporting indeterminate for UIP in four cases, typical UIP pattern in another four patients, and alternative diagnosis in the other two cases (NSIP and chronic granulomatous disease).

Among the 68 patients, the thoracic radiologist found three indeterminate for UIP cases during MDD that the first non-thoracic radiologist described as completely negative CT without noticing bilateral irregular reticulations and mild ground-glass opacity (GGO).

In addition, two cases described as typical UIP by non-expert radiologists were diagnosed differently during MDD, such as a case of chronic hypersensitivity pneumonitis and asbestosis, in which radiological data was integrated with medical history of inhalation of organic dust, clinical data, and laboratory test results.

We found no agreement between MDD and the non-expert radiologist in the determination of the UIP pattern (k Cohen’s = –0.04).

Thirty patients with a discordant first diagnosis did not show serious consequences owing to the diagnostic delay, because these patients were followed-up by the Pulmonary Medicine Unit specializing in ILDs and were already included in diagnostic and management procedures that included MDD with specialists in respiratory diseases, pathologists, and dedicated radiologists who revaluated the external HRCT findings of every patient. In addition, the interval between the original CT scan and MDD discussion was in the range of 3–6 months and at least one more additional scan or follow-up data available to the MDD team helped them arrive at the diagnosis of UIP pattern or alternative diagnosis.

Subsequently, during MDD, the expert radiologist documented 63 additional or associated findings of UIP pattern on HRCT imaging. The first opinion identified the presence of only 16 associated findings; and the remaining 47 cases were not documented in the first report (Table 2). A fair agreement was also shown in the detection of complications (k Cohen’s = 0.24). With respect to the 10 patients with IPF who developed consolidation (<3 cm), both radiologists documented these findings in nine cases, and only after monitoring and correlation with clinical and laboratory data in MDD was it probable to distinguish among four cases of lung cancer, three cases of infection, and three cases of acute exacerbation.

Table 2.

Associated findings on HRCT.

	Associated findings for thoracic radiologist in MDD (n = 63)	Absence for non-thoracic radiologist (n = 47)	Presence for both radiologists (n = 16)
Pulmonary emphysema	9	7	2
Consolidation	10	1	9
Esophagus dilatation	8	8	0
Diameter of pulmonary arteries (>27mm) or
PA:A ratio>0.9; Segmental pulmonary artery diameter to segmental bronchus diameter ratio>1	8
Hypertrophy of the right ventricle	3	11	0
PTX	2	0	2
Coronary artery calcifications	23	20	3

HRCT, high-resolution computed tomography; MDD, multidisciplinary discussion; PA:A, pulmonary artery to aorta; PTX, pneumothorax.

Discussion

The findings of the present study suggest that a systematic approach to HRCT is essential to reduce the list of differential diagnosis and reduce disagreements in interpreting the UIP pattern. The diagnosis of IPF can be definitively made by MDD. Therefore, the role of the non-thoracic radiologist is to raise the possibility of ILDs and refer to a specialized center. The primary aim of the present study was to identify the causes of discordance among non-thoracic and thoracic radiologists in MDD; the secondary aim was to improve the understanding of UIP pattern by non-expert radiologists through a more systematic approach to HRCT.

The HRCT interpretation algorithm for ILDs provides a first step represented by the ability to distinguish between non-fibrosing and fibrosing disorders; the second radiologist’s task is to identify UIP versus non-UIP patterns. Several studies have analyzed inter-observer variability in identifying honeycombing (21,22). As shown by our work, traction bronchiectasis/bronchiolectasis represents an important false-positive state of honeycombing. In order to increase the agreement in diagnosing traction bronchiectasis, we recommend evaluation of the pulmonary volume acquired in multiplanar reformation (MPR) with minimum intensity projection (MinIP) that allows the radiologist to follow the course of bronchi differentiating these structures from honeycombing that has no bronchial communication (Fig. 1) (23). This expedient may also enable the non-thoracic radiologist to make an easier differential diagnosis; specifically, in nine cases, we would have recorded an increase in the agreement between typical and probable patterns.

Fig. 1.

(a, b) Case of incorrect diagnosis: honeycombing in typical UIP (a) has been misinterpreted and mistaken for bronchiectasis in probable UIP (b). (c–f) MPR/MiNP tools allow us to follow the course of the bronchi distinguishing bronchiectasis (d, f) from honeycombing (c, e). UIP, usual interstitial pneumonia.

Another discordant diagnosis of honeycombing found in eight cases was represented by paraseptal emphysema superimposed on fine intralobular fibrosis; indeed in one case, the non-expert radiologist diagnosed emphysema instead of typical UIP and in seven cases, non-thoracic radiologists did not document this associated finding in the report. It is difficult to distinguish honeycombing from paraseptal emphysema, especially when honeycombing is in the single-chain form. However, even the non-thoracic radiologist could distinguish them by simply evaluating the distribution and thickness of the walls: emphysema has an upper lobe predominance and not visible walls, while honeycombing is mainly basal at the lower lobe with a subpleural involvement and thick walls (1–3 mm) (24).

Another common mistake is the incorrect identification of mild GGO of fibrosing disorders. In one case, it was confused with “pure” GGO, which is not a typical feature of UIP, and its presence in a patient with IPF should raise the possibility of an acute exacerbation (AE-IPF) or infection (Fig. 2). The non-thoracic radiologist should simply be aware of these associated findings of IPF in order to suspect them when the GGO appearance appears worsened and bilateral.

Fig. 2.

