Journal of

Clinical Medicine

Perspective
Etiologic Classification of Diffuse Parenchymal (Interstitial)
Lung Diseases
Matthias Griese

Department of Pediatric Pneumology, Dr. von Haunersches Kinderspital, University of Munich, German Center
for Lung Research, Lindwurmstr. 4a, D-80337 Munich, Germany; [email protected]

Abstract: Interstitial lung diseases (ILD) or diffuse parenchymal lung diseases (DPLD) comprise
a large number of disorders. Disease definition and classification allow advanced and personalized
judgements on clinical disease, risks for genetic or environmental transmissions, and precision
medicine treatments. Registers collect specific rare entities and use ontologies for a precise description
of complex phenotypes. Here we present a brief history of ILD classification systems from adult and
pediatric pneumology. We center on an etiologic classification, with four main categories: lung-only
(native parenchymal) disorders, systemic disease-related disorders, exposure-related disorders, and
vascular disorders. Splitting diseases into molecularly defined entities is key for precision medicine
and the identification of novel entities. Lumping diseases targeted by similar diagnostic or therapeutic
principles is key for clinical practice and register work, as our experience with the European children’s
ILD register (chILD-EU) demonstrates. The etiologic classification favored combines pediatric and
adult lung diseases in a single system and considers genomics and other -omics as central steps
towards the solution of “idiopathic” lung diseases. Future tasks focus on a systems’ medicine
approach integrating all data and bringing precision medicine closer to the patients.

Keywords: children’s interstitial lung disease (chILD); human phenotype ontology; interstitial
pneumonia; interstitial pneumonitis; idiopathic interstitial fibrosis; familial; surfactant; classifica-





 tion; categorization
Citation: Griese, M. Etiologic
Classification of Diffuse Parenchymal
(Interstitial) Lung Diseases. J. Clin.
Med. 2022, 11, 1747. https://doi.org/ 1. Introduction
10.3390/jcm11061747
Disease definition and classification play an important role for progress in human
Academic Editor: Francisco Dasí health. The taxonomies used directly reflect the underlying principles for best diagnosis,
treatment, and prophylaxis. The more precise the underlying complexities are studied,
Received: 30 December 2021
and this knowledge links to the disease of the individual, the better judgements on disease
Accepted: 18 March 2022
course, prognosis, and risks for genetic or environmental transmissions are targeted in
Published: 21 March 2022
personalized precision medicine.
Publisher’s Note: MDPI stays neutral A few decades ago, drugs with similar actions, e.g., different ß-blockers or inhaled
with regard to jurisdictional claims in steroids with only minor modifications, for usage in common diseases such as hyperten-
published maps and institutional affil- sion, asthma, and COPD dominated the progress in medicine. Currently, exploitation of
iations. molecularly well-defined, mostly rare diseases is in the center of rapid developments of
novel, targeted treatments. Detailed pathway knowledge and hypothesis-free approaches
make so far only symptomatically treatable conditions now drugable. An example is the
small molecule medications used in cystic fibrosis, making a substantial correction of the
Copyright: © 2022 by the author.
underlying genetic CFTR defect possible [1,2].
Licensee MDPI, Basel, Switzerland.
This article is an open access article
Splitting diseases into smaller and smaller entities is key for precision medicine. Nev-
distributed under the terms and
ertheless, the smart merging of etiologically similar diseases into categories (lumping)
conditions of the Creative Commons
allows targeting of similar diagnostic or therapeutic principles and more convenient mem-
Attribution (CC BY) license (https:// orizing in clinical practice. Such developments occur in subspecialty niches at a rapid pace.
creativecommons.org/licenses/by/ Specialized registers nicely capture the rich spectrum of individuals with their disease
4.0/). and can then build growing cohorts of well-defined novel entities. At the same time, such

J. Clin. Med. 2022, 11, 1747. https://doi.org/10.3390/jcm11061747 https://www.mdpi.com/journal/jcm

J. Clin. Med. 2022, 11, 1747 2 of 19

registers make the disease collections open to computerized ontologies and integration of
translational multi-omics and precision medicine.
Here, we summarize the development and practice of categorization systems in the area
of diffuse lung diseases from the experiences made in the children’s lung register/chILD-EU
register, a European pediatric rare lung disease register and biobank [3]. In the context of
current etiologic disease categorization, we discuss some issues of everyday interest and set
the stage for future developments for the integration of physicians’ and systems’ biology
scientists’ needs in an age-overarching approach.

2. Terminology—DLD, DPLD, ILD, chILD

Diffuse lung disease (DLD) is a term infrequently used. DLDs are lung diseases that
involve the entire lungs, i.e., from base to top, peripheral to central, and front to back
(Appendix A, Table A1). They can present in a patchy way or uniformly. Many airway
diseases such as asthma and COPD, or rarer ones such as cystic fibrosis and primary
ciliary dyskinesia are DLD, whereas neoplasms, pleural disorders, or gross structural lung
abnormalities affect the lungs much less frequently diffusely (Figure 1). Here, we focus on
the large group of diffuse parenchymal lung diseases (DPLDs) or interstitial lung diseases (ILDs).
Parenchyma is the functional part of an organ; in the lungs it comprises the components
that are involved in gas exchange. This includes the respiratory bronchioles, the pulmonary
alveoli, and the extracellular matrix and cells, outside of the lungs’ circulatory system.
The latter distinction is the reason why vascular disorders are sometimes departed from
parenchymal disorders. Here, we include them into the group of ILDs. Lung interstitium
is a network of connective tissue that supports the structure of the organ. We and others
elsewhere [4] do not distinguish between diseases that affect the lungs’ interstitium or its
parenchyma, but use the terms as synonyms.
Damage to lung parenchyma by varying patterns of inflammation and fibrosis results in
this large and heterogeneous group of non-neoplastic disorders. Importantly, these disorders
frequently affect not only the parenchyma but also the peripheral airways and vessels along
with their epithelial and endothelial linings. This is the reason why some airway diseases,
such as obliterating bronchiolitis and the vascular diseases, are listed under ILD.
ILD in children or pediatric ILD has been collected under the acronym chILD (or chILD
syndrome) in order to memorize easily and to identify a phenotype that requires prompt and
expert evaluation [5]. This separation has been helpful in the past to highlight an orphaned
field of diseases. However, it has become clear that such diseases may also occur in adults. If
reserved for a certain age group, these diseases may not be diagnosed appropriately, when
not expected to present at other ages. Thus, we prefer an age-overarching approach.
First, we focus on the classification systems for interstitial lung diseases, giving a brief
history. Then, we emphasize the value of etiologic classification also for registers, and
present the system currently applied therein. Lastly, we look on some future needs of
registers to realize personalized medicine for ILDs.
J. Clin. Med. 2022, 11, 1747 3 of 19

