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Summary
Background Diffuse parenchymal lung disease represents a diverse and challenging group of pulmonary disorders. Lancet Respir Med 2016;
A consistent diagnostic approach to diffuse parenchymal lung disease is crucial if clinical trial data are to be applied 4: 557–65
to individual patients. We aimed to evaluate inter-multidisciplinary team agreement for the diagnosis of diffuse Published Online
May 11, 2016
parenchymal lung disease.
http://dx.doi.org/10.1016/
S2213-2600(16)30033-9
Methods We did a multicentre evaluation of clinical data of patients who presented to the interstitial lung disease See Comment page 529
unit of the Royal Brompton and Harefield NHS Foundation Trust (London, UK; host institution) and required Department of Radiology
multidisciplinary team meeting (MDTM) characterisation between March 1, 2010, and Aug 31, 2010. Only patients (S L F Walsh MD), King’s College
whose baseline clinical, radiological, and, if biopsy was taken, pathological data were undertaken at the host Hospital NHS Foundation
institution were included. Seven MDTMs, consisting of at least one clinician, radiologist, and pathologist, from Trust, London, UK
(S R Desai MD); Interstitial Lung
seven countries (Denmark, France, Italy, Japan, Netherlands, Portugal, and the UK) evaluated cases of diffuse Disease Unit (Prof A U Wells MD,
parenchymal lung disease in a two-stage process between Jan 1, and Oct 15, 2015. First, the clinician, radiologist, M A Kokosi MD) and
and pathologist (if lung biopsy was completed) independently evaluated each case, selected up to five differential Department of Radiology
diagnoses from a choice of diffuse lung diseases, and chose likelihoods (censored at 5% and summing to 100% in (Prof D M Hansell FRSM), Royal
Brompton and Harefield NHS
each case) for each of their differential diagnoses, without inter-disciplinary consultation. Second, these specialists Foundation Trust, London, UK
convened at an MDTM and reviewed all data, selected up to five differential diagnoses, and chose diagnosis (J Jacob FRCR); Department of
likelihoods. We compared inter-observer and inter-MDTM agreements on patient first-choice diagnoses using Diseases of the Thorax
Cohen’s kappa coefficient (κ). We then estimated inter-observer and inter-MDTM agreement on the probability of (Prof V Poletti MD) and
Department of Radiology
diagnosis using weighted kappa coefficient (κw). We compared inter-observer and inter-MDTM confidence of (S Piciucchi MD), GB Morgagni
patient first-choice diagnosis. Finally, we evaluated the prognostic significance of a first-choice diagnosis of Hospital, Forlì, Italy;
idiopathic pulmonary fibrosis (IPF) versus not IPF for MDTMs, clinicians, and radiologists, using univariate Cox Department of Surgical
regression analysis. Pathology, Morgagni
Pierantoni Hospital, Forlì, Italy
(A Dubini MD); Université Paris,
Findings 70 patients were included in the final study cohort. Clinicians, radiologists, pathologists, and the MDTMs Sorbonne Paris Cité, EA2363
assigned their patient diagnoses between Jan 1, and Oct 15, 2015. IPF made up 88 (18%) of all 490 MDTM first- Réponses cellulaires et
fonctionnelles à l’hypoxie,
choice diagnoses. Inter-MDTM agreement for first-choice diagnoses overall was moderate (κ=0·50). Inter-MDTM
Bobigny, France
agreement on diagnostic likelihoods was good for IPF (κw=0·71 [IQR 0·64–0·77]) and connective tissue disease- (Prof H Nunes MD,
related interstitial lung disease (κw=0·73 [0·68–0·78]); moderate for non-specific interstitial pneumonia (NSIP; Prof D Valeyre MD,
κw=0·42 [0·37–0·49]); and fair for hypersensitivity pneumonitis (κw=0·29 [0·24–0·40]). High-confidence diagnoses Prof P Y Brillet MD); Assistance
Publique-Hôpitaux de Paris,
(>65% likelihood) of IPF were given in 68 (77%) of 88 cases by MDTMs, 62 (65%) of 96 cases by clinicians, and in
Service de Pneumologie
57 (66%) of 86 cases by radiologists. Greater prognostic separation was shown for an MDTM diagnosis of IPF than (Prof H Nunes, Prof D Valeyre),
compared with individual clinician’s diagnosis of this disease in five of seven MDTMs, and radiologist’s diagnosis of Service de Radiologie
IPF in four of seven MDTMs. (Prof P Y Brillet), and Service
d’Anatomie Pathologique
(M Kambouchner MD), Hôpital
Interpretation Agreement between MDTMs for diagnosis in diffuse lung disease is acceptable and good for a diagnosis Avicenne, Bobigny, France;
of IPF, as validated by the non-significant greater prognostic separation of an IPF diagnosis made by MDTMs than Serviço de Pneumologia