(a) Coronal view shows mild ground-glass opacity, a typical feature of the UIP pattern (fibrosis sign); (b, c) sagittal view CT of acute exacerbation of IPF shows superimposed “pure” ground-glass opacity (inflammation’ sign). CT, computed tomography; IPF, idiopathic pulmonary fibrosis; UIP, usual interstitial pneumonia.

In the present study, only three cases of indeterminate for UIP with bilateral reticulations and GGO were described by the first radiologist as a completely negative CT, without recommending follow-up or biopsy in patients who could receive early diagnosis and therapy (Fig. 3). The non-thoracic radiologist did not note the presence of bilateral irregular reticulations and mild GGO. With respect to reticulation, the primary task of the non-thoracic radiologist is to avoid underestimating this aspect, which can be an early sign of an underlying pathology and to establish whether it is smooth, nodular, or irregular like in the UIP pattern; when an irregular pattern is established, it is necessary to differentiate the UIP pattern of IPF from several diseases characterized by this feature (chronic fibrotic sarcoidosis, chronic hypersensitivity pneumonitis, drug toxicity, asbestosis, collagen vascular diseases) analyzing the associated CT signs and discussing the case in MDD by integrating radiological data with clinical and anamnestic data. The correlation with these data, in fact, was fundamental for the diagnosis by the MDD in the two cases of asbestosis and chronic hypersensitivity pneumonitis misdiagnosed by the non-expert radiologist (Fig. 4).

Fig. 3.

(a) Sagittal, (b) coronal, and axial (c) views in MPR show posterior fine reticulations (fibrosis sign) typical of indeterminate for UIP misdiagnosed. Traction of pulmonary fissures of the right lung is also shown in (c). MPR, multiplanar reformation; UIP, usual interstitial pneumonia.

Fig. 4.

(a, b) Case of chronic Hp with radiological characteristics partially similar to IPF (traction bronchiectasis and bronchiolectasis, patchy ground-glass attenuation and subtle centrilobular nodules, mosaic oligemia and lobular air trapping, reduced lung volume, variable distribution in the peripheral subpleural regions and also in the peribronchovascular interstitium) and diagnosed in MDD, integrating radiological data with anamnestic data for inhalation of organic dusts, clinical data, and laboratory test results. (c) Case of asbestosis in a patient with a history of exposure to asbestos fibers and typical radiological features such as traction bronchiectasis and bronchiolectasis with highly irregular morphology and thick walls, honeycombing, patchy distribution, and bilateral disease with basal predominance with pleural plaques magnified in (d). Hp, hypersensitivity pneumonitis; IPF, idiopathic pulmonary fibrosis; MDD, multidisciplinary discussion.

In addition, in our work, typical UIP and probable UIP have also been mistaken for NSIP in three cases. This discordant diagnosis can be avoided by the non-thoracic radiologist simply by evaluating the distribution of architectural distortion, i.e. by evaluating whether it is peripheral (UIP pattern) or if there is subpleural sparing typical of NSIP (25,26).

The main aims were to show the discordance on typical UIP and probable UIP which can change management (e.g. biopsy), the misdiagnosis of indeterminate for UIP which can delay treatment as this may be an early form of UIP, the discordance between UIP cases, and alternative diagnosis which has great clinical, diagnostic, and therapeutic implications.

Further, IPF is complex because of the co-existence of co-morbidities and complications usually undiagnosed by non-dedicated radiologists (Fig. 5). The last aim was to show that, from our experience, these aspects escape the eyes of the non-expert radiologist who must first know the existence of these complications in order to research them.

Fig. 5.

IPF complications/co-morbidities misdiagnosed: coronary artery disease (a), hypertrophic bronchial arteries (b), and esophagus traction and dilatation due to pulmonary fibrosis (c). IPF, idiopathic pulmonary fibrosis.

Although we exclusively evaluated the radiological diagnosis, MDD represents the fulcrum of the diagnosis and management of patients with IPF, allowing integration of radiological aspects with clinical, anamnestic, pathological, and eventually surgical interventional aspects.

The radiologist’s task remains to identify the correct UIP pattern on HRCT and associated findings, but the final definite diagnosis of IPF is made by MDD because typical and probable UIP patterns could be present in disorders other than IPF (27). To reduce intra- and inter-observer variability, it is essential to identify ancillary findings and correlate everything in MDD (28 –31).

The radiologist is a central figure in the management of these patients. We also aimed to underline the importance of awareness courses to receive sufficient radiological training to recognize the pathology, quickly refer the patient, already well examined, to a second specialized center to reduce the time between first CT by an inexperienced radiologist and a correct diagnosis in the second specialized center. It is also necessary to form teams of radiology experts in UIP radiological pattern who will participate in the MDD to make an early diagnosis of UIP and associated findings. Thus, the objectives to be achieved are represented by responding to the needs of the patient and creating expert centers with dedicated teams where the patients could be sent.The limitation of our work is represented by the fact that we have exclusively highlighted the radiological diagnosis of a single thoracic radiologist of MDD. It would have been interesting to evaluate the opinion of two thoracic radiologists included in MDD.

In conclusion, our results of no agreement between MDD and the non-expert radiologist in the determination of the UIP pattern (k Cohen’s = –0.04) and associated findings have allowed us to investigate some expedients which may also enable the non-thoracic radiologist to make an easier differential diagnosis using simple tools and a more systematic approach to HRCT to improve the evaluation of imaging crucial aspects.

Footnotes

Declaration of conflicting interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) received no financial support for the research, authorship, and/or publication of this article.

ORCID iDs

Francesca Ricci

Paola Rogliani

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