Figure 1. Overview of interstitial (diffuse parenchymal) lung diseases and their neighbors. Diffuse
lung diseases involve the entire lungs, i.e., from base to top, peripheral to central, and front to
back. Many airway disorders, including COPD, asthma, and cystic fibrosis, can be diffuse, whereas
others remain more localized; few pleural diseases, gross structural abnormalities such as congenital
pulmonary malformation type 0, or pleural disorders are diffuse. The numerically largest group of
diffuse lung diseases are the interstitial (diffuse parenchymal) lung diseases (ILD). These consist of
four large etiologic categories of diseases, affecting the lung interstitium or parenchyma, (1) the lung-
only (native parenchymal) disorders, (2) the systemic disease-related disorders, (3) exposure-related
disorders, and (4) the vascular disorders. ILDs from all age groups are included.

3. Brief History of ILD Classification Systems

In adults, where the frequency of ILD is at least more than 10-fold larger than in
children [6], many ILDs are diagnosed unambiguously [7]. These include sarcoidosis, hy-
persensitivity pneumonitis, or Langerhans histiocytosis; such conditions were traditionally
marginal for the intense work done in adult pulmonology to differentiate the idiopathic
interstitial pneumonias [7]. In contrast, the pediatric classifications covered all the entities
just mentioned due to their rarity in children, introduced novel, molecularly defined ILDs,
such as the surfactant dysfunction disorders, and included new disease categories linked
to the disruption of lung development. In the following section, we review and align the
entities of the major published ILD classification systems used in adults and children. Our
goal was to provide a harmonized view, which allows an age-overarching approach that is
useful for the integration of clinical, register, and molecular work (Table 1).
J. Clin. Med. 2022, 11, 1747 4 of 19

Table 1. Compilation of classifications of interstitial lung diseases (ILDs) or diffuse parenchymal lung diseases (DPLDs).

Incidence and A National Diffuse Lung Interstitial Lung

ATS/ERS ATS/ERS ERS/ATS ERS Task Force Classification of Internet-Linked Disease in Disease in
Internatl. Multi- Respiratory Research on Chronic Diffuse Lung Pediatric Database for Infancy and Childhood:
Category disciplinary Society Disease in Diffuse Pediatric Childhood:
(This Paper) Consensus Statement: Statement Interstitial Lung Children Parenchymal Interstitial Lung Expanding the Clinical and
Classification Update (Fischer et al., Disease (Deutsch 2007) Lung Diseases Diseases chILD Genetic Aspects
2002 (Travis et al., 2013) 2015) (Clement 2004) (Griese et al., (Nathan et al Classification (Kitazawa and
2009) Kure 2015)
2012) (Rice et al., 2013)
adult adult adult pediatric pediatric pediatric pediatric pediatric pediatric

Lung only Diffuse

Diffuse Diffuse Diffuse developmental
(or native Congenital developmental developmental ILD specific to developmental
parenchymal) disorders and
disorders disorders disorders (A1) infancy disorders growth
disorders abnormalities
Growth Growth
abnormalities abnormalities
reflecting deficient Growth
alveolarisation abnormalities
deficient
alveolarisation (A2)
Specific Specific
Infant conditions Conditions
conditions of of undefined conditions of specific to
undefined etiology (A3) undefined infancy
etiology etiology
Histological
Idiopathic Idiopathic Surfactant DPLD–related to Alveolar patterns Genetic
interstitial interstitial dysfunction alveolar surfac- disorder related associated with surfactant
pneumonias: pneumonias disorders tant region (A4) ILD surfactant dysfunctions
disorders
Idiopathic pulmonary fibrosis (IPF),
nonspecific interstitial pneumonia
(NSIP), cryptogenic organi-zing Unclear RDS in Interstitial
pneumonia (COP), acute interstitial Other forms of the ma- pneumonia
interstitial ture/almost unrelated to
pneumo-nia (AIP), desquamative pneumonia mature neonate surfactant
interstitial pneumonia (DIP), (Ax/Ay) protein disorder
idiopathic pleuroparenchymal
fibroelastosis
Respiratory
bronchiolitis- Small airways
interstitial lung disease
disease (RB-ILD)
J. Clin. Med. 2022, 11, 1747 5 of 19

Table 1. Cont.

Incidence and A National Diffuse Lung

ATS/ERS ATS/ERS Classification of Internet-Linked Disease in Interstitial Lung
Internatl. Multi- Respiratory ERS/ATS ERS Task Force Diffuse Lung Pediatric Database for Infancy and Disease in
Category disciplinary Society Research on Chronic Disease in Diffuse Pediatric Childhood: Childhood:
(This Paper) Consensus Statement: Statement Interstitial Lung Children Parenchymal Interstitial Lung Expanding the Clinical and
Classification (Fischer et al., Disease Genetic Aspects
Update 2015) (Clement 2004) (Deutsch 2007) Lung Diseases Diseases chILD (Kitazawa and
2002 (Travis et al., 2013) (Griese et al., (Nathan et al Classification Kure 2015)
2009) 2012) (Rice et al., 2013)
Unclassifiable
idiopathic Unclear RDS in ILD with no
the NON-
interstitial neonate (Bx) diagnosis
pneumonias
DPLD of known Interstitial lung
cause (e.g. Interstitial DPLD of known DPLD—related
Systemic disease Disorders related to systemic dis- Systemic disease Disorders related
associated with pneumonia with association (e.g. to systemic to systemic disease related to
related disorders auto-immune connective ease pro- associated ILD a primary
collagen features tissue disorders) disease processes disease
cesses (B1) systemic disease
vascular disease)
Granulomatous
DPLD e.g. Granulomatous
diseases
sarcoidosis
Other forms of
DPLD (e.g. Metabolic
disorders
LAM, HX)
Disorders of the DPLD—In the Host disorders
immunocompro- immunocompro- (presumed
Infectious ILD immuno-
mised mised host or
host transplanted (B3) compromised)
Idiopathic DPLD—Related
Lymphoid to reactive lym- Lymphoproliferative
lymphoid
interstitial phoid le- disease
pneumonia (LIP) interstitial
pneumonia sions (B5)
DPLD—In the
DPLD of known presumed
association (e.g. Disorders of the immune intact Host disorders Exposure-related
Exposure-related DPLD of known normal host host, related to Exposure related
drug, aspiration, exposures ILD Hypersensi- (presumed Interstitial
disorders cause e.g. drugs presumed
infection, immune intact tivity pneumonitis immune intact) lung disease
(infect/non-
environment) infect)
(B2)
Disorders DPLD—Related Disorders
Vascular masquerading as to lung vessels Alveolar masquerading as
disorders vascular disorder
interstitial structural related ILD interstitial
disease processes (B4) disease
J. Clin. Med. 2022, 11, 1747 6 of 19

