diagnostics

Review
The Evolving Concept of the Multidisciplinary Approach in the
Diagnosis and Management of Interstitial Lung Diseases
Stefano Sanduzzi Zamparelli 1 , Alessandro Sanduzzi Zamparelli 2,3, * and Marialuisa Bocchino 2

1 Division of Pneumology, A. Cardarelli Hospital, 80131 Naples, Italy; stefanosanduzzi@gmail.com

2 Department of Clinical Medicine and Surgery, Section of Respiratory Diseases, University Federico II,
Azienda Ospedaliera dei Colli-Monaldi Hospital, 80131 Naples, Italy; marialuisa.bocchino@unina.it
3 Staff of UNESCO Chair for Health Education and Sustainable Development, University Federico II,
80131 Naples, Italy
* Correspondence: sanduzzi@unina.it

Abstract: Background: Interstitial lung diseases (ILDs) are a group of heterogeneous diseases charac-
terized by inflammation and/or fibrosis of the lung interstitium, leading to a wide range of clinical
manifestations and outcomes. Over the years, the literature has demonstrated the increased diag-
nostic accuracy and confidence associated with a multidisciplinary approach (MDA) in assessing
diseases involving lung parenchyma. This approach was recently emphasized by the latest guidelines
from the American Thoracic Society, European Respiratory Society, Japanese Respiratory Society, and
Latin American Thoracic Association for the diagnosis of ILDs. Methods: In this review, we will
discuss the role, composition, and timing of multidisciplinary diagnosis (MDD) concerning idiopathic
pulmonary fibrosis, connective tissue disease associated with ILDs, hypersensitive pneumonia, and
idiopathic pneumonia with autoimmune features, based on the latest recommendations for their
diagnosis. Results: The integration of clinical, radiological, histopathological, and, often, serological
data is crucial in the early identification and management of ILDs, improving patient outcomes.
Based on the recent endorsement of transbronchial cryo-biopsy in idiopathic pulmonary fibrosis
guidelines, an MDA helps guide the choice of the sampling technique, obtaining the maximum
Citation: Sanduzzi Zamparelli, S.; diagnostic performance, and avoiding the execution of more invasive procedures such as a surgical
Sanduzzi Zamparelli, A.; Bocchino, lung biopsy. A multidisciplinary team should include pulmonologists, radiologists, pathologists, and,
M. The Evolving Concept of the often, rheumatologists, being assembled regularly to achieve a consensus diagnosis and to review
Multidisciplinary Approach in the cases in light of new features. Conclusions: The literature highlighted that an MDA is essential
Diagnosis and Management of to improve the accuracy and reliability of ILD diagnosis, allowing for the early optimization of
Interstitial Lung Diseases. Diagnostics therapy and reducing the need for invasive procedures. The multidisciplinary diagnosis of ILDs is an
2023, 13, 2437. https://doi.org/
ongoing and dynamic process, often referred to as a “working diagnosis”, involving the progressive
10.3390/diagnostics13142437
integration and re-evaluation of clinical, radiological, and histological features.
Academic Editors: Paola Confalonieri
and Barbara Ruaro Keywords: interstitial lung diseases; idiopathic pulmonary fibrosis; hypersensitive pneumonia;
connective tissue disease–interstitial lung diseases; idiopathic pneumonia with autoimmune features;
Received: 13 April 2023
multidisciplinary diagnosis; multidisciplinary team
Revised: 19 June 2023
Accepted: 29 June 2023
Published: 21 July 2023

1. Introduction
Interstitial lung diseases (ILDs) represent a huge and heterogenous group of pul-
Copyright: © 2023 by the authors. monary disorders, characterized by varying degrees of inflammation and fibrosis of the
Licensee MDPI, Basel, Switzerland. lung with different prognoses and management options. Despite extensive analysis, the
This article is an open access article
diagnosis of ILDs remains challenging, as the specific etiology cannot be identified in
distributed under the terms and
10–20% of cases, due to the common respiratory clinic and the frequent overlap of radio-
conditions of the Creative Commons
logic and/or histopathologic patterns among various diseases [1]. Although idiopathic
Attribution (CC BY) license (https://
pulmonary fibrosis (IPF) is the prototype of a progressive fibrotic disease associated with a
creativecommons.org/licenses/by/
poor prognosis and premature mortality, it is associated with over 40% of non-IPF ILDs [2].
4.0/).

Diagnostics 2023, 13, 2437. https://doi.org/10.3390/diagnostics13142437 https://www.mdpi.com/journal/diagnostics