the separation of a diagnosis made by individual clinicians or radiologists. Furthermore, MDTMs made the diagnosis (Prof A Morais MD) and
Pathology Department
of IPF with higher confidence and more frequently than did clinicians or radiologists. This difference is of particular
(C Souto Moura MD), Centro
importance, because accurate and consistent diagnoses of IPF are needed if clinical outcomes are to be optimised. Hospitalar São João, Porto,
Inter-multidisciplinary team agreement for a diagnosis of hypersensitivity pneumonitis is low, highlighting an urgent Portugal (J M Pereira MD);
need for standardised diagnostic guidelines for this disease. Faculdade de Medicina,
Universidade do Porto, Porto,
Portugal (Prof A Morais);
Funding National Institute of Health Research, Imperial College London.
diffuse parenchymal lung disease in place with versus individual specialists, we compared the mortality
consistent attendance by at least one clinician, of each team’s diagnosis of IPF. We compared diagnoses
radiologist, and pathologist. For the retrospective by separating the entire cohort into a binary IPF diagnosis
examination of clinically indicated data, the institutional category (IPF [if first-choice diagnosis for a patient is
ethics review board of Royal Brompton and Harefield IPF] and not [if first-choice diagnosis is of another cause])
NHS Foundation Trust waived the need for informed for each MDTM, clinician, and radiologist, based on
patient consent. assigned diagnoses. Pathologist diagnoses are not shown
due to small number of cases (appendix). We calculated
Evaluation of cases the survival period for each patient from the date of
The evaluation of every case took place in two stages referral to the host institution to the minimum of date of
between Jan 1, and Oct 15, 2015. At first, clinicians, death, date the patient was last known to be alive, or
radiologists, and pathologists had to review the cases June 1, 2015 (end of the study period). We obtained vital
independently without interspecialty consultation. status for every patient on June 1, 2015, by evaluating
Clinicians had access to all the presenting clinical their electronic patient record.
information (age, sex, smoking history, history of
established connective tissue disease, symptoms Statistical analysis
[including those suggestive of connective tissue disease], We used Cohen’s kappa coefficient (κ) to evaluate
autoantibody profile, exposure history, drugs at inter-observer and inter-MDTM agreement for patient’s
presentation, bronchoalveolar lavage result [if done], first-diagnosis. We used Cohen’s weighted-kappa
and angiotensin converting enzyme concentration [if coefficient (κw) to evaluate inter-observer agreement and
assessed]), pulmonary function tests, and high-resolution inter-MDTM agreement for an estimation of the probability
CT (no access to the original high-resolution CT report or of each diagnosis. We converted the percentage diagnostic
the pathology result). Radiologists and pathologists had likelihood given for each diagnosis to a five point scale
access to only the age, sex, and smoking history for the (0–4), representing clinically useful probabilities (0 for
patient, and the high-resolution CT (radiologist) or condition not included in the differential diagnosis; 1 for
digitalised surgical lung biopsy slides (pathologist) taken low probability [5–25%]; 2 for intermediate probability
at presentation. Pathologists had access to all pathology [30–65%]; 3 for high probability [70–95%]; and 4 for
data that were available in the form of digitalised slides pathognomonic [100%]). For example, if the differential
(in .svs format), which were viewed using Aperio diagnoses given by an MDTM were IPF
ImageScope (version 12.3) viewing software. This digital (65% diagnostic likelihood), non-specific interstitial
viewing application has all the imaging functionality pneumonia (NSIP; 25% diagnostic likelihood), and
normally available to pathologists in routine clinical hypersensitivity pneumonitis (10% diagnostic likelihood),
practice and the host institution uses it to evaluate cases the probability grades would be 2 for IPF, 1 for NSIP, and
referred from outside institutions for additional opinions. 1 for hypersensitivity pneumonitis. We calculated weighted-
For each patient, observers (clinicians, radiologists, kappa coefficient values between paired observers (for
and pathologists) had to select up to five differential statements of inter-observer agreement), and between