3.1. The Idiopathic Interstitial Pneumonia (IIP) Classification Systems in Adults

In 1969, Liebow and Carrington proposed a classification for the chronic forms of
interstitial pneumonias. This and following categorizations until today were mainly based
upon histopathology. The authors differentiated five types: usual interstitial pneumonia
(UIP), bronchiolitis obliterans interstitial pneumonia and diffuse alveolar damage (BIP),
desquamative interstitial pneumonia (DIP), lymphocytic interstitial pneumonia (LIP), and
giant cell interstitial pneumonia (GIP) [8]. In that classification the different histopatterns
could be caused by microbial or toxic exposures; they did not focus on the idiopathic
forms. During the following decades, the concept of “idiopathic”, i.e., those without
known etiology, disease groups developed further [9]. In particular, Katzenstein proposed
several revisions and updates, the latest classification including four forms of idiopathic
interstitial pneumonias, i.e., UIP, DIP/respiratory bronchiolitis interstitial lung disease,
acute interstitial pneumonia, and non-specific interstitial pneumonia [10]. Müller and
Colby added bronchiolitis obliterans organizing pneumonia to that collection [11].
In 2002, the American Thoracic Society/European Respiratory Society International
Multidisciplinary Consensus on the Classification of the Idiopathic Interstitial Pneumonias [7]
was published to set an international standard, which was a first move away from the
primacy of pathology in categorizing the idiopathic interstitial pneumonias (IIP). This was
necessary with the advent of high-resolution computerized tomography and the focus on
a multidisciplinary team approach, trying to include also patients who did not have a diagnosis
based on a lung biopsy for various reasons. The goal of the consensus was to better define
the clinical manifestations, the histo-pathology, and the radiologic features of patients with
IIP. Seven forms of IIPs were differentiated (Table 1). In their publication, they further
differentiated two groups of DPLD with known cause, a group with granulomatous DPLD,
and other forms of DPLD. A major paradigmatic change of this new classification was the
definition of a set of histologic patterns, which provided the basis for a final clinico-radiologic-
pathologic diagnosis. This multidisciplinary team approach still put the primary weight on
the pathologist because histologic pattern result was rated over the imaging patterns seen
by radiologists. However, the final clinic-pathologic diagnosis, including a judgement of the
disease as “idiopathic”, should only be made after an in-depth review of all clinical, imaging,
and histological data by the pulmonologist, radiologist, and pathologist.
In 2013, a revision of the 2002 IIP classification was published, integrating important
developments and experiences from the previous decade [12]. The seven main disease
entities were preserved. Among these, idiopathic NSIP was accepted as a distinct clinical
entity and no longer as “provisional”. Some important disease characteristics were more
stressed by extra-grouping, i.e., chronic fibrosing IIPs (IPF, NSIP), smoking-related condi-
tions (RB-ILD, DIP), and acute/subacute IIPs (cryptogenic organizing pneumonia (COP)
and acute interstitial pneumonia (AIP)). The rare histologic patterns of acute fibrinous and
organizing pneumonia (AFOP) and interstitial pneumonias with a bronchiole-centric distri-
bution were recognized. Idiopathic pleuro-parenchymal fibroelastosis and unclassifiable
idiopathic interstitial pneumonias were added as new groups. The latter was an important,
clinically relevant step. In addition, for the first time, grading of disease behavior was
included. This acknowledged the heterogeneity of the differential natural progression of
IIPs, i.e., of NSIP and IPF. In the same line, the role of acute exacerbations and of molecular
and genetic disease markers was put into perspective.
In 2015, an official European Respiratory Society/American Thoracic Society research
statement introduced the quite controversial disease term of interstitial pneumonia with
autoimmune features (IPAF) [13]. IPAF should be used to identify individuals with IIP and
features suggestive of, but not definitive for, a connective tissue disease (CTD).

3.2. The Pediatric Classification Systems (chILD)

In 2004, a report of the “European Respiratory Society Task force on chronic intersti-
tial lung disease in immunocompetent children” stated that these disorders were poorly
J. Clin. Med. 2022, 11, 1747 7 of 19