Diagnostics 2023, 13, 2437 2 of 17

Based on this, the paramount significance of achieving an accurate and early diagnosis,
along with the timely initiation of disease-specific therapy, becomes evident to alter the
outcome [3,4].
Since 2001, the American Thoracic Society (ATS) and the European Respiratory Society
(ERS) have introduced a critical change in the diagnostic process of ILDs, highlighting the
importance of a multidisciplinary diagnosis (MDD) based on the integration of clinical,
radiologic, and pathologic data [5]. A face-to-face discussion between different health
professionals, traditionally represented by an ILD-expert respiratory physician, and other
figures, such as radiologists and histopathologists, aims to use available clinical data to
generate a consensus diagnosis with the highest possible level of accuracy.
Before this review, despite the literature demonstrating an exceedingly low inter-
observer agreement between expert thoracic pathologists, histopathological evaluation
was considered the gold standard for ILD diagnosis [6,7]. In addition to the low level
of consensus on the histological sample between different doctors, the main limitation
of this kind of diagnosis was linked to the extreme variability of the histological data,
concerning the representativity of the sample taken strongly depending on the operator’s
experience. In this context, out of 133 lung biopsies taken from 83 ILD patients, the
Nicholson et al. study [8] showed a poor inter-observer agreement among 10 thoracic
pathologists, with a 0.38 kappa coefficient of agreement (κ), making a 100% confidence
diagnosis in only 39% of cases. Notably, more than 50% of the inter-observer variation was
related to the differential diagnosis between nonspecific interstitial pneumonia (NSIP) and
usual interstitial pneumonia (UIP). The uncertainty linked to the histopathologic data is at
a maximum in NSIP patterns because of the presence of different pathological patterns in
different lobes in the same patient. Moreover, divergent pathological diagnoses can be often
caused by surgical lung biopsy (SLB) sampling error [9]. In this context, Flaherty et al. [10]
demonstrated that a histopathological diagnosis based on a single lung biopsy site can be
inaccurate, in particular about NSIP/UIP differentiation, with around 26% of patients with
discordant diagnoses. Furthermore, histopathological diagnosis is not fixed, but it can be
modified in 20% of cases, particularly when an intermediate pattern is present [11]. It is
important to bear in mind that even a histopathologic UIP pattern is not surely related to
IPF, as demonstrated in Tominaga’s study [12]. In this study, the integration of clinical and
radiological data from 95 IPF patients confirmed by a histological pattern compatible with
UIP led to a progressive reduction in post-MDD IPF diagnosis.
More recently, MDA was first emphasized by the 2013 ATS/ERS update for interstitial
idiopathic pneumonia’s (IIP’s) [13] management and further reinforced by the 2018 Fleis-
chner statement [14]. These guidelines proposed updated IPF diagnostic criteria, endorsing
the formulation of an MDD of IPF, mainly in the absence of definitive radiological or
histopathological findings. Based on the literature, which has shown a variable frequency
of IPF ranging from 60 to 90% for patients with probable UIP patterns, MDD is mandatory
in all ILD patients who lack a definite UIP pattern on high-resolution chest tomography
(HRCT). The impact of this approach is supported by Kondoh’s study [15], where out of
179 patients with probable HRCT UIP patterns, an IPF diagnosis was established in 50% of
cases following MDD.
The growing confidence in MDD as a highly accurate assessment of ILDs was empha-
sized in the 2021 guidelines from the ATS, ERS, Japanese Respiratory Society (JRS), and
Latin American Thoracic Association (ALAT) [16]. In addition to its role in determining the
need for biopsy investigations and avoiding invasive procedures—UIP or probable UIP
patterns on imaging in the appropriate clinical setting is enough to make a diagnosis of IPF—
MDD can also aid in selecting the most appropriate sampling tool for lung parenchyma,
such as transbronchial cryo-biopsy (TBLC) or SLB. According to this guideline [16], a
biopsy is generally considered when an indeterminate or inconsistent HRCT UIP pattern
conflicts with clinical data. Data from the literature suggest restricting the use of MDD to
more complex diagnostic cases, with a focus on clinician consensus when the diagnostic
IPF criteria are more evident—UIP on HRCT, a rapidly progressive disease course, and
Diagnostics 2023, 13, 2437 3 of 17

no identifiable triggers. This approach, as emphasized by the retrospective evaluation of

318 ILD patients made by Chaudhuri et al. [17], is associated with the potential to change
the diagnosis.
In contemporary practice, multidisciplinary assessment (MDA) has become the stan-
dard approach for evaluating ILDs due to its high level of diagnostic confidence and
inter-observer agreement. Although initially developed for IIP’s diagnosis, an MDA is now
widely used as the standard in the evaluation of ILDs, not only those that are idiopathic
but also those related to an underlying connective tissue disease (CTD) or linked with
autoimmune features such as idiopathic pneumonia with autoimmune features (IPAF) [11].
In contrast to an IPF diagnosis, many ILDs are not covered by evidence-based diagnostic
guidelines; therefore, a level of disagreement in MDD is predictable [13]. Furthermore,
apart from assessing new cases, MDT discussions are key for reconsidering a previous
diagnosis according to disease behavior and response to therapy.

2. MDD Has a Crucial Role in Guiding the Choice of Lung Tissue Sampling Procedures
In the most challenging cases, when histological data are required, the latest ERS
guideline [16] emphasizes the role of MDD in guiding the choice of biopsy technique and in
the evaluation of samples. Based on European epidemiological studies [18–20], it has been
found that 28–38% of IPF patients were diagnosed using SLB. However, in cases where SLB
is not feasible, TBLC is a valid alternative. The latter is a method capable of obtaining lung
tissue samples due to the use of a cryoprobe—either 1.9 mm or 2.4 mm—and, thanks to the
Joule–Thomson principle, this procedure is performed [21] in intubated patients with deep
sedation or general anesthesia, has a high diagnostic yield (>70%), and an excellent safety
profile (adverse event rate lower than 20% and negligible mortality). TBLC is a technique
well-tolerated by patients, and is capable of providing large biopsy specimens, leading to
high-confidence diagnoses of UIP in about 50% of cases [22,23]. The literature highlights the
impact of integrating TBLC with MDT data, which increases the high-confidence diagnosis
of IPF from 16% to 63%, changing the first clinical-radiological diagnosis in 26% of cases.
Agreement between TBLC and SLB has been reported ranging from 38% to 70.8%, but it can
improve with the number of samples taken [24]. As postulated in the latest ERS guidelines
on TBLC in the diagnosis of ILDs [21], TBLC is recommended as the preferred method
when MDT evaluation requires the integration of histopathological data. If the first sample
is uninformative, rather than a repetition of it, it is indicated to perform an SLB as an
add-on test. In addition, it is recommended to discuss MDD before any type of procedure
to plan the biopsy and to evaluate the sample with a higher grade of accuracy. Although
TBLC has a lower diagnostic yield compared with SLB, the latest TBLC guideline suggests
this method as the first step in ILD diagnosis due to its lower adverse event rates, shorter
length of hospitalization, and lower costs, particularly if it is performed at experienced
centers. It is important to note that TBLC should be performed at expert centers due to
the potential risk of complications such as pneumothorax, bleeding, or exacerbation of IPF
in some classes of patients—such as massive emphysema, pulmonary hypertension, and
upper localization of lesions [1,2]. The higher level of diagnostic accuracy is associated
with the sampling procedure, particularly when executed from at least two different sites—
different segments of the same lobe or different lobes. This approach increases the chance
of identifying the ILD’s histologic heterogeneity, with a success rate of 92–96% when
two samples are taken. However, it is important to note that performing biopsies from
multiple sites also doubles the risk of pneumothorax—that at two sites is 24.6% vs. that
at one site is 15.2%—and tanking samples close to the pleura area (within 1 cm), where
the pathologic changes of IPF are most prominent [24]. TBLC increases its utility when
implemented by MDD, enabling the discussion of difficult cases and the interpretation
of histological samples by different experts including pulmonologists, radiologists, and
rheumatologists to improve the possibility of ILD diagnosis. Although TBLC is not as
effective as SLB in obtaining peripheral specimens, its diagnostic yield is comparable to that
of SLB, because subpleural and/or para-septal fibrosis are not critical criteria in making
Diagnostics 2023, 13, 2437 4 of 17