diagnoses and provide a diagnostic likelihood (censored paired multidisciplinary teams (for statements of inter-
at 5% increments and summing to 100% in each case) MDTM agreement), which were expressed as median
from a drop-down menu of diffuse lung diseases (IQR) values for all unique combinations of pairs (21 for
(appendix). The only stipulation was that diagnoses were seven observers or seven multidisciplinary teams). See Online for appendix
considered in the context of the current 2013 version of Weighting of the kappa coefficient allowed us to quantify
the ATS/ERS classification and terminology for idiopathic the extent of disagreement, by assigning greater emphasis
interstitial pneumonias.8 to large differences between scores. Weighted-kappa
Once the cases had been reviewed independently, the coefficients were categorised as poor (0<κw≤0·20), fair
clinician, radiologist, and pathologist convened as a (0·20<κw≤0·40), moderate (0·40<κw≤0·60), good
multidisciplinary team to review the cases together and (0·60<κw≤0·80), and excellent (0·80<κw≤1·00). This
provide up to five diagnoses with diagnostic likelihoods approach has been used in previous investigations9,11 of
(also censored at 5% increments and summing to inter-observer agreement for diagnosis in diffuse lung
100% in each case). All clinical information supplied in diseases.
the first stage, including pulmonary function tests, Additionally, for each patient the first-choice diagnosis
high-resolution CT at presentation and digitalised was considered low confidence (diagnostic likelihood
surgical lung biopsy slides were available to the <70%) or high confidence (diagnostic likelihood ≥70%).
multidisciplinary team. These categories were based on the diagnostic likelihood
In this study we aimed to evaluate inter- categories used to assess the clinical probability of
multidisciplinary team agreement for the diagnosis of pulmonary embolism in the PIOPED study.12
diffuse parenchymal lung disease. To validate the We used univariate Cox regression analysis to identify
diagnosis made by the MDTMs at the seven centres associations between mortality and MDTM, clinician,
and radiologist diagnoses in terms of IPF versus not IPF. Role of the funding source
Reported hazard ratios (HRs) are for diagnosis of IPF The funders of the study had no role in study design,
versus not IPF. We tested the assumptions of proportional data collection, data analysis, data interpretation, or
hazards by visual inspection of the log–log plot of writing of the report. The corresponding author had full
survival, comparison of the Kaplan-Meier observed access to all of the data in the study and had final
survival curves with the Cox predicted curves for the responsibility for the decision to submit for publication.
same variable, and graphical and formal analysis of
Schoenfeld residuals (analysis not shown). Results are Results
reported as HRs, 95% CIs, and p values, and are We identified 113 consecutive new patient referrals, who
graphically shown as Kaplan-Meier survival curves. We required local MDTM characterisation, from the clinical
completed statistical analyses using Stata (version 12; database of the host institute between March 1, 2010, and
StataCorp, College Station, Texas). Aug 31, 2010. We excluded 43 (38%) of 113 referrals on the
basis that their initial work-up high-resolution CT scan
(29 patients), lung function (four patients), or surgical
Patients (n=70)
lung biopsy (ten patients) were completed by the referring
Age (years) 60·9 (15·5) institution (appendix). The remaining 70 (62%) of
Sex 113 patient referrals were included as the final study
Men 24 (34%) cohort. Basic patient demographics are in table 1. 13 (19%)
Women 46 (66%) of 70 patients had an established diagnosis of a connective
Smoking tissue disease (seven patients had systemic sclerosis,
Never 38 (54%) three had rheumatoid arthritis, two had Sjögren’s
Previously smoked 24 (34%) syndrome, and one had mixed connective tissue disease)
Current 8 (11%) at the time of presentation to the host institution, and
Established connective tissue disease history 13 (19%) 22 (31%) of 70 cases underwent surgical lung biopsy at the
Biopsy taken host institution (table 1). In patients in whom a surgical
Yes 22 (31%) lung biopsy was not done (table 1), a confident diagnosis
No 48 (69%) had been made by the host institution without the need
DLco (% predicted) 44·8 (14·5%) for a surgical lung biopsy sample. Vital status was known
FEV1 (% predicted) 73·0 (20·5%) for all patients at the end of the study period (June 1, 2015).