investigated in children and most of the strategies applied by pediatricians were linked to
studies in adult patients [14]. Basically, the categorization scheme presented was similar to
that of the 2002 adult statement, except that “congenital disorders” were added as a new
group and several other important pediatric entities were listed under “Other forms of
interstitial pneumonia”. To the latter belonged alveolar proteinosis, eosinophilic pneumo-
nia, infantile/idiopathic hemosiderosis, persistent tachypnea of infancy, and pulmonary
interstitial glycogenosis. Although very heterogeneous, these entities made up a decent
fraction of ILD in children. Of importance, genetically defined surfactant dysfunction
disorders (SP-B, SP-C deficiency), forms of familial cryptogenic fibrosing alveolitis, and
molecularly well-defined syndromes such as Hermansky–Pudlak syndrome or IPPs due to
inborn errors of metabolism were added. This was a remarkable advance, going beyond
the adult classification systems.
In 2007, a mainly pathology-based classification scheme for diffuse lung disease in
children under the age of 2 years was published [15]. It was based on the analysis of
187 cases with lung biopsy. The most prominent feature was the clearer separation of
four categories of disorders more prominent in infancy from the other disorders (Table 1).
Among these disease categories were disorders of early lung development. If they affected
the entire lungs, they were called diffuse developmental disorders [15]. Such disorders lead
to severe structural and functional lung abnormalities and are often lethal, with typical
examples being alveolar capillary dysplasia with misalignment of the pulmonary veins,
acinar dysplasia, and congenital alveolar dysplasia [16]. Conditions that only affect proper
development of the alveoli were collected under the term growth abnormalities reflecting
deficient alveolarization. Examples were infants with trisomy 21, pulmonary hypoplasia, or
chronic lung disease of prematurity (BPD). The third group was difficult to appreciate and
called “specific conditions of undefined etiology”. It contained two, histological diagnosis
pulmonary interstitial glycogenosis and neuroendocrine cell hyperplasia of infancy. The last
group contained disorders suggestive of a metabolic abnormality in surfactant metabolism,
the surfactant dysfunction disorders. More than 10% of the biopsies were excluded as
insufficient and were collected under the label “unclassifiable”. Thereafter, the system was
successfully applied to 259 diagnostic biopsies [17].
In 2009 and 2015, this classification system was utilized and expanded to all cases
of chILD, irrespective of whether a histopathological diagnosis was available or not and
irrespective of the age of the child. To accommodate cases that could not be resolved, addi-
tional categories such as unclear respiratory distress in the mature neonate (group Ax), the
almost mature neonate (group Ay), and in the non-neonate (group Bx) [18,19] were added.
Another important change was the removal of the category “disorders masquerading as
ILD” and the introduction of DPLD related to lung vessels’ structural processes (B4) and
DPLD related to reactive lymphoid lesions (B5). Due to the large number of 861 chILD
cases assessed, a very broad spectrum of ILD was accommodated and some entities were
expanded (DPLD in the presumed immunocompromised host or transplanted (B3)) or refo-
cused (DPLD in the presumed immune intact host, related to exposures (B2)). Importantly,
this study established and empirically tested a workflow of the pediatric ILD categorization
system. The steps included the generation of a final working diagnosis, the decision on the
presence or absence of ILD, the decision if the condition assessed was part of a systemic
condition or related solely to the lung, and, lastly, the allocation to a predefined disease
category and subcategory. Blind re-testing of a random sample set by two independent
raters allocated more than 80% of the re-categorized cases identically. Non-identical al-
location was due to a lack of appreciation of all available details, insufficient knowledge
of the classification rules by the raters, incomplete patient data, and shortcomings of the
classification system itself [19].
The French network for pediatric interstitial lung diseases published in 2012 their
database categorization system [20]. The categories were linked to the initial ERS scheme
from 2004 and accentuated separately granulomatous diseases, metabolic disorders, and
infectious ILD.
J. Clin. Med. 2022, 11, 1747 8 of 19

Such an expansion of the categories was in line with the 2013 published expansion
of the chILD classification, based on the histopathological evaluation of 229 biopsies, of
which more than 50% were obtained beyond the age of 2 years [21]. The authors added
the categories lymphoproliferative disease, small airways disease, interstitial pneumonias
unrelated to surfactant protein deficiencies, and other patterns of diffuse lung disease.
An important additional notion from this study was the observation that many cases
showed mixed histological patterns. Often overlap between groups of disorders more
prevalent in infancy were seen. Similarly, patients with a major histological pattern associ-
ated with surfactant protein disorders had various minor patterns, including hypoplasia,
CPI, DIP, PAP, ELP, NSIP, PH, PIG, or cholesterol pneumonitis.
In 2015, Kitazawa and Kure contributed the Japanese experience. They argued strongly
in favor of an etiological classification system [22]. Additionally, in 2015, the team from
the children’s interstitial and diffuse lung disease research network applied their chILD
classification scheme from 2007 to children with diffuse lung disease and biopsied between
the age of 2 to 18 years [23]. They introduced at front a central clinical decision, i.e., was
the patient clinically immune compromised or immune competent? This decision may be
difficult in everyday practice, as it is often not easily determined [24]. Also in 2015, Armes et al.
detailed a pattern-based, algorithmic approach to histological diagnosis of chILD [25]. They
stressed and broadened the significance of hypertensive disease as an important component
of diffuse lung disease in children. Although several authors have used the 2007 chILD
classification system with no or little adaptations [26–28], recently it became more and more
clear that a new classification of childhood diffuse lung diseases is needed [29].

4. Diagnostic Algorithm and Etiologic Grouping of Interstitial Lung Diseases

Usually clinicians suspect an interstitial lung disease if chronic respiratory symptoms,
often starting with exercise intolerance and dyspnea, hypoxemia, and diffuse bilateral in-
terstitial imaging abnormalities, are present (see algorithm Figure 2). Other, more common
entities are excluded. A broad history and serological investigations are key for initial
diagnosis [30]. Advanced testing, in particular, genetic analysis to identify known entities,
will support making molecular diagnosis; however, this is currently mainly reserved for
a specialized clinical or research setting (see Section 5). Comprehensive consideration of all
available data, at best in a multidisciplinary team (MDT), concludes with the most precise
diagnosis [31]. This will be the basis for further treatment and judgements of prognosis.
Follow up of cases in an active register is highly recommended (Figure 2) [3].
When making the diagnosis as described in the algorithm physicians intuitively try
to give a cause for the lung disease, i.e., hypothesize about its etiology. Thus, we group
a patient accordingly and have specifiers in mind to describe disease characteristics. The ILD
is differentiated into four categories: lung-only (or native parenchymal) disorders, systemic
disease-related disorders, exposure-related disorders, and vascular disorders (Table 2).
The native parenchymal disorders are “lung-only” or “isolated pulmonary” conditions,
i.e., diseases not part of systemic conditions and not related to exposures or to vascular
disorders. An important specifier to group these disorders further is age. Conditions
emerging exclusively during the lung development period (pre-natal to 18 years old)
and typically manifesting during early childhood are labelled as “developmental” lung
disorders (Table 1). The previous grouping into diffuse developmental disorders (A1),
alveolarization disorders (A2), infant conditions of undefined etiology (A3), and alveolar
surfactant region disorders (A4) is kept (Table 2). Fortunately, due to improved recognition
and care, many of these patients will survive into adulthood; thus, pulmonologists need
to be aware of conditions such as pulmonary hypoplasia due to diaphragmatic hernia or
premature birth.
J. Clin. Med. 2022, 11, 1747 9 of 19

Figure 2. Diagnostic algorithm for the identification and etiologic classification of ILD.

Table 2. Classification of interstitial lung diseases (ILDs) used in the chILD-EU register (full list
available www.childeu.net, accessed on 29 December 2021).