an IPF diagnosis [25]. However, despite its growing diffusion and expertise, skepticism
surrounding TBLC persists due to the lack of standardization and the need for larger
histologic samples for studying pathogenesis and molecular patterns [14,26].
When less invasive approaches fail, SLB is considered the reference standard. Typically
obtained thoracoscopically, SLB leads to larger samples that contain peripheral structures
of the secondary pulmonary lobule, resulting in a diagnostic yield of 90% [6,7]. In addition
to its significant costs and risks, including a mortality rate of around 2%, the use of SLB
is limited in advanced stages of the disease, elderly patients, and patients with multiple
comorbidities [1,2].
According to Montufar et al. [27] and Troy et al. [28], TBLC is suggested as a method
of choice compared with SLB, which remains the gold standard, especially when applied
in the context of MDD. On the other hand, the lack of a standard technique for TBLC
has led Lynch et al. [14] to consider SLB as a histologic tool for ILD diagnosis. Given the
heterogenous spectrum of ILDs, it is necessary to assess the optimal diagnosis approach for
different sampling modalities that need to be tailored to specific patients. An insightful
approach is proposed by Castillo et al. [29], suggesting the selection between the two
sampling techniques based on the clinical context. When HRCT central findings are
observed, patients’ lung function is compromised, and the bronchoscopy team has high
expertise, TBLC is recommended as a first option. Conversely, if peripherical lesions are
present, lung function is preserved, and a higher diagnostic yield is required, SLB should
be the first to be considered. Ultimately, it is also critical to consider the patient’s point
of view; their preference may lean towards undergoing an endoscopic procedure rather
than a surgical one. In the attempt of making an ILD diagnosis, instead of finding the
best method to obtain lung samples, it is critical to determine the best contest which uses
different techniques. The existing literature on SLB vs. TBLC still presents conflicting
evidence, as both approaches have their advantages and limitations.
When TBLC or SLB cannot be performed, histological diagnosis can be obtained via
video-assisted thoracic surgery (VATS) biopsy, which is an extremely invasive technique
requiring endotracheal intubation and mechanical ventilation. This sampling approach,
chosen based on multidisciplinary agreement, is associated with high morbidity (up to
30%) and mortality rate (up to 4%), particularly in elderly patients [30]. In recent years,
non-intubated VATS biopsy performed in awake subjects under loco-regional anesthesia
has slowly emerged as a safety technique with minimal complications for patients with
undetermined ILDs. This approach, compared with classical VATS, has a lower ratio
of complications (odds ratio for postoperative complications: 8.1, p = 0.011) and faster
recovery times. Also, it is associated with the use of anesthetics different than those for
muscle relaxants, the non-use of double-lumen tube intubation, and positive pressure
ventilation injuries [31]. In a recent review by Rossi et al. [32], which aimed to analyze
the differences between the two approaches, no statistically significant differences were
found regarding the identification of histopathological features. Although the width of
the biopsies is significantly deeper with traditional VATS (31.5 mm vs. 25.6 mm; p = 0.01),
both techniques have shown a diagnostic yield close to 100% (same biopsy length, average
number of sampled lobes, and mean number of slides). By contrast, awake VATS was
characterized by a higher level of diagnostic confidence (100% vs. 75%; p = 0.007) and
an older cohort of patients (69.5 vs. 64.5 years old; p = 0.02). In these cases, the choice
among the two approaches depends on the level of expertise of the thoracic surgeons
and anesthesiologists within the MDT. This evaluation, without sacrificing diagnostic
performance, should be considered a careful evaluation of the risk–benefit ratio for every
single patient, taking into account the disease severity, patient comorbidities, and the
increased mortality associated with potential acute exacerbations related to intubation.
However, due to the limited diffusion of the awake VATS, further studies are necessary
to validate its safety and efficacy.
On the basis of the data published by the INPULSIS study [4], which analyzed the
effect of nintedanib in reducing lung function decline in IPF patients, more recent studies
Diagnostics 2023, 13, 2437 5 of 17

such as the INBUILD and SENSCIS trials [33,34] investigated the benefits of the use of
antifibrotic agents across a range of progressive fibrotic lung diseases (PF-ILDs), including
unclassifiable ILD, fibrotic hypersensitive pneumonia (HP), fibrotic NSIP, IPAF, CTD-ILD,
and other less common fibrotic variants. PPF-ILDs represent a subset of fibrotic ILDs
sharing with IPF the disease’s natural course, characterized by radiological, functional,
and clinical evidence of progression over time despite therapy. According to the INBUILD
trial [33] and the 2022 ATS/ERS/ALAT/JRS IPF update [16], the definition of a PF-ILD
is an ILD other than IPF that has radiological evidence of pulmonary fibrosis, with at
least two of the following three criteria occurring within the past year: (i) worsening
respiratory symptoms, (ii) decline in forced vital capacity (FVC) ≥5 or diffusing capacity
of the lungs for carbon monoxide (DLCO) ≥10%, (iii) and/or radiological evidence of
disease progression.
Despite the PF-ILD usually requiring antifibrotic therapy, biopsy should also be
performed in an attempt to differentiate ILD subtypes, identifying patterns more prone to
progression, leading to earlier initiation of therapy, and helping to choose between starting
antifibrotic or immunosuppressive therapy in cases where both might be indicated, such
as fibrotic HP. According to the prognostic value of lung biopsy in the identification of
PF-ILDs, TBLC represents a valid alternative to SLB if performed at skilled centers, due to
its significantly lower morbidity and mortality [35].
Based on these findings, Wells et al. [36] highlighted the value of ‘lumping’ IPF with
other forms of PF-ILDs, in opposition to a ‘splitting’ approach with the ultimate goal of
precision medicine: in this context, it is still challenging to choose when to perform a biopsy,
considering each patient individually, mainly when MDD is not available.