FVC (% predicted) 79·0 (19·6%) 70 patients resulted in the assignment of 490 first-
choice MDTM diagnoses (70 patients evaluated by
Where appropriate, data are mean (SD) and n (%). DLco=diffusing capacity of the
lungs for carbon monoxide. FEV1=forced expiratory volume in 1 s. FVC=forced
seven MDTMs). First-choice diagnoses are shown in
vital capacity. table 2. The NSIP and organising pneumonia overlap with
interstitial lung disease category was combined with the
Table 1: Patient demographics and characteristics
NSIP category. The four most prevalent first-choice
diagnoses (connective tissue disease-related interstitial
lung disease, IPF, hypersensitivity pneumonitis, and
Number of first-choice NSIP) were the focus of subsequent analyses. The
diagnoses (n=490) remaining diagnosis categories whose frequency was less
Connective tissue disease-related interstitial 146 (30%) than 10% of the total number of first-choice diagnoses
lung disease (other, sarcoidosis, drug-related interstitial lung
Idiopathic pulmonary fibrosis 88 (18%) disease, occupational lung disease, pleuroparenchymal
Hypersensitivity pneumonitis 46 (9%) fibroelastosis, and organising pneumonia) were combined
Idiopathic non-specific interstitial pneumonia 42 (9%) into an others diagnosis category. The final diagnosis
Unclassifiable interstitial lung disease 38 (8%) categories were connective tissue disease-related
Other 37 (8%) interstitial lung disease, IPF, idiopathic NSIP,
Sarcoidosis 20 (4%) hypersensitivity pneumonitis, and others.
Drug-related interstitial lung disease 18 (4%) Inter-observer agreement (between clinicians,
Smoking-related interstitial lung disease 16 (3%) radiologists, and pathologists) and inter-MDTM
Occupational lung disease 14 (3%) agreement for first-choice diagnosis are listed in table 3.
Pleuroparenchymal fibroelastosis 10 (2%) Overall inter-MDTM agreement for first-choice diagnosis
Organising pneumonia or non-specific 8 (2%) in patients was moderate (table 3). Inter-MDTM
interstitial pneumonia overlapping disease agreement for a first-choice diagnosis of IPF or of
Organising pneumonia 7 (1%) connective tissue disease-related interstitial lung disease
was good, but for a first-choice diagnosis of idiopathic
Table 2: First-choice diagnoses given by seven multidisciplinary teams
NSIP or hypersensitivity pneumonitis was fair (table 3).
for 70 cases of diffuse lung disease
In the subgroup analysis of patients in whom a surgical
disease in these cases would most likely be classified as Table 4: Weighted kappa values (κw) for estimation of diagnostic likelihood for individual diagnoses of
connective tissue disease-related interstitial lung disease. diffuse parenchymal lung disease
To investigate whether in these 13 cases there was high
agreement for this diagnosis resulted in an increase in
agreement on non-connective tissue disease diagnoses diagnoses were made with high confidence. In this
and, particularly, affected agreement on a diagnosis of subgroup, median prevalence of first-choice diagnoses
IPF, we did a post-hoc subgroup analysis in the 57 (81%) made with high confidence were 60·4% (37·5–75·0) by
of 70 cases who did not have an established diagnosis of clinicians, 66·6% (39·6–83·3) by radiologists, and 68·7%
connective tissue disease. In this analysis, although (IQR 52·8–87·5) by the multidisciplinary teams.
inter-MDTM agreement for a first-choice diagnosis of For the diagnosis of IPF, supportive non-significant
connective tissue disease-related interstitial lung disease increases in diagnostic confidence by MDTMs (68 [77%]
decreased (from κ=0·57 to κ=0·42), no significant change of 88) were shown, compared with clinicians (62 [65%] of
was observed in inter-MDTM agreement for a first- 96) or radiologists (57 [66%] of 86; p=0·23). In the
choice diagnosis of IPF (κ=0·58), idiopathic NSIP 22 (31%) of 70 cases that underwent surgical lung biopsy
(κ=0·24), or hypersensitivity pneumonitis (κ=0·23; (therefore a total of 154 diagnoses by seven pathologists),
appendix). 15 (10%) of 154 cases were assigned a first-choice
347 (70%) of 490 first-choice multidisciplinary team diagnosis of IPF, of which 12 (8%) were assigned with
diagnoses were made with high confidence (appendix). high confidence.