Category Specifier Subcategories (Major Examples)

Alveolarization (A2)
Diffuse (A1) - Pulmonary hypoplasia
Lung only (native - Alveolar capillary dysplasia, misalign - Pulmonary hypoplasia associated
Developmental
parenchymal) disorders pulmonary veins (ACDMPV) with diaphragmatic hernia
- Congenital alveolar dysplasia (CAD) - Chronic lung disease of
prematurity (BPD-cLD)
Infant tachypnea (A3) Surfactant region (A4)
- Chronic tachypnea of infancy (CTI) - Chronic pneumonitis of infancy (CPI)
(usual, aberrant) - Surfactant protein B deficiency
- Neuroendocrine cell hyperplasia of - Other surfactant dysfunction disorders
infancy (NEHI) - Undefined ILD in mature neonate
- Pulmonary interstitial - Undefined ILD in almost (gest. age
glycogenosis (PIG) 30–36 weeks) mature neonate
- ABCA3 deficiency
- Surfactant protein C deficiency - Acute interstitial pneumonia (AIP)
- Lipoid pneumonitis, - Desquamative interstitial
cholesterol pneumonia pneumonia (DIP)
- Nonspecific interstitial - Idiopathic pleuro-parenchymal
All ages pneumonia (NSIP) fibroelastosis
- Idiopathic pulmonary fibrosis - Eosinophilic pneumonitis
(IPF)/Usual interstitial - Undefined ILD in NON-neonate
pneumonitis (UIP) - Unclassifiable idiopathic
- Cryptogenic organizing interstitial pneumonias
pneumonia (COP)
J. Clin. Med. 2022, 11, 1747 10 of 19

Table 2. Cont.

Category Specifier Subcategories (Major Examples)

- Diffuse alveolar hemorrhage due to
- Collagen vascular/connective tissue vasculitic disorders
related disorders (CTD-ILD) - ITGA3 (Integrin α3) mutations with
- Eosinophilic granulomatosis with kidney, lung, skin disease
polyangiitis (EGPA, Churg Strauss) - Niemann-Pick disease
- Granulomatosis with polyangiitis - Nkx2.1 gene defect
Systemic disease (GPA, Wegener) (brain-thyroid-lung syndrome)
Immuno competent - Metabolic disorders - Lysinuric proteinuria
related disorders - PAP secondary to associated diseases
- Disorders related to chromosomal
abnormalities - Sarcoidosis
- Aminoacyl-tRNA synthetase - TBX4 mutation (small
(-ARS) deficiency patella syndrome)
- Birt-Hogg-Dube syndrome - Hoyeral Hreidasson Syndrome
- Granulomatous diseases (congenital dyskeratosis)
- Telomere-related-diseases
- Phagocyte-PAP.CSF2RA or CSF2RB - Phagocyte-GATA2 def (MonoMac
Immuno deficient (PAP due to GMCSF
receptor deficiency) syndrome).GATA2

- Chronic allograft dysfunction,

Transplanted
idiopathic pneumonia syndrome
- Autoimmune pulmonary alveolar
proteinosis (PAP) - Follicular bronchitis/ bronchiolitis
- Lymphocytic interstitial
- Antisynthetase syndrome
pneumonia (LIP)
- Celiac disease/pulmonary
Immune- - Interstitial pneumonia with
dysregulated hemorrhage (Lane-Hamilton)
auto-immune features (IPAF)
- Anti-basement membrane antibody - ZNFX1 deficiency
disease (Goodpasture) - Immune-dysregulated Hermansky
- Granulomatous lymphocytic Pudlak syndrome
interstitial lung disease (GLILD)
- COPA defect - OAS1 deficiency
Auto-inflammatory - STING-associated vasculopathy,
infantile-onset.TMEM173 - Other interferonopathies

Exogen allergic - Radiation lung injury

alveolitis/hypersensitivity - Respiratory bronchiolitis-interstitial
Exposure related disorders Non-infectious pneumonitis
lung disease (RB-ILD)
- Drug induced ILD
- Pneumoconiosis - Occupational lung diseases

- Infectious/post-infectious
Infectious bronchiolitis obliterans (PIBO) - Mac-Leod-Swyer-James-Syndrome
- Diffuse panbronchiolitis
- Diffuse pulmonary (alveolar)
hemorrhage (DPH) - Pulmonary capillary
- Idiopathic pulmonary hemorrhage hemangiomatosis (PCH)
Vascular disorders
(hemosiderosis) (IPH) with or without - Pulmonary vena-occlusive disease
associated features - Lymphangiomatosis
- Pulmonary capillaritis

The “lung-only” conditions may occur at all ages and, nevertheless, are likely to
have strong genetic etiology factors, as yet unknown to a large extent. Recently, several
conditions previously thought to exclusively occur in childhood, e.g., SFTPC or ABCA3
deficiency, have been demonstrated to occur at all ages [32]. Up to now, in adults these
conditions were lumped under interstitial idiopathic pneumonias (Table 1). Future investi-
gations of the biology will help define etiologic entities (see Section 6).
Although having a prominent pulmonary phenotype, many ILDs are systemic disease-
related disorders (Table 2). This is a large group and contains well-known conditions
such as collagen vascular disorders (CTD-ILD), sarcoidosis, antisynthetase syndrome, or
granulomatosis with polyangiitis (GPA, Wegener). Increasing molecularly well-defined
entities including aminoacyl-tRNA synthetase deficiencies [33], Birt–Hogg–Dube syndrome,
brain-thyroid-lung syndrome, small patella syndrome (TBX4 mutation), telomere-related
diseases [34], or ZNFX1 deficiency are differentiated [35]. Patients in this group may be
J. Clin. Med. 2022, 11, 1747 11 of 19

further specified as immunocompetent, immunodeficient, immune dysregulated, auto-

inflammatory, or transplanted.
Many ILDs are the result of exposure to inhaled materials. We separated this etio-
logically important group from the lung-only disorders to put their prevention into the
focus. In practice, there will be some overlap; for example, with chronic hypersensitivity
pneumonitis the clear demonstration of the relevance of an exposition is often difficult. The
earlier such a diagnosis is made, the better the prognosis of the patients will be.
Lastly, vascular disorders, which are often undiagnosed as a lung biopsy may be nec-
essary, represent an important group in the differential diagnosis of ILDs. These conditions
only affect the vessels of the lungs. If the vascular disease can be diagnosed as part of
a systemic condition, the disease is categorized under “systemic disease-related disorders”.
If not, or not yet, the disease is provisionally categorized here and can be specified fur-
ther with the addition “associated with”, e.g., idiopathic pulmonary hemorrhage with
autoimmune features, until a definite diagnosis is made.
Major examples of subcategory entries from the four categories are given in Table 2;
the chILD-EU register can make up-to-date lists available (www.childeu.net, accessed on
29 December 2021).