3. Genomic Classifier and Its Role in Supporting MDD

Another topic covered by the latest IPF guidelines [16] was the recent introduction of
genomic classifier testing (GCT) to clinical use. This technique utilizes machine learning to
analyze the whole-transcriptome RNA sequencing and the gene expression patterns in lung
tissue samples obtained by transbronchial biopsy, thereby improving the diagnostic yield
of ILD [37,38]. By categorizing the presence or absence of diagnostic features, GCT enables
distinguishing UIP from non-UIP histopathology. This supports the MDT in making a more
confident diagnosis of IPF in patients without a definite UIP pattern on chest imaging.
A recent systematic literature review [39] estimated that GCT can differentiate UIP
and non-UIP histopathology with a sensitivity of 68% (95% Confidence Interval (CI),
55–73%) and a specificity of 92% (95% CI, 81–95%). This provides valuable support to
physicians and MDTs in confirming the diagnosis of UIP in patients without a definitive
radiologic pattern for UIP. Opposite to the diagnostic confidence improvement of a UIP
histopathology-predicted pattern using GCT, non-UIP histopathology prediction may
require further confirmation through SLB or TBLC due to the frequent occurrence of false-
negative results. Higher confidence in the diagnostic evaluation of ILD can be implemented
via the integration of GCT results with clinical and radiologic information in an MDD
context. Two different studies [38,40] have shown that the diagnostic accuracy of GCT
increases from 56% to 89% (agreement, k = 0.64) and from 43% to 93% (agreement, k = 0.75)
after MDT evaluation.
The integration of GCT into the MDD process increases diagnosis confidence levels,
particularly in cases where chest imaging shows an indeterminate UIP pattern or probable
UIP with confounding clinical factors—such as autoantibodies, ILD-associated medication,
and a history of environmental or work exposure. This integration increases the proportion
of IPF cases diagnosed from 31% to 92%. In a study by Kheir et al. [40], the addition of
GCT to the clinical and radiological data resulted in a mild increase ranging from 17% to
29% in the proportion of high-confidence diagnoses, despite a high overall agreement of
92% between the GCT and the final MDD of UIP or non-UIP. The combination of GCT with
TBLC can further improve the diagnostic yield in patients with a probable UIP pattern on
HRCT imaging, while TBLC alone may be used in cases with a confident non-UIP diagnosis.
Diagnostics 2023, 13, 2437 6 of 17

However, GCT implementation appears to be less beneficial when the HRCT scan shows
patterns inconsistent with UIP.
While additional studies are needed to define its precise accuracy due to the high
frequency of false-negative results, GCT provides important diagnostic information. When
integrated with clinical and radiological elements, it may reduce the need for additional and
more invasive sampling as SLB or TBLC. A review conducted by Richeldi et al. [41], which
analyzed the impact of radiological data integration in reducing false-negative results,
reported that GCT sensitivity increased from 60.3% to 79.2% when in conjunction with the
HRCT pattern of UIP.

4. MDD Inter-Observer Agreement

Since its institution in the assessment of ILDs, the MDA has been associated with
increased levels of diagnostic confidence and improved inter-observer agreement. The
effectiveness of this approach, which involves progressive improvement of a provisional
diagnosis through the integration of different data, has already been investigated in
the literature.
Flaherty et al. [11] conducted a study to assess the impact of an integrated expert ap-
proach in ILD and were the first to demonstrate that the integration of clinical, radiological,
and pathological data increases confidence in IPF diagnosis and improves inter-observer
agreement (0.39 vs. 0.88) compared with the first approach. Among all ILDs, IPF has the
highest level of diagnostic agreement between community and academic physicians.
Although limited to IPF diagnosis, Thomeer et al. [42] demonstrated that accuracy in
diagnosis is improved by higher levels of agreement between clinicians, even from different
European centers, improving accuracy at 87.2%.
In recent decades, due to the crescent development in radiology, HRCT has gradually
contributed an improved impact on MDD. In a study by Aziz et al. [43] involving 168 ILD
patients, after integrating HRCT data, they found that the clinician’s first-choice diagnosis
changed in 51% of cases, improving diagnostic accuracy. The diagnostic role of HRCT was
also confirmed by Travis’s [44] study, in which, among 105 biopsy-proven NSIP patients,
21 were disconfirmed after merging radiological data.
As mentioned earlier, although the literature shows that MDD improves diagnostic
agreement and accuracy in clinical practice compared with individual diagnoses made
by clinicians, radiologists, and histopathologists, there is still no established reference
standard. In his study, Walsh [45] highlighted the existence of significant discordance
between different MDTs that evaluated the same clinical, imaging, and histopathological
data [11,42]. Despite the dynamic integration of clinical, radiological, and pathological
data in the MDD process leading to improved diagnostic accuracy, Walsh’s study [45]
did not observe this improvement. This discrepancy may be attributed to the fact that
diagnostic accuracy was more frequently obtained by radiologists and pathologists who,
in that particular study, did not have access to clinical data. Consequently, the diagnostic
process relied on pattern interpretation, resulting in increased confidence but not necessarily
improved accuracy [11].