Median prevalence of first-choice multidisciplinary team We reviewed the 15 cases who the pathologists gave a
diagnoses made with high confidence was 67·1% first-choice diagnosis of IPF to ascertain whether in
(IQR 54·3–88·8). Median prevalence of first-choice patients who had had a surgical lung biopsy, the final
diagnoses made with high confidence was 58·9% MDTM diagnosis was usually IPF. In six of 15 cases,
(IQR 52·9–71·4) by clinicians, 68·6% (35·7–85·7) by despite the pathologist giving a first-choice diagnosis of
radiologists, and 72·7% (59·1–81·8) by pathologists IPF, the final MDTM first-choice diagnosis was not IPF.
(appendix). In the subgroup analysis of the 48 (69%) of Furthermore, in only two of 15 cases was IPF not already
70 patients who did not undergo a surgical lung biopsy, suggested by either the clinician or radiologist in the
237 (71%) of 336 first-choice multidisciplinary team MDTM (appendix).
example, in a patient with classic appearances for usual our methodology has allowed us to show that there is good
interstitial pneumonia on high-resolution CT, a rapidly agreement on the likelihood of IPF and, as previously
progressive disease course, and no identifiable triggers, stated, reflects consistent application of established
multidisciplinary discussion is unlikely to alter a diagnostic guidelines for this disease. By contrast, MDTM
clinician’s initial impression of IPF. Our findings suggest agreement on the likelihood of hypersensitivity
that formal multidisciplinary input might not be pneumonitis was low, reinforcing the view that MDTMs
necessary in every case of suspected IPF if expert clinical were unclear on how this diagnosis is made.
evaluation is available, which could be of particular Two separate observations from our study warrant
relevance to centres with restricted access to appropriate further discussion. First, 13 patients had an established
radiology or pathology expertise.13 diagnosis of a connective tissue disease at presentation.
A strength of our findings is that the greater agreement However, after MDT evaluation, a connective tissue
on multidisciplinary diagnosis is mirrored by the disease diagnosis was constructed in an additional
non-significant improvement in prognostic separation eight cases or more by five of the seven MDTMs based on
of a multidisciplinary distinction between IPF and other presenting clinical symptoms and serology. Separation of
diagnoses compared with the clinicians’ or radiologists’ patients with idiopathic interstitial pneumonia from
distinction. To show this, we selected patients from those with connective tissue disease-related interstitial
2010 data when they first presented to the host institution, lung disease can be challenging—some patients present
to allow an analysis of 5-year survival. An added with subtle clinical features or serological abnormalities,
advantage of this approach was that these patients were suggesting an autoimmune process, but do not meet
referred to the Royal Brompton and Harefield NHS established criteria for a specific connective tissue
Foundation Trust in a pre-antifibrotic drug era, therefore disease.20–22 In 2015, an ERS/ATS task force was formed to
mortality differences between patients with IPF and establish consensus on how to classify these patients,
those without this disease were not confounded by and a set of diagnostic criteria has been suggested.23–26
antifibrotic therapy. The fact that non-significant After removal of patients with an established diagnosis of
improvements are present but inconclusive might reflect connective tissue disease, our subgroup analysis showed
powering limitations. Additionally, this inconsistency acceptable levels of agreement on connective tissue
might indicate that multidisciplinary discussion adds disease-related interstitial lung disease (by contrast
prognostic value in the subgroup of patients in which with hypersensitivity pneumonitis), underlying the
there is significant diagnostic uncertainty. importance of reaching an international consensus on
By contrast with those with IPF, many patients with disease definitions. Furthermore, the high frequency of
non-IPF interstitial lung diseases are not covered by connective tissue disease-related interstitial lung disease
evidence-based diagnostic guidelines, therefore their diagnoses made in our study highlights the importance
diagnosis is driven by clinical reasoning and analysis of of formal rheumatology input within the MDTM, which
all available data in a multidisciplinary setting. In these might include face-to-face rheumatological consultation
situations, a level of disagreement between MDTMs is with patients suspected of having an undiagnosed
predictable and borne out by the poor level of inter-MDTM connective tissue disease.