5. Genetics Is an Important Step towards Resolving “Idiopathic” Lung Disease

The concept of strong genetic etiologic factors for diffuse lung diseases was developed
in pediatrics, as many of the genetically driven disorders manifest early in life. Indeed,
the first mono-genetically caused diffuse chronic interstitial lung diseases were identified
almost 30 years ago and related to surfactant dysfunction, i.e., caused by mutations in
SFTPB, SFTPC, or ABCA3 [36–38]. Meanwhile, many other conditions were added, al-
lowing non-invasive and targeted approaches to diagnosis and treatment. Most of the
conditions are rare (fewer than 5 in 10,000 people) or ultra-rare. For their study, collection
in registers is pivotal, not only to benefit from the accumulated experience in management
but also to learn about their natural disease course and underlying mechanisms. There is
ongoing exploration of undiagnosed cases from registries, with increasing success rates
to identify the etiologic. With technology advances, more and more genetically complex
conditions are uncovered [39].
Based on several decades of research into the causes of pediatric and familial ILD in
adults and the broad introduction of rare diseases into the public, genetic analysis in patients
with fibrosing ILD is primarily done in specialized ILD centers, but it is approaching
clinical routine (Figure 2). This may have a profound impact on patient care. It must
be clearly stated that there is a current lack of an international consensus statement and
recommendations on genetic analysis in ILD. Similar to the numerous other diseases with
a genetic base, physicians need expertise and guidance on when to order which genetic test
and offer counseling together with the results. In particular, screening of asymptomatic
family members is an important field for daily practice, without recommendations yet.
Until then, genetic analysis should be primarily done in a well-controlled research setting
in specialized ILD centers.
The approximately 10% prevalence of ILD in a first-degree relative of a patient with
IPF illustrates the strong familial linkage of ILD [40,41]. In 2016, in adults with suspected
mono-genic pulmonary fibrosis, in 40% of the patients a Mendelian disease cause was
identified, i.e., a disease-causing genetic variant constellation [42]. Approximately 25% of
families with fibrosing lung disease had an identified mutation in genes mostly involved
in telomere homeostasis (TERT, TERC, RTEL1, PARN, DKC1, TINF2, NAF1), and less
frequently in surfactant homeostasis (SFTPC, SFTPA1, SFTPA2, ABCA3, NKX-2.1). With
advancing technology, these numbers continuously increase [43]. The manifestation risks
for lung disease caused by the rare genetic variants can be very strong and go far beyond
the odds of 20. The latter effect is known from the relatively common constellation of
homozygous, less frequent promoter allele rs35705950 of MUC5B encoding mucin-5B [44].
J. Clin. Med. 2022, 11, 1747 12 of 19

6. Next Steps: Systems’ Medicine and Personalized Treatments

Simplified pathophysiological models that explain cell, organ, or body functions may
allow easy communication between physicians and with patients [45] but utilize only
a fraction of the available information. Currently, large amounts of phenotypic and di-
verse molecular data are produced [46,47], and efforts are ongoing for their integration
to ensure a most comprehensive picture of diseases (Figure 3). In order to integrate the
forthcoming wealth of health- and disease-related information, systems’ medicine is in
position. These data include knowledge of individual genetic variants, allowing person-
alized treatments and multi-omics data, such as transcriptomics, proteomics, epigenetics,
functional genomics, reverse genetics from transcript manipulation, and deep phenotyping
including information from multiple body sensors, environmental exposures, or complex
psychosocial influences [48].

Figure 3. Etiologic disease classification of ILDs drives diagnostic and treatment opportunities. The
integration of more and more disease-related data from deeper analysis and systems’ medicine will
result in personalized medicine, allowing more precise diagnosis and treatment.

7. Registers for Diffuse Lung Diseases and Their Working Features

Decent case collections or larger patient cohorts are key for all ongoing research de-
velopments in rare diseases. To this end, registers with associated biobanks are pivotal
treasures for exploration. To build such cohorts, enthusiastic efforts are necessary for both
patients to voluntary participate and physicians to actively submit data and biomaterials.
Fortunately, over the last decade many registers for diffuse lung disease and other rare lung
diseases were established (see listing in https://clinicaltrials.gov/, accessed on 29 Decem-
ber 2021). For adults, a wealth of national and international registers exists, whereas few do
so for pediatric diffuse lung disease. The latter includes the Australasian Registry Network
for Orphan Lung Disease (ARNOLD) focusing on chILD in immunocompetent patients,
the French register “Respirare”, the United States chILD network, and, in particular, the
European chILD-EU register and biobank (www.childeu.net, accessed on 29 December
2021). The last one mentioned offers protocols for diagnosis and initial treatment and
a multidisciplinary review of incoming cases, as well as advanced genetic diagnostics and
J. Clin. Med. 2022, 11, 1747 13 of 19

pediatric histopathologic expertise [3]. Registers also serve as very important and efficient
tools to assess diagnostic and therapeutic needs of rare disease entities and to prepare
for clinical trials therein. Such analyses are of particular interest for collaborations with
industry, e.g., to prepare necessary pediatric investigational plans (PIP).
In the context of this paper, an important problem all registers face concerns the dis-
ease classification schemes used in their repositories. In particular, when linking the data
for common analyses it is necessary to map the diseases and the many descriptors utilized
carefully to avoid comparing apples and oranges. For such purposes, ontologies were
developed. Ontologies are collections of terms that specify the properties of a complex
concept and the relations of the terms. As an example, Ryerson et al. specified a standard-
ized framework to classify the likelihood of a diagnosis for adult fibrotic interstitial lung
disease. They defined the terms “confident”, “provisional with high or low likelihood”,
and “unclassifiable”. This addition of a clinical modifier and other subontologies, such as
clinical course, mode of inheritance, age of manifestation, and frequency, are essential steps
towards deep phenotyping of diseases [49]. The Human Phenotype Ontology (HPO) is
another example of a collection of terms assisting in describing medically relevant pheno-
types so that they are useful for supporting clinical differential diagnosis and translational
research interests [50]. These terms allow bio-informatic computations over the clinical
phenotype and combining those data with the huge amounts of -omics data for precision
medicine. For ILD, we have recently added many novel terms and disease annotations to
the current HPO [51].