5. MDD as a Tool in the Dynamic Process of Diagnosis

The 2018 Fleischner Society statement [14] endorsed the concept of progressive and
dynamic integration of clinical, radiological, and pathological data, emphasizing the need to
re-evaluate previous diagnoses based on disease progression and therapy response, which
may lead to changes to the initial diagnosis. The available literature [11,46] has shown that
MDD results in a change in diagnosis in 40% to 53% of cases. Ageely et al. [47] confirmed
that MDD provided a new diagnosis or modified a preexisting diagnosis in 37% of the
cases when compared with the diagnosis pre-MDD. The study reported a 41% concordance
rate between pre-MDD and MDD, with the highest level of agreement observed in IPF
diagnosis (81%). In contrast to IPF, due to the lack of consensus of diagnostic criteria and
Diagnostics 2023, 13, 2437 7 of 17

evidence-based guidelines, the concordance rate for HP diagnosis was low, and a relatively
high proportion of cases referred to as HP were previously deemed as unclassifiable ILD.
In this context, the concept of a “working diagnosis” has emerged, allowing for the
justification of disease-specific therapy even in the absence of a definite diagnosis, re-
evaluating the case in the following controls [48]. While strict adherence to guidelines
maximizes diagnostic accuracy, in clinical practice it may lead to delays in diagnosis and
treatment when dealing with unclassifiable cases. Nowadays, if diagnostic criteria are not
fully met for a confident ILD diagnosis, the integration of data and expert evaluation may
result in a provisional diagnosis with a high level of confidence, guiding the diagnostic and
therapeutic process. Cases that cannot reach a confident or provisional diagnosis even after
expert MDD are considered unclassifiable ILD, a category endorsed in the 2013 updated
classification [13]. The incidence rates of unclassifiable ILD vary from 10% to 44%, reflecting
large variability that can be explained by inconsistent definitions [46,49]. In Ageely et al.’s
study [47], it was found that 12% of the patients who did not fulfill diagnostic criteria
received a provisional diagnosis that was useful to their management. In 21% of cases, ILD
was defined as unclassifiable due to a lack of histopathological data at first assessment,
being diagnosed after MDD review by a subsequent biopsy.
To standardize the heterogeneous terminology, Ryerson et al. [50] proposed the sub-
classification of the ILD diagnosis probability into “confident”, “provisional”, and “unclas-
sifiable ILD” categories based on the degree of diagnostic confidence (>90%, between 89
and 50%, and <50%, respectively). The implications of using these terms on the decision
to perform a biopsy or initiate a specific therapy were shown in an international study
involving 404 clinicians who evaluated 60 cases of suspected IPF. The findings revealed an
attitude that deviates from current guidelines. In cases where there was a provisional high
level of confidence in the IPF diagnosis, only a minority of patients (29.6%) underwent SLB.
Instead of a definite diagnosis as defined by current guidelines, a “working diagnosis” ap-
proach was adopted, leading to the prescription of antifibrotic therapy without performing
a biopsy in 63% of patients with a diagnostic likelihood of 70%, as well in 63% and 41.5% of
cases with provisional high confidence and low confidence IPF diagnoses, respectively [51].
Around 10% of patients presenting with a not-definite HRCT UIP pattern cannot undergo
SLB due to factors such as advanced age, advanced disease, or poor clinical conditions.
These patients do not fall into any specific diagnostic category and, therefore, do not
have access to the available treatments. In such cases, less-invasive procedures like
TBLC are available, providing high diagnostic confidence when performed by skilled
physicians [52].
In some cases, more than one MDD meeting is needed to reach a diagnosis, as reported
by De Sadeleer et al. [46]. The literature data suggest that considering atypical cases as “not
yet classified”, rather than unclassifiable ILD, as a definite diagnosis may only be achieved
through clinical, radiologic, and histopathologic data. This highlights the importance of a
dynamic approach to ILD patients. An exception is represented by cases in which a specific
guideline-based diagnosis may never be achieved, such as if SLB is contraindicated due
to factors such as advanced age, advanced disease, or comorbidities. This emphasizes the
importance of early referral to centers with high ILD expertise, particularly for patients
with initial unclassifiable diagnoses who require additional diagnostic tests and lung biopsy.
MDD meetings also play a crucial role in changing patient management, including the
initiation or discontinuation of therapy, as shown in 39% of patients in the Ageely study [47].
It is worth noting that management was changed in 46% of patients, even for those with
high-concordant pre-MDD and MDD. This emphasizes the central role of expert opinion
not only in making a diagnosis, but also in drawing up an appropriate treatment—such
as anti-fibrotic drugs for IPF or progressive fibrotic ILDs and immunosuppressive/anti-
inflammatory therapy for non-fibrotic ones.
The introduction of disease behavior in the diagnostic process within guidelines
obliges the MDD group to revise, confirm, and, in boundary cases, reformulate diagnoses,
leading to increased confidence [14]. Although ILD diagnosis can change over time owing
Diagnostics 2023, 13, 2437 8 of 17

to emerging clinical or serological results, there are only a few studies that have analyzed
the role of MDD in follow-up and response to therapy. In a retrospective study [53]
that evaluated 56 patients over 7 months of follow-up, it was found that dynamic re-
evaluation of new clinical data or HRCT patterns can modify the initial MDD diagnosis
in 10.7% of cases, or the level of agreement in 25% of cases, highlighting the need for
continued expert meetings during the follow-up phase. Despite the growing importance
of MDD, the Australian IPF Registry (AIPFR) [54] has shown that in 23% of cases, IPF
guidelines were not followed by referring physicians. Following MDD of 93 ILD patients,
the diagnosis was changed in 53% of cases, and 71% of unclassifiable diseases were
reclassified, significantly impacting the therapeutic approach and leading to an increase
in antifibrotic drugs.
While MDD is globally recognized for its utility in making a final diagnosis, there is
no reference standard available to measure its validity. Notably, the majority of MDD eval-
uations concern only the diagnosis aspect, whereas therapeutic and disease management
decisions are still often made by a single physician, typically the clinician who resolved the
diagnostic uncertainty, and, frequently, is the pulmonologist alone [55,56].