agreement in the current study for diagnoses of NSIP Second, dynamic exchanges of clinical, radiological,
and hypersensitivity pneumonitis.8,14–16 The diagnosis of and pathological information between experts in a
hypersensitivity pneumonitis is well known to be multidisciplinary process has previously been suggested
challenging because it relies on an array of data, which to result in higher-confidence diagnoses.4 However, in
are not definitive when considered in isolation.15 our study the proportion of high-confidence diagnoses
Furthermore, at least on high-resolution CT, patterns of (≥70%) assigned after MDTM evaluation did not increase
NSIP, usual interstitial pneumonia, or organising compared with the proportion of high-confidence
pneumonia might be the only expressions of this diagnoses assigned by the individual components of the
disease.16–19 The low MDTM agreement for the diagnosis MDTM. In most MDTMs, high-confidence diagnoses
of hypersensitivity pneumonitis in our study highlights were more frequently assigned by radiologists and
an urgent need for international consensus on what pathologists than were MDTM diagnoses or diagnoses
hypersensitivity pneumonitis actually is. assigned by clinicians. In our study, radiologists and
Our use of the weighted kappa to investigate inter- pathologists did not have access to clinical information,
MDTM and inter-observer agreement on diagnostic so their interpretation was based almost entirely on
probabilities is similar to other studies9 of diagnostic pattern recognition, which might conceivably result in
agreement, but warrants particular consideration. We used more confident, but not necessarily more accurate,
the weighted kappa converting the diagnostic likelihoods diagnoses. Although one benefit of the multidisciplinary
to a five-point probability scale, which enabled examination process is that diagnoses might be challenged and must
of the range of diagnostic likelihoods from minimal be publicly defended, it is possible that extra discussion
likelihood to pathognomonic. Since exclusion of IPF in creates additional difficulties in some cases that initially
diagnosis is as important as making a diagnosis of IPF, seem straightforward when evaluated by individuals in
isolation. However, we must highlight that in the specific Pharmaceuticals Japan Ltd, Ashai Kasei Pharmaceutical Corporation,
case of IPF, MDTMs made the diagnosis of IPF with Astellas Pharmaceutical Incorporated, AstraZeneca, Bayer, Boehringer
Ingelheim, and Chugai Pharmaceuticals. JF has received personal fees
high confidence more frequently than did clinicians or from Astellas Pharmaceutical Incorporated, Pathology Institute
radiologists. Corporation, Chugai Pharmaceuticals, and Sakura Finetek Japan. AGN
Our methodology has some limitations. Since patients has received personal fees from Sanofi, Intermune, Boehringer
were selected from a pre-antifibrotic drug era, IPF was Ingelheim, and Actelion. KRF has received personal fees from
Boehringer Ingelheim, Genentech, Ikaria, Immuneworks, Veracyte,
possibly not as prevalent in our study cohort as it would Roche, Gilead, Biogen, Afferent, Aeolus, and Pharmakea; and has
be now at most referral centres, which expend more time received grants from Boehringer Ingelheim, Genentech, Roche, and
in their evaluation of patients for approval for antifibrotic Afferent. DMH has received personal fees from Boehringer Ingelheim,
treatment. However, as discussed, the inclusion of Sanofi, AstraZeneca, Roche, and GlaxoSmithKline. The other authors
declare no competing interests.
patients who had not had antifibrotic drugs allowed us
to evaluate the veracity of MDTM diagnosis for IPF Acknowledgments
We thank the National Institute of Health Research Respiratory Disease
against the outcomes. Second, unlike a real-world Biomedical Unit (Royal Brompton and Harefield NHS Foundation Trust,
multidisciplinary process, no observers had face-to-face London, UK) and Imperial College London (London, UK). DMH is the
consultations with patients and therefore did not have recipient of a National Institute of Health Research Senior Investigator
the benefit of obtaining a clinical history or doing Award.
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