8. The Etiologic Classification of ILD

The chILD-EU register evaluated an etiologic grouping successfully some years
ago [19] and continuously rolled it out to more than 1000 cases of diffuse lung diseases.
This simple and universal system for diffuse lung disorders separates ILD from airway
disorders, pleural disorders, neoplasms, and gross structural abnormalities of the lungs
(Figure 1). The four ILD categories defined above (lung-only disorders, exposure-related
disorders, systemic disease-related disorders, and vascular disorders) proved robust with-
out the need to generate new groups. This simple, basic structure is easy to recall, and
specifiers allow further subcategorizations and descriptions (Table 2). Hierarchical ordering
structures are avoided. Modern electronic search systems can accommodate additional
complexity from structured term collections.
Sometimes patients with unclassifiable conditions are neglected or lost, as no clear
diagnostic label is applied. However, such conditions are the driving force of future
developments as they carry an increased likelihood that they harbor extreme phenotypes
with potential for strong mono-causal origins. There are numerous examples for new
diseases discovered by focusing on such cases [33,35]. We suggest as an important feature
including “unclassifiable” conditions into classification systems and indicating why they
are inconclusive with the help of modifier terms. In the same line, etiologic disease
classifications’ systems can be in place irrespective of if we currently know the exact
etiology or not.
Whereas it is globally accepted that children cannot be treated as small adults, and
that a closed classification system for pediatric ILD was useful during the establishment of
chILD, it is of great advantage to have a common classification system, which accommo-
dates lung diseases from patients of all ages. Important arguments in favor of a common
system come from the fact that more and more of the affected children and young adoles-
cents, previously exclusively treated in pediatric pneumology, now reach adulthood [52].
These grown-ups need to be transitioned into medical services for adults. This also concerns
knowledge of the neonatal or infancy history and the diseases associated. For example, it
is of importance for a pneumologist who cares for a 23-year-old subject to know that the
patient was born at 24 weeks of gestation and ventilated for chronic lung disease of prema-
turity over 4 months. Conversely, there are conditions, such as the telomere-associated lung
diseases, that are more frequent in young adults but may also occur in childhood. The pe-
J. Clin. Med. 2022, 11, 1747 14 of 19

diatric pneumologists should also know such conditions to diagnose them early. Therefore,
pediatric specialists in ILD should be included in working groups on ILD classifications or
position statements [53]. Inclusion of the pediatric perspective has been realized to some
extend by the European Respiratory Society in recent task forces on ILDs.
Pursuing an etiology-based classification has many advantages but is not always easy.
In the case of multifactorial etiology, we focus on establishing the most likely etiology in
a given patient. If necessary, we fall back to a phenotypic/descriptive diagnosis, judiciously
using both concepts, the etiologic one improving clinical research as well as serving the
patient in daily clinical practice. Thus, assignment of such cases to any single etiology
may be to an extent arbitrary, but in most cases there is a predominant cause to which
the case is assigned, which is obviously helpful and valuable for many reasons (Table 3).
However, any etiologic classification highly depends on the degree of investigation and
investigatory technology. If clinically indicated but not followed by the appropriate investi-
gations, e.g., chest CT, genetic analysis, lung biopsy, or detailed antibody measurements,
an advanced diagnosis and classification cannot be made. Any effort should be made
for a particular patient to clarify the diagnosis and associated treatment and prognosis.
The suggestions made here are not meant to speak for the world but may be a base for
discussion towards a comprehensive age-overarching classification of diffuse lung diseases
in broad, international, expert consensus groups.

Table 3. Advantages of an etiology-based classification of interstitial lung diseases.

Etiology is the driving force for most progress towards treatment of conditions
Etiology, as the one major criterion, is primarily used for all classification-decisions in the system
Hierarchically simple and universal system, which can be easily memorized on a major level
Flat, two-level structure (four major, primary levels and not branched second level, which can accommodate any large number of
different entities)
Minimizes contradictions often experienced in hierarchical classifications
Open to further subclassification by convenient specifiers and descriptors
Avoids neglect of unclassifiable conditions by also including conditions with currently not exactly known etiology or even for cases
in which the absence of information includes classes as “undefined” or “probable”
Ability to annotate relationships between etiologies at all levels of granularity
The system does not ignore tradition of old classification schemes
Open to all ages, accommodating easily age-specific disease manifestations
Supports closer collaboration of pediatric and adult pneumologists, and, for the patients, an improved transition of grown-ups into
adult medical services
Computational methods may overcome the relatively large number of conditions resulting, which is seen by some as a disadvantage
Computations over phenotype, multi-omics, environmental, or psychosocial data easily possible
Proven applicability in electronic databases of a large ILD register
Usage of standardized collections of terms (ontologies) for merging with other machine-based systems (big data analysis)

Realistically, no single classification will meet all needs. Thus, ongoing efforts for the
integration and merging of equivalent disease concepts are necessary. Different physicians
and researchers annotate the relationships and levels of granularity with which they are
concerned. Computing technology has to merge equivalent concepts by iterative curator-
assisted inference of the different vocabularies. The Mondo Disease Ontology currently does
this approach. Mondo, derived from the Latin word ‘mundus’, meaning ‘for the world’,
aims to harmonize disease definitions across the world (https://mondo.monarchinitiative.
org/, accessed on 29 December 2021).
J. Clin. Med. 2022, 11, 1747 15 of 19

9. Conclusions
We reviewed the development of ILD classifications in pediatric and adult pneu-
mology and suggest an age-overarching etiologic classification of lung diffuse diseases
able to accommodate the conditions in an easily memorable way. Genetic testing needs
to be integrated more and more into the diagnostic algorithms and may help resolving
idiopathic interstitial lung diseases. In particular, the etiologic grouping and longitudinal
observation of the diffuse parenchymal lung diseases in registers may support integrating
the tremendous -omics data becoming available.

Funding: Supported by the Deutsche Forschungsgemeinschaft (DFG) Gr 970/9-1.

Institutional Review Board Statement: Not applicable.
Informed Consent Statement: Not applicable.
Data Availability Statement: An updated classification of interstitial lung diseases (ILDs) used in
the chILD-EU register is available from www.childeu.net (accessed on 29 December 2021).
Conflicts of Interest: M. Griese has been provided paid services in clinical study development to
Böhringer Ingelheim, Germany. and Roche, UK.