6. MDD’s Role in Evaluating Prognosis

The role of MDD in evaluating prognosis was demonstrated by De Sadeleer [46] in
a large study involving 938 patients, where the diagnosis was reached in 79.5% of cases,
modified in 41.9% of cases after MDD, and not achieved only in 19.5% of the patients. This
suggests that further investigations were required in 16% of the total cohort. In this study,
IPF patients demonstrated a worse prognosis than those diagnosed as non-IPF after MDD
[Hazard ratio (HR) 4.31, p < 0.001]. However, patients who were initially identified as
IPF but had a change in their diagnosis after expert discussion showed a better prognosis
compared with those diagnosed as IPF (HR 0.37, p = 0.094) [43]. In another study by
Nakamura et al. [57], among 33 patients initially identified as unclassifiable-ILD, MDD
confirmed the initial diagnosis in 54.5% of cases, changing the diagnosis in the remaining
ones. The IFIGENIA trial [42], a randomized placebo-controlled trial conducted on IPF
patients, in which N-Acetylcysteine was associated with azathioprine plus steroid therapy,
cases diagnosed as IPF by clinicians alone were disproved in 12.8% of cases after discussion
with thoracic radiologists and expert pathologists.
The literature indicates that MDD is considered effective at achieving a first-choice
diagnosis for both IPF and CTD-ILD with good agreement (κ = 0.60 and κ = 0.64, respec-
tively), but fair for idiopathic NSIP and HP (κ = 0.25 and κ = 0.24, respectively). However,
this lack of confidence is related to the absence of defined classification criteria available
for such diseases [45]. As mentioned before, besides the diagnostic process, MDD should
be performed to evaluate disease prognosis in particular conditions. For example, in a
study involving 47 IPF patients who underwent MDD including SLB, the integration of
different data allowed for the identification of negative prognostic factors for survival [58].
MDD can also be applied to select the appropriate drug and related timing therapy. In
a cohort of patients with CTD-ILD, Kalluri [59] highlighted the higher level of clinician
participation in managing their disease compared with IPF patients who received care
within a single setting.
Table 1 shows the evidence summarized of how MDD can change the initial diagnosis
by integrating clinical, radiological, and pathological data.
Diagnostics 2023, 13, 2437 9 of 17

Table 1. The impact of MDD on changing the final diagnosis.

Study Change in Diagnosis after MDD

Aziz et al. [43] 51.0%
Ageely et al. [47] 37.0%
Kondoh et al. [15] 50.0%
Jo et al. [54] 53.0%
De Sadeleer et al. [46] 41.9%
Nakamura et al. [57] 45.5%
Thomeer et al. [42] 12.8%
Han et al. [53] 10.7%
Castelino et al. [60] 28.0%
Levi et al. [61] 50.4%
MDD: Multidisciplinary discussion.

7. MDD in Evaluating HP
Among all ILDs, HP is particularly challenging to diagnose, as it requires the integra-
tion of anamnestic, clinical, radiological, and histopathological data. HP is an immune-
mediated disease that affects the lungs of susceptible individuals after repeated exposure
in time to identified or unidentified inciting agents, such as organic powders and low-
molecular-weight chemical particles. Differentiating HP from other ILDs can be extremely
challenging due to the highly variable clinical, radiological, and histopathological features
of HP, as well as the overlap with those belonging to other ILDs, and shearing features
of other acute and chronic pulmonary diseases [62]. The identification of clear inhalation
exposure, in particular in cases of fibrotic/chronic disease, can be challenging. Therefore,
the latest ATS/JRS/ALAT HP guidelines [63] emphasize the role of an MDT that includes
a clinician, a radiologist, and a pathologist, who work together to integrate data from
multiple domains to achieve an accurate diagnosis.
The diagnosis of HP requires a multidisciplinary approach involving clinical, radi-
ological, and, in some cases, lymphocytosis on bronchoalveolar lavage (BAL) fluid or
histopathological data. In addition to the CHEST guidelines [64] criteria for HP diagnosis—
which include a clinical history of exposure to a potential antigen and a typical HP pattern
on HRCT scan—according to the ATS/JRS/ALAT guidelines [63] a confident diagnosis of
HP requires evidence of BAL lymphocytosis. Both guidelines emphasize the critical role
of MDD in the diagnostic management of HP via the integration of clinical, anamnestic,
radiologic, and BAL data. The ATS/JRS/ALAT guidelines [63] highlight that BAL should
be performed along with exposure history and an HRCT scan before MDD. On the other
hand, the CHEST guidelines [64] suggest performing this technique only after an MDD of
clinical and radiological data, avoiding performing it in those cases that have a high pre-test
probability of HP. In contrast to typical HP cases, in which a confident diagnosis can be
achieved by avoiding the lung biopsy performance, in patients who have a suspicion of HP
but atypical features a lung sample is suggested, considering the individual risk–benefit
ratio. Particularly due to the extensive overlap between fibrotic HP and IPF, it is challenging
to achieve a confident diagnosis and consequent early management. Guler et al. [65] have
highlighted the validity of MDD as the reference standard for the diagnosis of fibrotic HP.
MDD is associated with a stronger prognostic value and plays a crucial role in diagnostic
decision-making in complex cases.

8. MDD in Evaluating CTD-ILDs

CTDs, including rheumatoid arthritis (RA), systemic lupus erythematosus (SLE),
inflammatory idiopathic myopathies (IIMs), Sjögren’s syndrome (SS), systemic sclerosis
(SSc), and mixed connective tissue disease (MCTD), encompass a wide spectrum of systemic
Diagnostics 2023, 13, 2437 10 of 17

autoimmune disorders that share common underlying mechanisms of pathogenesis. Due