Abbreviations

ABCA3 ATP-binding cassette transporter A3

ACDMPV Alveolar capillary dysplasia with misalignment of the pulmonary veins
AFOP Acute fibrinous and organizing pneumonia
AIP Acute interstitial pneumonia
BIP Bronchiolitis obliterans interstitial pneumonia and diffuse alveolar damage
BPD Chronic lung disease of prematurity, bronchopulmonary dysplasia
chILD Children’s interstitial lung disease
CAD Congenital alveolar dysplasia
COP Cryptogenic organizing pneumonia
COPA Coatomer protein complex, alpha subunit
CPI Chronic pneumonitis of infancy
CTD Connective tissue disease
DAH Diffuse alveolar hemorrhage
DIP Desquamative interstitial pneumonia
DLD Diffuse lung disease
DPLD Diffuse parenchymal lung disease
CSF2RA Granulocyte-macrophage colony-stimulating factor receptor, alpha
CSF2RB Granulocyte-macrophage colony-stimulating factor receptor, beta
EGPA Eonsinophilic granulomatosis with polyangiitis
FARS1 Phenylalanyl-tRNA synthetase 1, cytosolic
FARSA Phenylalanyl-tRNA synthetase, alpha subunit
FARSB Phenylalanyl-tRNA synthetase, beta subunit
FB Follicular bronchiolitis
GIP Giant cell interstitial pneumonia
GPA Granulomatosis with polyangiitis
HSP Hypersensitivity pneumonitis
HPO Human phenotype ontology
ILD Interstitial lung disease
IP Interstitial pneumonia, interstitial pneumonitis (IP)
IPAF Interstitial pneumonia with autoimmune features
IPF Idiopathic interstitial fibrosis
IPP Idiopathic interstitial pneumonia
LAM Lymphoangioleimyomatosis
LIP Lipid interstitial pneumonia
MARS Methinonyl-tRNA synthetase
J. Clin. Med. 2022, 11, 1747 16 of 19

NEHI Neuro-endocrine cell hyperplasia of infancy (without biopsy proven: persistent

tachypnea of infancy (PTI))
NKX2.1 NK2 homeobox 1
NSIP Non-specific interstitial pneumonia
PAP Pulmonary alveolar proteinosis
PTI Persistent tachypnea of infancy (with biopsy proven: NEHI)
PIG Pulmonary interstitial glycogenosis
RB-ILD Respiratory bronchiolitis-interstitial pneumonia
RTEL1 Regulator of telomere elongation helicase 1
SFTPA1 Surfactant protein A1 deficiency
SFTPA2 Surfactant protein A2 deficiency
SFTPB Surfactant protein B deficiency
SFTPC Surfactant protein C deficiency
SP-B Surfactant protein B
SP-C Surfactant protein C
TERC Telomerase RNA component
TERT Telomerase reverse transcriptase
UIP Usual interstitial pneumonia
ZNFX1 Zinc finger NFX1-type domain-containing protein 1

Appendix A

Table A1. Glossary of terms used in description of diffuse lung diseases.

Definition Terms Defined in Ontologies *

Diseases that involve the entire lungs, i.e., from MONDO:0005275 lung disease
Diffuse lung diseases (DLDs) base to top, peripheral to central, and front to HP:0002088 Abnormal lung morphology
back. Can be patchy or uniform. HP:0020034 Diffuse
Diseases affecting the lung interstitium. The
term may mislead, as neighboring structures
such as airways and vessels are involved to
various extents. MONDO:0015925 interstitial lung disease
Interstitial lung diseases (ILDs) HPO synonyms: abnormal pulmonary HP:0006530 Abnormal pulmonary
interstitial morphology, abnormality in area interstitial morphology
between air sacs in lung, abnormal lung
parenchyma morphology, interstitial
pulmonary disease, interstitial lung disease.
UBERON:0008946 lung parenchyma
A network of connective tissue that supports
Lung interstitium OBO:PO_0005421 parenchyma
the structure of the lungs.
HP:Not available, as no abnormality
MONDO:0017015 primary interstitial lung
disease specific to childhood
Children’s interstitial lung ILD in children; used synonym for DPLD in MONDO:0010621 CHILD syndrome
disease (chILD) children or pediatric DPLD HP:0006530 Abnormal pulmonary
interstitial morphology
HP:0011463 childhood onset
The term chILD or chILD syndrome has been
coined to memorize easily and to identify
chILD syndrome Not available
a phenotype that requires prompt and
expert evaluation
MONDO:0005275 lung disease
Diseases affecting the parenchyma of the lungs.
Diffuse parenchymal lung OBO:PO_0005421 parenchyma
Synonymously used for interstitial
diseases (DPLDs) HP:0002088 Abnormal lung morphology
lung disease.
UBERON:0008946 lung parenchyma
Parenchyma is the functional part of an organ.
Lung parenchyma comprises the components
of the lung that are involved in gas exchange OBO:PO_0005421 parenchyma
Lung parenchyma and include the respiratory bronchioles, the UBERON:0008946 lung parenchyma
pulmonary alveoli, and the extracellular matrix HP: Not available, as no abnormality
and cells, outside of the lungs’
circulatory system.
J. Clin. Med. 2022, 11, 1747 17 of 19

Table A1. Cont.

Definition Terms Defined in Ontologies *

Idiopathic, cryptogenic Of unknown cause, both used synonymously. Not available
Lung parenchyma inflammation and/or MP:0001861 lung inflammation
Interstitial pneumonia, interstitial fibrosis (contrary to airspace disease typically HP:0002090 Pneumonia
pneumonitis (IP) seen in bacterial pneumonia), both MONDO:0005249 pneumonia
used synonymously. MP:0001862 interstitial pneumonia
Lung-only (or native Disorders manifesting as isolated in the
Not available
parenchymal) disorders lung parenchyma.
Native (belonging to the lung by origin,
manifesting over the life time, i.e., before, at, or
after birth during childhood, adolescence,
adulthood, or senescence) parenchymal
disorders (develop over lifetime). Native
Native means here during the biography, during Not available
development until death. The condition may
be inherited, but manifestation may be over
the lifetime
Not synonymous to congenital or hereditary,
which indicate that the condition was acquired
before birth.
Lung disorders related to (caused
Exposure-related disorders Not available
by) exposure.
Lung disorders related to (caused by) systemic MONDO:0015938 systemic disease
Systemic disease-related disorders
disease processes. MONDO:0000001 disease or disorder
Lung disorders related to (or originating) from MONDO:0005385 vascular disease
Vascular disorders MONDO:0000001 disease or disorder
the vasculature.
Development of the lungs is their process of
Developmental disorders growth to maturity. The term developmental OBO:HsapDv_0000080 immature stage
disorders is avoided as deviation from
normal development
* https://beta.monarchinitiative.org/tools/text-annotate (accessed on 29 December 2021).

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