to their frequent multiorgan involvement, each CTD may show lung parenchymal damage
before or during the disease. This is particularly notable in myositis spectrum disorders
such as any-synthetase syndrome (ASS), where ILD may manifest as the predominant or
sole feature in 10–30% of cases of ILD [66]. However, the identification of the etiology
at the base of this lung involvement is extremely difficult due to the overlapping clinical
characteristics, serology, and radio-histological patterns. Despite some radiological patterns
such as NSIP or organizing pneumonia (OP) being more typical of CTD-ILD, a definite UIP
pattern does not exclude an underlying autoimmune disease, which is frequently observed
in RA and rarely in SSc [67].
Although there are no definite recommendations for CTD-ILD diagnosis due to its
highly heterogeneous presentation, the first attempt to standardize a diagnostic process
was made by the Thoracic Society of Australia and New Zealand [68]. They introduced
the concept of an MDA involving a respiratory clinician, radiologist, pathologist, and
rheumatologist to achieve the best possible outcome by avoiding invasive procedures such
as lung sampling and increasing diagnostic confidence. As highlighted by the study of
Møller et al. [69], an MDA is crucial to establishing a confident diagnosis in CTD-ILDs,
in particular in those cases presenting with an NSIP pattern. Their retrospective analysis
demonstrated that the diagnosis was changed in a statistically significant number of patients
after MDD evaluation, leading to the classification of 25.8% of cases previously identified
as iNSIP.
The ATS/ERS/JRS/ALAT guidelines [16] for IPF diagnosis have reinforced the con-
cept of an MDD evaluation for ILDs. These guidelines have emphasized the need to
exclude CTD-related lung involvement and recommend the involvement of radiologists,
pathologists, pulmonologists, and, if necessary, rheumatologists, in the MDT to improve the
diagnostic agreement. Notably, the current IPF guidelines routinely recommend perform-
ing the independent serological test as C-reactive protein (CRP), erythrocyte sedimentation
rate (ESR), antinuclear antibodies (ANA), rheumatoid factor (RF), myositis panel, and
anti-cyclic citrullinated peptide (ACPA), and consulting a rheumatologist in the case of
positivity of those serological tests or if there are clinical manifestations suggesting an
underlying rheumatological disease—such as females younger than 60 years [70]. In cases
of suspected CTD-ILDs, further investigation should be carried out based on the clinical
suspicion of a rheumatologist, which may involve additional tests such as biochemical
screening (including autoantibodies), capillaroscopy, or ultrasound. Another scenario in-
volves ILD patients with indeterminate HRCT UIP patterns, which are frequently observed
during CTD. In such cases, before performing additional tests such as capillaroscopy or
ultrasound, a screening test including ANA, RF, ACPA, and creatine phosphokinase (CPK)
dosage should be performed [71].
Another diagnostic challenge arises with IPAF, which is a relatively newly character-
ized nosological entity. IPAF refers to an ILD where clinical or serological abnormalities
typical of CTD are present but insufficient to satisfy the classification criteria of a defined
autoimmune disease. Without a rheumatologic evaluation, there is a risk of misclassifying
these patients [72]. The importance of an MDA is also expressed by the same definition
of IPAF. The diagnosis of IPAF is based on radiological and/or histological identification
of ILD in the absence of precise etiology, having excluded other CTDs, and presenting at
least two of three clinical, serological, or morphological domains [73]. This recent proposal
of classification criteria for IPAF represents an effort to underline the need to involve a
rheumatologist in the MDT, especially in helping to diagnose lung involvement associated
with a clear underlying CTD or with autoimmune features [13,74].

9. MDT Composition and Timing

Despite the importance of MDD, there are no indications about the optimal compo-
sition of the expert team or the timing of these meetings. Typically, the MDT for ILDs
includes a pulmonologist, a radiologist, and a pathologist, all of whom are experts in ILDs.
Diagnostics 2023, 13, 2437 11 of 17

Depending on the cases, other physicians like specialists in rheumatology, thoracic surgery,
lung transplantation, and occupational medicine can be involved. The level of expertise
among participants determines the frequency of these meetings [46]. The current gold
standard for ILD diagnosis is a dynamic integrated process that requires direct interaction
between clinicians, radiologists, and pathologists when an SLB is available [11].
A multidisciplinary approach to palliative care, involving ILD experts, a palliative
respiratory care expert, a nurse, a respiratory therapist, a physiotherapist, and a dietitian is
effective compared with the standard approach, which typically involves ILD experts and a
nurse only. This comprehensive approach results in improved efficacy in the management
of patients, in terms of a reduced number of emergency visits and hospital admissions [59].
Another substantial difference in clinical practice, compared with the ERS/ATS guide-
lines [16], is the role of the rheumatologist during ILD evaluation. According to these
guidelines, the presence of a rheumatologist in MDD meetings is not mandatory for every
newly identified ILD. Instead, their involvement is restricted to cases with positive autoan-
tibodies tests, suspected CTD clinical manifestations, or in cases with unusual features of
IPF, such as female sex, age younger than 60 years, and absence of tobacco habit. The en-
gagement of a rheumatologist expert among MDD participants could be useful to identify
systemic clinical manifestations, particularly in patients with clinical and histopathological
features inconsistent with IPF. Even though one in five ILD cases can be related to CTD,
a systematic evaluation [75] of diagnostic ILD practices conducted in 2019 showed that
only 37.1% of MDT cases include a rheumatologist, indicating a significant impact on the
final diagnosis. Despite current IPF guidelines, the involvement of a rheumatologist in
the diagnostic process is entrusted by the experience of the individual pulmonologist. A
study by De Lorenzis et al. [76] emphasized the importance of a collegial discussion of
challenging cases of CTD-ILDs. Such discussions when including a rheumatologist could
add some important details overlooked by the evaluation of the pulmonologist alone.
This multidisciplinary approach can increase confidence in the diagnosis and enhance the
therapeutic management of the patient.
Chartran’s retrospective study [77] highlighted the role of the rheumatologist in the
MDT for ILD patient evaluation. The study found that the initial IPF diagnosis was often
changed after MDD, particularly after the identification of specific autoimmune antibod-
ies. The authors underlined the need to extend the screening of autoimmune profiles
because about one-third of the patients were ANA-negative and not all cases presented
systemic manifestations. Another retrospective observational study [60] involving 50 pa-
tients showed that MDD led to a final diagnosis of CTD-ILD in 25 patients, 7 of whom were
initially identified as IPF with completely different prognostic and therapeutic implications.
In a prospective study [61] of 60 patients, where the MDT also included a rheumatologist,
21.9% of IPF cases and 28.5% of HP cases showed their diagnosis modified, favoring CTD
disease and avoiding invasive procedures such as bronchoscopies and lung biopsy. Despite
the evidence in the literature, there is a lack of clear guidance on the timing of rheuma-
tologist involvement during multidisciplinary meetings, in particular during ILD-CTD or
IPAF evaluation.
Although MDD represents the gold standard in ILD diagnosis, it is not always practi-
cable in a clinical routine because of a lack of skilled experts or difficulties in organizing
meetings due to the geographical distance between the participants or time-related limita-
tions. Fujisawa et al. [78] emphasized the role of validated digital platforms, which allow
easier access to various data via the Web. Their study involving 465 ILD patients showed
that MDD could reformulate the initial diagnosis in 49% of cases. Table 2 provides an
overview of the progression and development of the MDD concept over the years according
to different guidelines.
Diagnostics 2023, 13, 2437 12 of 17

Table 2. Evolution of the MDD process according to guidelines.

Document Year ILD Type Changes in the Diagnostic Process

MDD: for IPF replacement of histology via the
integration of clinical and radiological typical data
ATS/ERS Multidisciplinary consensus
2001 IIP MDT: pulmonologists, radiologists,
classification of the IIPs [5]
and pathologists
Aim: diagnosis as a dynamic process
MDD: in all ILDs, in particular in differencing
An official ATS/ERS statement: update of the
NSIP from HP, in coexisting patterns, in rare
international multidisciplinary classification of 2013 IIP
histologic patterns, and unclassifiable IIP
the IIPs [13]
Aim: when to perform a biopsy; disease behavior
MDD: integration of clinical, serological, and
An official ERS/ATS research statement: morphological domains
2015 IPAF
IPAF [11] MDT: clinic, radiologist, pathologist,
and rheumatologist
MDD: in case of atypical characteristics or features
related to non-IPF etiology
MDD: clinician, radiologist, and pathologist;
rheumatologist can be helpful
Diagnostic criteria for IPF [14] 2018 IPF
MDT timing and place: weekly/monthly; direct
or telemedicine
Aim: diagnosis, management, and revaluation
over time
MDD: in patients with atypical exposure history,
radiological features, or cellularity on BAL;
histopathological sampling should be made after
Diagnosis of HP in Adults: An Official
2020 HP MDD in low/moderate confidence diagnosis
ATS/JRS/ALAT Clinical Practice Guideline [63]
MDT: clinician, radiologist, and pathologist
Aim: diagnosis and re-evaluation based on
additional clinic/pathologic data
MDD: BAL is not mandatory in the diagnosis, but
should be performed after MDD in patients with
Diagnosis and Evaluation of HP: CHEST low/moderate test probability of HP; lung samples
2021 HP
Guideline and Expert Panel Report [64] should be made after MDD in atypical cases
Aim: confident diagnosis avoiding
invasive procedures
MDD: face-to-face discussion between experts
integrating clinical, radiological, histopathological,
Diagnosis and management of CTD-ILDs in
and serological data
Australia and New Zealand: A position
2021 CTD-ILD MDT: respiratory physicians, radiologists,
statement from the Thoracic Society of Australia
pathologists, immunologists, and rheumatologists
and New Zealand [68]
Aim: confidence diagnosis avoiding
invasive procedures
MDD: IPF diagnosis for UIP or possible UIP HRCT
IPF (an Update) and Progressive Pulmonary
pattern in the appropriate clinical setting without
Fibrosis in Adults: An Official
2022 IPF and PPF confirmation via lung biopsy
ATS/ERS/JRS/ALAT Clinical Practice
Aim: diagnosis with less invasive procedures and
Guideline [16]
working diagnosis
MDD: multidisciplinary diagnosis, ILD: interstitial lung disease, ATS: American Thoracic Society, ERS: Eu-
ropean Respiratory Society, IIP: idiopathic interstitial pneumonia, IPF: idiopathic pulmonary fibrosis, MDT:
multidisciplinary team, NSIP: non-specific interstitial pneumonia, HP: hypersensitive pneumonia, IPAF: idio-
pathic pneumonia with autoimmune features, JRS: Japanese Respiratory Society, ALAT: Latin American Thoracic
Society, BAL: bronchoalveolar lavage, CTD: connective tissue disease, UIP: usual interstitial pneumonia, HRCT:
high-resolution chest tomography.
Diagnostics 2023, 13, 2437 13 of 17

10. Conclusions
According to the common symptoms and frequent overlapping of radiological and/or
histological data, the importance of multidisciplinary management of ILDs has gradually
become more evident over the years. Based on the integration of clinical, radiological,
histopathological, and often serological data, an MDA improves the accuracy and reliability
of ILD diagnosis, reducing the need for invasive procedures such as SLB or TBLC. In
challenging cases that require histologic data, such as when faced with the presence of an
indeterminate or inconsistent HRCT UIP pattern, the MDT plays a crucial role in selecting
the most suitable technique (SLB or TBLC) with the best diagnostic yield and minimal
invasiveness, thereby reducing the risk of side effects. After the evaluation of integrated
clinical and radiological elements, TBLC is suggested as the first option in central lesions
with compromised lung functions only in centers with high expertise, while SLB remains
the gold-standard technique for peripherical lesions and preserved lung function. Further
studies are required to evaluate the diagnostic yield and the risk profile associated with
awake/non-intubated VATS biopsy.
The MDD of ILDs should not be considered a static process, but a working diagnosis,
based on the progressive integration of clinical, radiological, and pathological data available,
allowing for the initiation of a specific therapy even with a diagnosis of probability. The
periodic evaluation of the disease progression and the response to therapy increase the
accuracy of diagnosis, confirming or modifying the therapy and ensuring optimal patient
care and outcomes.
Since its institution for IPF diagnosis due to its high level of diagnostic confidence
and inter-observer agreement, MDD has progressively expanded to other ILDs, replacing
histopathology as the diagnostic gold standard. In recent years, the literature has empha-
sized the importance of an MDA in the diagnosis of ILDs other than IPF, such as HP or
CTD-ILDs, defining the composition of the MDT. Notably, the absence of evidence-based
diagnostic guidelines in non-IPF ILDs contributes to a certain level of disagreement in MDD.
In this context, more studies are required to confirm the role of MDD in the diagnostic and
therapeutic management of ILDs.

Author Contributions: A.S.Z. had the concept for this review, revised the manuscript, approved the
submitted version, and served as the corresponding author. S.S.Z. wrote the review and organized the
work. M.B. revised the manuscript and approved the submitted version. A.S.Z., M.B. and S.S.Z. are
responsible for the overall content as guarantors. All authors have read and agreed to the published
version of the manuscript.
Funding: This research received no external funding.
Institutional Review Board Statement: Not applicable.
Informed Consent Statement: Not applicable.
Data Availability Statement: No new data were created or analyzed in this study. Data sharing is
not applicable to this article.
Conflicts of Interest: The authors declare no conflict of interest.

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